clinical study vs research

Clinical Trials Versus Clinical Studies: What’s The Difference?

There are varying opinions on what constitutes a clinical study or a clinical trial. According to Good Clinical Practice (GCP) – specifically the ICH E6 guidelines – the terms clinical trial and clinical study can be used synonymously. GCP defines a clinical trial or study as:

“Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.”

Others distinguish between clinical studies and clinical trials. The National Institutes of Health (NIH), for example, describes two kinds of clinical study: “A clinical study involves research using human volunteers (also called participants) that is intended to add to medical knowledge. There are two main types of clinical studies: clinical trials (also called interventional studies) and observational studies.”

Observational Versus Interventional

These two main types of clinical study – observational and interventional – describe the approaches taken in each:

• In observational studies, researchers observe study participants and record the effects of their current treatment without making any changes. Observational studies tend to be less involved for participants, who might need to complete questionnaires, for example. Participants will typically be people undergoing treatment for a medical condition, and the researchers will collect information about the results of that treatment without changing it or comparing the results to a control group.
• In interventional studies – clinical trials – an intervention is tested in a group of participants, usually compared to a control group that does not receive the intervention but a placebo in its place. A clinical trial could be testing a potential drug, procedure or device. Clinical trials have evolved over hundreds of years and have a structured framework.

Medicine authorities like the Food and Drug Administration (FDA) in the US or the European Medicines Agency (EMA) in the EU require clinical trials proving the safety and efficacy of a drug before they will allow it on the market. They often then require the company or research institute that developed an approved drug to monitor its safety and efficacy over time through observational studies.

The Clinical Trial: An Important Clinical Research Study

The clinical trial is an intervention study – a specific type of clinical research study that aims to answer a defined question about a treatment. The treatment under investigation could be a new drug, medical device or behavior, for example. The question being posed is usually around the safety or efficacy of the intervention.

A clinical trial is preceded by a long process of preclinical research. First, the intervention is studied in the lab. These tests begin in vitro and often involve toxicity screening. Then they will progress to animals, such as mice or ferrets, for further toxicity and safety testing and to gather initial efficacy results. Animals are needed at this stage, as bodies are much more complex than pure tissues grown in the lab. It’s important to understand the impact of an intervention on various biological systems, such as the nervous and circulatory systems, before the drug is tested in patients.

If an intervention still appears promising after preclinical research, it will enter the five phases of a clinical trial:

• Phase 0 – pharmacodynamics and pharmacokinetics trial on a small number of people
• Phase I – safety trial on a small number of people
• Phase II – efficacy trial with a control versus test group to determine dosage and efficacy
• Phase III – safety and efficacy trial with a large number of people (usually over 1,000)
• Phase IV – continuous monitoring through observation

Understanding Clinical Research

The distinction between types of clinical research study differs depending on who is defining them, and this is an important consideration for those undertaking clinical studies to take a treatment to market. For example, the NIH refers to interventional studies, while the FDA calls them clinical trials. This is the kind of information you can expect a CRO to know.

If you have specific questions about the research you want to undertake, or you’re looking for support with your trial, you can contact Siron Clinical .

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Research Types Explained: Basic, Clinical, Translational

“Research” is a broad stroke of a word, the verbal equivalent of painting a wall instead of a masterpiece. There are important distinctions among the three principal types of medical research — basic, clinical and translational.

Whereas basic research is looking at questions related to how nature works, translational research aims to take what’s learned in basic research and apply that in the development of solutions to medical problems. Clinical research, then, takes those solutions and studies them in clinical trials. Together, they form a continuous research loop that transforms ideas into action in the form of new treatments and tests, and advances cutting-edge developments from the lab bench to the patient’s bedside and back again.

Basic Research

When it comes to science, the “basic” in basic research describes something that’s an essential starting point. “If you think of it in terms of construction, you can’t put up a beautiful, elegant house without first putting in a foundation,” says David Frank, MD , Associate Professor of Medicine, Medical Oncology, at Dana-Farber Cancer Institute. “In science, if you don’t first understand the basic research, then you can’t move on to advanced applications.”

Basic medical research is usually conducted by scientists with a PhD in such fields as biology and chemistry, among many others. They study the core building blocks of life — DNA, cells, proteins, molecules, etc. — to answer fundamental questions about their structures and how they work.

For example, oncologists now know that mutations in DNA enable the unchecked growth of cells in cancer. A scientist conducting basic research might ask: How does DNA work in a healthy cell? How do mutations occur? Where along the DNA sequence do mutations happen? And why?

“Basic research is fundamentally curiosity-driven research,” says Milka Kostic, Program Director, Chemical Biology at Dana-Farber Cancer Institute. “Think of that moment when an apple fell on Isaac Newton’s head. He thought to himself, ‘Why did that happen?’ and then went on to try to find the answer. That’s basic research.”

Clinical Research

Clinical research explores whether new treatments, medications and diagnostic techniques are safe and effective in patients. Physicians administer these to patients in rigorously controlled clinical trials, so that they can accurately and precisely monitor patients’ progress and evaluate the treatment’s efficacy, or measurable benefit.

“In clinical research, we’re trying to define the best treatment for a patient with a given condition,” Frank says. “We’re asking such questions as: Will this new treatment extend the life of a patient with a given type of cancer? Could this supportive medication diminish nausea, diarrhea or other side effects? Could this diagnostic test help physicians detect cancer earlier or distinguish between fast- and slow-growing cancers?”

Successful clinical researchers must draw on not only their medical training but also their knowledge of such areas as statistics, controls and regulatory compliance.

Translational Research

It’s neither practical nor safe to transition directly from studying individual cells to testing on patients. Translational research provides that crucial pivot point. It bridges the gap between basic and clinical research by bringing together a number of specialists to refine and advance the application of a discovery. “Biomedical science is so complex, and there’s so much knowledge available.” Frank says. “It’s through collaboration that advances are made.”

For example, let’s say a basic researcher has identified a gene that looks like a promising candidate for targeted therapy. Translational researchers would then evaluate thousands, if not millions, of potential compounds for the ideal combination that could be developed into a medicine to achieve the desired effect. They’d refine and test the compound on intermediate models, in laboratory and animal models. Then they would analyze those test results to determine proper dosage, side effects and other safety considerations before moving to first-in-human clinical trials. It’s the complex interplay of chemistry, biology, oncology, biostatistics, genomics, pharmacology and other specialties that makes such a translational study a success.

Collaboration and technology have been the twin drivers of recent quantum leaps in the quality and quantity of translational research. “Now, using modern molecular techniques,” Frank says, “we can learn so much from a tissue sample from a patient that we couldn’t before.”

Translational research provides a crucial pivot point after clinical trials as well. Investigators explore how the trial’s resulting treatment or guidelines can be implemented by physicians in their practice. And the clinical outcomes might also motivate basic researchers to reevaluate their original assumptions.

“Translational research is a two-way street,” Kostic says. “There is always conversation flowing in both directions. It’s a loop, a continuous cycle, with one research result inspiring another.”

Learn more about research at Dana-Farber .

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Clinical Research Versus Medical Treatment

What is clinical research.

Clinical research refers to studies in which people participate as patients or healthy volunteers. Different terms are used to describe clinical research, including:

What is Clinical Research

Read the What is Clinical Research? text alternative

clinical studies

clinical trials

Clinical research may have a number of goals, such as:

developing new treatments or medications

identifying causes of illness

studying trends

evaluating ways in which genetics may be related to an illness.

The idea for a clinical research study—also known as a clinical trial—often starts in the laboratory. After researchers test new therapies or procedures in the laboratory and in animal studies, the most promising experimental treatments are moved into clinical trials, which are conducted in phases. During a trial, more information is gained about an experimental treatment, its risks, and its effectiveness.

Strict rules for clinical studies have been put in place by National Institutes of Health and the FDA. Some studies involve promising new treatments that may directly benefit participants. Others do not directly benefit participants, but may help scientists learn better ways to help people.

Confidentiality is an important part of clinical research and ensures that personal information is seen only by those authorized to have access. It also means that the personal identity and all medical information of clinical trial participants is known only to the individual patient and researchers. Results from a study will usually be presented only in terms of trends or overall findings and will not mention specific participants.

Clinical research is much different from the medical treatment you receive in a Healthcare Provider's office.

Who should consider clinical trials and why?

Some people participate in clinical trials because none of the standard (approved) treatment options have worked, or they are unable to tolerate certain side effects. Clinical trials provide another option when standard therapy has failed. Others participate in trials because they want to contribute to the advancement of medical knowledge.

All clinical trials have guidelines, called eligibility criteria, about who can participate. The criteria are based on such factors as age, sex, type and stage of disease, previous treatment history, and other medical conditions. This helps to reduce the variation within the study and to ensure that the researchers will be able to answer the questions they plan to study. Therefore, not everyone who applies for a clinical trial will be accepted.

It is important to test drugs and medical products in the people they are meant to help. It is also important to conduct research in a variety of people, because different people may respond differently to treatments.  FDA seeks to ensure that people of different ages, races, ethnic groups, and genders are included in clinical trials. Learn more about FDA’s efforts to increase diversity in clinical trials .

Where are clinical trials conducted?

Clinical trials can be sponsored by organizations (such as a pharmaceutical company), Federal offices and agencies (such as the National Institutes of Health or the U.S. Department of Veterans Affairs), or individuals (such as doctors or health care providers). The sponsor determines the location(s) of the trials, which are usually conducted at universities, medical centers, clinics, hospitals, and other Federally or industry-funded research sites.

Are clinical trials safe?

FDA works to protect participants in clinical trials and to ensure that people have reliable information before deciding whether to join a clinical trial. The Federal government has regulations and guidelines for clinical research to protect participants from unreasonable risks. Although efforts are made to control the risks to participants, some may be unavoidable because we are still learning more about the medical treatments in the study.

The government requires researchers to give prospective participants complete and accurate information about what will happen during the trial. Before joining a particular study, you will be given an informed consent document that describes your rights as a participant, as well as details about the study, including potential risks. Signing it indicates that you understand that the trial is research and that you may leave at any time. The informed consent is part of the process that makes sure you understand the known risks associated with the study.

What should I think about before joining a clinical trial?

Before joining a clinical trial, it is important to learn as much as possible. Discuss your questions and concerns with members of the health care team conducting the trial. Also, discuss the trial with your health care provider to determine whether or not the trial is a good option based on your current treatment. Be sure you understand:

what happens during the trial

the type of health care you will receive

any related costs once you are enrolled in the trial

the benefits and risks associated with participating. 

What is FDA’s role in approving new drugs and medical treatments?

FDA makes sure medical treatments are safe and effective for people to use. We do not develop new therapies or conduct clinical trials. Rather, we oversee the people who do. FDA staff meet with researchers and perform inspections of clinical trial study sites to protect the rights of patients and to verify the quality and integrity of the data.

Learn more about the Drug Development Process .

Where can I find clinical trials?

One good way to find out if there are any clinical trials that might help you is to ask your doctor. Other sources of information include:

FDA Clinical Trials Search . Search a database of Federally and privately supported studies available through clinicaltrials.gov. Learn about each trial’s purpose, who can participate, locations, and who to contact for more information.

Clinicaltrials.gov. Conduct more advanced searches

National Cancer Institute or call 1–800–4–CANCER (1–800–422–6237). Learn about clinical trials for people with cancer.

What is a placebo and how is it related to clinical trials?

A placebo is a pill, liquid, or powder that has no treatment value. It is often called a sugar pill. In clinical trials, experimental drugs are often compared with placebos to evaluate the treatment’s effectiveness.

Is there a chance I might get a placebo?

In clinical trials that include placebos, quite often neither patients nor their doctors know who is receiving the placebo and how is being treated with the experimental drug. Many cancer clinical trials, as well as trials for other serious and life-threatening conditions, do not include placebo control groups. In these cases, all participants receive the experimental drug. Ask the trial coordinator whether there is a chance you may get a placebo rather than the experimental drug. Then, talk with your doctor about what is best for you.

How do I find out what Phase a drug is in as part of the clinical trial?

Talk to the clinical trial coordinator to find out which phase the clinical trial is in. Learn more about the different clinical trial phases and whether they are right for you.

What happens to drugs that don't make it out of clinical trials?

Most drugs that undergo preclinical (animal) research never even make it to human testing and review by the FDA. The drug developers go back to begin the development process using what they learned during with their preclinical research. Learn more about drug development .

Learn more about the basics of clinical trial participation, read first hand experiences from actual clinical trial volunteers, and see explanations from researchers at the NIH Clinical Research Trials and You Web site. 

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October 18, 2016

Understanding Clinical Studies

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Part of the challenge of explaining clinical research to the public is describing the important points of a study without going into a detailed account of the study’s design. There are many different kinds of clinical studies, each with their own strengths and weaknesses, and no real shorthand way to explain them. Researchers sometimes don’t explicitly state the kind of study they’re talking about. To them, it’s obvious; they’ve been living and breathing this research for years, sometimes decades. But study design can often be difficult even for seasoned health and science communicators to understand.

The gold standard for proving that a treatment or medical approach works is a well-designed randomized controlled trial. This type of study allows researchers to test medical interventions by randomly assigning participants to treatment or control groups. The results can help determine if there’s a cause-and-effect relationship between the treatment and outcomes. But clinical researchers can’t always use this approach. For example, scientists can’t ethically study risky behaviors by asking people to start smoking or eating an unhealthy diet. And they can’t study the health effects of the environment by assigning people to live in different places.

Thus, researchers must often turn to some type of observational study, in which a population’s health or behaviors are observed and analyzed. These studies can’t prove cause and effect, but they can be useful for finding associations. Observational studies can also help researchers understand a situation and come up with hypotheses that can then be put to the test in clinical trials. These types of studies have been essential to understanding the genetic, infectious, environmental, and behavioral causes of disease.

We’ve developed a one-page guide to clarify the different kinds of clinical studies researchers use, to explain why researchers might use them, and to touch a little on each type’s strengths and weaknesses. We hope it can serve as a useful resource to explain clinical research, whether you’re describing the results of a study to the public or the design of a trial to a potential participant. Please take a look and share your thoughts with us by sending an email to [email protected] .

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Clinical Trials VS Clinical Studies – What’s The Difference?

Clinical trials and studies are sometimes used interchangeably but they are actually different subgroups of clinical research. A clinical trial is a part of a clinical study. Participants in studies and trials agree to participate under the scientists’ or doctors’ guidelines.

If you’re considering clinical research or participating in a clinical trial, it’s a good idea to know what you’re getting into. Let’s take a look at the different between clinical studies and clinical trials.

What is a Clinical Study?

Clinical studies assist researchers and clinicians in understanding medical conditions and treatments. Clinical trials and observational studies are the most popular forms of clinical studies. Both teach doctors and nurses about new pharmaceuticals, devices, surgical procedures, and therapies to treat or prevent patients’ ailments. They also develop diagnostic tools to detect and prevent diseases.

Who Conducts Clinical Studies?

Sponsors finance medical studies. Sponsors include university medical centers, pharmaceutical businesses, volunteers, and federal entities like the National Institutes of Health (NIH and the Department of Defense (DoD). Investors in clinical trials frequently seek new medical insights or possible remedies.

Who Leads a Clinical Study?

Doctors are the principal investigators or leaders of all research investigations. The lead investigator is the head of a research team and the team typically include professionals of varied skill levels like doctors, nurses, social workers, etc. The research is mainly done in hospitals, health facilities, or universities.

Can Anyone Participate in a Study?

The research team follows tight guidelines when setting study conditions. This assures success and that can determine who is allowed to participate in a study. Membership eligibility is based on predetermined criteria. Common factors include age, gender, ethnicity, presence of a certain disease, disease stage, and previous medical treatment.

Researchers occasionally randomly select people and ask them to participate if they meet particular requirements.

What’s a Clinical Trial?

Clinical trials are part of clinical studies. Participants must follow certain protocols and interventions of the clinical trial. Medicines, technologies, and behavioral changes are some of the interventions involved. Occasionally, a combination of intervention or protocols are used.

What Are Scientists Looking for in Clinical Trials?

Trials help doctors discover insights on new illness treatments and prevention methods. The study team meticulously records participant replies to study protocols. Clinical trials can:

• Compare current and old medical procedures
• Evaluate two well-established medical therapies and compare their results
• Compare the effects of a new drug to those obtained using a placebo to determine its effectiveness

How Do Trials Work?

The FDA has a four-step clinical trial approach to help researchers find effective dosages, identify potential side effects, and, ideally, secure FDA approval for widespread clinical use. Each phase must focus on safety and effectiveness. The phases are:

• Phase I clinical trials are small-scale experiments on healthy adults of diverse ages. This phase assesses the efficacy and side effects to determine the dose.
• Phase II clinical trials involve 100–300 patients and is used to assess if a pharmaceutical or medical device is safe and effective for treating an illness or symptom.
• Phase III clinical trials typically involve thousands of participants. Researchers analyze doses, populations, and other features. In Phase III, the FDA may approve an experimental drug or technology for widespread use.
• Phase IV clinical trials are the final step in drug or device development. During Phase IV, the  efficacy and safety in larger representative groups is evaluated. Due to the delayed onset of side effects and other adverse responses, Phase IV patients receiving the new medication or treatment in a real-world settings are carefully watched.

How to Participate in Clinical Trials

Before you enroll in a clinical trial, consult your doctor. They may need to provide permission for you to participate.  Your doctor’s office may enroll patients in a clinical study or refer you to another center if your doctor gives permission. You can also search for a trial or join a free service that alerts you to new clinical trials.

If you’re interested in participating in a clinical trial, regularly check back on our website for all our volunteer opportunities. If you have any questions, please fill out our online contact form .

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What is the Difference Between A Clinical Trial and A Clinical Study

People often use the terms "clinical trial" and "clinical study" interchangeably. Both fall under the umbrella term "clinical research," which is the study of health and illness in humans. This research involves people voluntarily participating under conditions set by the clinical researchers. If considering participating in clinical research , it's important to understand the differences between these terms.

What is a Clinical Study?

A clinical study is research using human participants to help experts learn about different medical conditions and treatments. There are two primary types of clinical studies: clinical trials and observational studies. Both are designed to help health care professionals expand their knowledge of viable treatment—or preventative—options for patients, including medications, medical devices, surgery techniques, and therapies (e.g. radiation). Clinical studies may also focus on the development of diagnostic tools to help detect or prevent diseases and other medical conditions.

Who Creates a Clinical Study?

Clinical studies are often sponsored by entities that pay for the research. Typical sponsors are academic medical centers, pharmaceutical companies, voluntary groups, and federal agencies, such as the National Institutes of Health (NIH), Department of Veterans Affairs (VA), and Department of Defense (DoD). Sponsors initiating clinical research want to learn more about medical conditions or identify viable treatments.

Who is in Charge of the Clinical Study?

Every study is led by a principal investigator, usually a medical doctor. It's common for studies to have research teams that include experts of varying degrees of expertise and experience. A clinical study team is often composed of doctors, nurses, social workers, and other types of healthcare professionals. Studies often take place in different facilities, including hospitals, community clinics, universities, or doctors' offices.

Can Anyone Join a Study?

When study parameters are built, the research team sets stringent protocols to help the study succeed. This determines eligibility criteria. Who can join will depend on if they meet established inclusion and exclusion criteria. Common criteria include:

• Having specific illnesses or health conditions
• Stage of a disease
• Previous treatment history for a medical condition

Sometimes research teams choose individuals and ask them to participate if they meet predetermined eligibility factors.

What is a Clinical Trial?

A clinical trial is a component of a clinical study. People who participate in clinical trials are directed to follow the specific interventions set by the initial research protocols for the purpose of the study. Interventions may include drugs, devices, or modifications to a participants' behavior (e.g. diet and exercise). Sometimes it'll be a combination of one or more protocols.

What are Research Teams Looking for in Trials?

Trials are designed to help professionals gain insight and knowledge that will help identify effective new treatments or preventative strategies for medical conditions. The research team carefully tracks participants and how they react to the protocols within the study's parameters. To meet these goals, a clinical trial may:

• Compare new with traditional, already-established medical treatments or interventions.
• Compare two established medical treatments or interventions.
• Compare a new drug treatment's effectiveness to a placebo (inert compound).

These are only a handful of techniques used. What the research teams establish depends upon the type of study and the outcome they're seeking (e.g. treatment for specific cancer types or medications to combat diseases) to determine safety and effectiveness.

How are Trials Conducted?

Trials are broken into four phases which are defined by the U.S. Food and Drug Administration (FDA) and established to help researchers find the right dosages, identify potential side effects, and, if all goes as hoped, gain FDA approval for clinical use. Each phase emphasizes a focus on safety and effectiveness.

• Phase I clinical trials are experimental treatments, usually performed on a small group of (often) healthy people of a wide age range. This phase focuses on safety and side effects to determine correct uses or dosages.
• Phase II clinical trials increase the number of participants (100 to 300), putting an emphasis on effectiveness and obtaining preliminary data to see if a drug (or device) works in people with certain diseases or conditions. Phase II can last years.
• Phase III clinical trials increase participants further, frequently to thousands of participants. Researchers look at different populations and dosage amounts, along with using the treatment with other parameters (e.g. drug combinations). If Phase III succeeds, the FDA may approve the experimental drug or device for widespread use.
• Phase IV clinical trials are the final stage where researchers monitor the drug or device's effectiveness and safety in large, diverse populations. Sometimes, side effects or other adverse reactions don't occur immediately, so safety is carefully monitored throughout Phase IV trials in patients that are receiving the new treatments in real-world settings.

People participate in clinical trials for many reasons. Some suffer from diseases where current treatment options don't work for them or there are no treatments at all. Healthy people participate to aid the development of new treatments or preventative measures.

How Can People Join Clinical Trials?

People who want to participate in clinical trials should first speak with their doctor. If their doctor agrees, they may be enrolled in a clinical trial through their medical office or be referred to another center. Other ways to join are to search for clinical trials or join clinicalconnection.com to receive notifications when new trials are available.

ClinicalConnection, founded by pharmaceutical research professionals, has been helping connect people with clinical trials since 2000.

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Difference between Clinical Trial and Clinical Study

Frequently asked questions.

Yes. The status of enrolment of the trial subjects shall be intimated to the CLA on quarterly basis or as appropriate as per the duration of treatment in accordance with the approved clinical trial protocol, whichever is earlier. Further, six monthly status report of each clinical trial, as to whether it is ongoing, completed or terminated, shall be submitted in SUGAM portal. In case of termination of any clinical trial the detailed reasons for such termination shall be communicated to CLA.

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Clinical Trials vs. Clinical Research: What’s to Know?

“Wherever the art of medicine is loved, there is also a love of humanity” – Hippocrates

When new drugs, vaccines, and medical devices are developed and marketed, one of the most important things to address is safety—the tracking of adverse events related to the usage of medicinal products.  But what goes on behind the scenes before a game-changing drug makes its market entry? The answer is clinical trials and clinical research. Let’s consider each of these activities

Clinical Trials

A clinical trial is a type of clinical research study. A clinical trial is an experiment designed to answer specific questions about possible new treatments or new ways of using existing (known) treatments. Clinical trials are done to determine whether new drugs or treatments are safe and effective. They are usually part of a long, careful process that may take many years to complete.  Clinical trials are conducted in four phases:

• Phase 1 – Tests carried out using an experimental drug or treatment on a small group, typically between 20 to 100 people, to evaluate the treatment for factors including identification of a safe dosage range, patient safety, and detection of side-effects.
• Phase 2 – Experimental drug or treatment is given to a larger group of 100 to 300 people to evaluate its safety and to determine the drug’s efficacy.
• Phase 3 – Testing of drug on a larger group of 300 to 3000 people to assess efficacy, effectiveness and safety.
• Phase 4 – Post-marketing studies commence after treatment approvals by the approved regulatory body for drugs, e.g., the National Agency for Food and Drug Administration and Control (NAFDAC) in Nigeria and the Food and Drug Administration (FDA) in the US.

 Clinical Research

Clinical research is the study of health and illness in people. It is a more encompassing discipline investigating how to prevent, diagnose and treat illness. Clinical research describes many different elements of scientific investigations. Simply put, it involves human participants and helps translate basic research carried out in laboratories into new information and treatments to benefit patients. There are different types of clinical research including treatment research, epidemiological studies, diagnostic research, and others.

Critical Contribution to Healthcare

Clinical research, therefore, includes the processes of clinical trials, epidemiological research, and health services. It also covers education, outcome management, and mental health services for participating individuals. These elements are all vital for medical innovation.

Clinical trials will not be a success without volunteers and participants. However, volunteers and participants must be informed of the risks and benefits of a successful clinical trial.

Volunteers who participate in these studies may benefit from accessing highly-effective treatments that could be deployed for debilitating illnesses. A volunteer can also gain full access to new medical treatments before they are widely available.

Without a doubt, the year 2020 presented many challenges to the healthcare industry–the COVID-19 pandemic ranking as the global antagonist. Those challenges are yet to be completely eliminated even in 2021, but they have brought endless opportunities to improve clinical trial processes across the world.

At Xcene Research, we continue to work at supporting clinical sites and sponsors in creating more efficient, decentralized processes with the patient always top of mind. Bringing care directly to patients is what we do best and we are excited to be part of this new frontier.

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Clinical Research vs Lab Research: An In-depth Analysis

Clinical research , a cornerstone in advancing patient care, involves human subjects to test the safety and effectiveness of new treatments , ranging from drugs to diagnostic tools. Unlike clinical research , laboratory research focuses on the foundational science behind medicine without direct human involvement , contributing significantly to medical lab science.

The contrast between clinical research vs lab research highlights the diverse approaches in the scientific pursuit of better healthcare, where every medical advancement once relied on volunteer participation in clinical studies 1 . Bridging these two fields promises to accelerate the translation of lab discoveries into practical medical applications, underscoring the importance of collaboration in future developments in medical lab science 1 2 .

The Evolution of Clinical Research

The evolution of clinical research traces its origins back to ancient times, with the world's first recorded clinical tria l found in the "Book of Daniel" where a dietary intervention was observed to improve health after 10 days. This historical milestone was followed by significant advancements including Avicenna's rules for drug testing in his ‘ Canon of Medicine’ and Ambroise Pare's accidental trial in 1537 , which introduced a novel therapy for wounded soldiers. The modern era of clinical trials was marked by James Lind's controlled trial on scurvy in 1747 , laying the foundational principles for contemporary clinical research methodologies. The progression from these early experiments to the structured, ethical, and scientifically rigorous trials of today highlights the dynamic nature of clinical research. This evolution was further shaped by the introduction of the placebo in the early 1800s and the establishment of ethical frameworks , starting with the Hippocratic Oath and later formalized by the Nuremberg Code in 1947 . The development of clinical research has been instrumental in advancing medical science, with each phase of clinical trials meticulously designed to ensure the safety and efficacy of new treatments for the benefit of patient care.

Key Components of Laboratory Research

Clinical Research Facility Sciences, pivotal in the realm of medical lab science, leverage laboratory data and services extensively for disease diagnosis, monitoring, and treatment 2 4 . These sciences are underpinned by professionals who, after obtaining a Bachelor's degree in fields such as clinical research facility science or biomedical sciences from NAACLS-accredited programs, perform crucial laboratory tests, analyze specimens, and furnish healthcare providers with critical insights into the results' significance and validity 2 . Notably, these activities are conducted in laboratory settings without involving human subjects, emphasizing the distinction between clinical and laboratory research 2 .

The infrastructure of laboratories is meticulously designed to support the complex and sensitive nature of laboratory tests and analyses. This includes sturdy tables and ample counter space for heavy equipment, overhead and adjustable shelving for efficient space utilization, and cabinets and drawers for organized storage. Additionally, the deployment of fume hoods, customized for specific research needs, is essential for the safe handling of chemicals. Compliance with safety regulations and proper storage of flammable items underscore the operational standards necessary for high-quality testing and analysis in medical breakthroughs 6 .

The scientific process in laboratory research unfolds through several key steps: hypothesis formulation, experiment design, data collection, data analysis, and report writing. This structured approach begins with formulating a tentative explanation for a phenomenon, followed by planning and conducting experiments using appropriate methods and tools. The subsequent collection and analysis of data facilitate testing the hypothesis, culminating in the documentation of the entire process and findings in a formal report or paper 7 . This systematic methodology underscores the rigorous and methodical nature of laboratory research, contributing significantly to advancements in medical lab science.

Bridging the Gap: Collaboration between Clinical and Laboratory Research

Bridging the gap between clinical and laboratory research involves fostering collaborative environments that leverage the strengths of both fields to advance medical science. Medical scientific studies bifurcate into clinical laboratory scientists, who interpret critical data for healthcare professionals, and clinical researchers, who lay the groundwork for medical education and understanding 4 . This collaboration is pivotal for both building the future of medicine and administering its current benefits 4 . Enhanced operational efficiency is achieved through cross-departmental synergy, reducing redundancies in resource and personnel utilization, and fostering faster adoption of best practices and innovations across the lab 8 . These collaborations are exemplified by real-world success stories from renowned institutions like Mayo Clinic and Stanford Health Care, which have demonstrated the profound impact of integrated efforts on medical advancements 8 .

Key strategies for effective collaboration include regular meetings to address challenges, the integration of digital communication platforms with lab databases for swift sharing of results, and the establishment of clear guidelines for consistency in sample collection and result dissemination 8 . Unified objectives ensure that despite methodological differences, the end goals of improving patient care and advancing medical knowledge remain aligned 8 . Furthermore, the adoption of cloud-based data systems and AI technologies not only facilitates seamless data sharing but also automates routine tasks, thereby enhancing productivity and enabling the discovery of new insights 9 .

Challenges such as competition, ethics reviews, insufficient research funds, and the recruitment of project managers underscore the complexities of collaborative efforts 9 . However, the benefits, including improved reputation, publication quality, knowledge transfer, and acceleration of the research process, often outweigh the costs and risks associated with collaboration 9 . Collaborative relationships in Translational Medical Research (TMR) among clinicians highlight a strong willingness to collaborate, with preferences varying across different stages of research and between preferring independent and interdependent relationships 9 . This willingness to collaborate is crucial for bridging the gap between clinical and laboratory research, ultimately leading to groundbreaking advancements in medical science.

Future Trends in Clinical and Laboratory Research

The future of clinical and laboratory research is poised for transformative changes, driven by technological advancements and evolving healthcare needs. Notably:

Greater Efficiency through Automation : The integration of automation in research processes promises to streamline workflows, reducing manual labor and enhancing precision 13 .

Collaboration and Capacity Sharing : Partnerships between research institutions will facilitate shared resources and expertise, optimizing research outputs 13 .

Remote Sample Support and Diagnostic Data Interoperability : These advancements will enable more inclusive research and improved patient care by allowing data to flow seamlessly between different healthcare systems 13 .

Artificial Intelligence and Machine Learning : AI and machine learning are set to revolutionize both clinical and laboratory research by providing advanced data analysis, predictive modeling, and personalized medicine approaches 13 14 .

Staffing Solutions and Digital Workflows : Addressing staffing shortages through innovative solutions, alongside the adoption of digital workflows, will be crucial for maintaining research momentum 14 .

New Diagnostic Technologies : The development of novel diagnostic methods and technologies, including next-generation sequencing and biomarker-based screenings, will enhance disease diagnosis and treatment 14 .

Regulatory Changes and Patient-Centric Approaches : Increased FDA oversight of laboratory-developed tests and a shift towards patient-centric research models will ensure safer and more effective healthcare solutions 14 16 .

Precision Medicine and Big Data Analytics : The focus on precision medicine, supported by real-world evidence and big data analytics, will tailor treatments to individual patient needs, improving outcomes 15 .

Decentralized Clinical Trials and Digital Health Technologies : The rise of decentralized trials and digital health tools, including remote monitoring, will make research more accessible and patient-friendly 15 .

Innovation in Testing and Consumer Health : Laboratories will explore new frontiers in diagnostics, such as multi-drug-of-abuse testing and T-cell testing, while also responding to consumer health trends with at-home testing services 14 18 .

These trends underscore a dynamic shift towards more efficient, patient-centered, and technologically advanced clinical and laboratory research, setting the stage for groundbreaking discoveries and innovations in healthcare 13 14 15 16 18 .

Through this detailed exploration, we have seen the distinct yet intertwined roles that clinical and laboratory research play in the advancement of medical science and patient care. By comparing their methodologies, evolution, and collaborative potential, it becomes clear that both domains are crucial for fostering innovations that can bridge the gap between theoretical knowledge and practical healthcare solutions. The synergy between clinical and laboratory research, as highlighted by various examples and future trend predictions, establishes an essential framework for the continual improvement of medical practices and patient outcomes.

As we look toward the future, the significance of embracing technological advancements, enhancing collaboration, and adopting patient-centric approaches cannot be overstressed. These elements are pivotal in navigating the challenges and leveraging the opportunities within clinical and laboratory research landscapes. The potential impacts of such advancements on the field of medicine and on societal health as a whole are immense, underscoring the imperative for ongoing research, dialogue, and innovation in bridging the gap between the laboratory bench and the patient's bedside.

What distinguishes clinical research from laboratory research? Clinical research involves studies that include human participants, aiming to understand health and illness and answer medical questions. Laboratory research, on the other hand, takes place in environments such as chemistry or biology labs, typically at colleges or medical schools, and does not involve human subjects. Instead, it focuses on experiments conducted on non-human samples or models.

How does a clinical laboratory differ from a research laboratory? Clinical laboratories are specialized facilities where laboratory information and services are utilized to diagnose, monitor, and treat diseases. Research laboratories, in contrast, are settings where scientific investigation is conducted to study illness and health in humans to answer medical and behavioral questions.

In what ways do clinical research and scientific research differ? Clinical research is a branch of medical research that directly applies knowledge to improve patient care, often through the study of human subjects. Scientific research, including basic science research, aims to understand the mechanisms of diseases and biological processes, which may not have immediate applications in patient care.

Can you outline the various types of medical research analysis? Medical research can be categorized into three primary types based on the study's nature: basic (experimental) research, clinical research, and epidemiological research. Clinical and epidemiological research can be further divided into interventional studies, which actively involve treating or intervening in the study subjects, and noninterventional studies, which observe outcomes without intervention.

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Clinical Trials

Observational studies, who conducts clinical studies, where are clinical studies conducted, how long do clinical studies last, reasons for conducting clinical studies, who can participate in a clinical study, how are participants protected, relationship to usual health care, considerations for participation, questions to ask, what is a clinical study.

A clinical study involves research using human volunteers (also called participants) that is intended to add to medical knowledge. There are two main types of clinical studies: clinical trials (also called interventional studies) and observational studies. ClinicalTrials.gov includes both interventional and observational studies.

In a clinical trial, participants receive specific interventions according to the research plan or protocol created by the investigators. These interventions may be medical products, such as drugs or devices; procedures; or changes to participants' behavior, such as diet. Clinical trials may compare a new medical approach to a standard one that is already available, to a placebo that contains no active ingredients, or to no intervention. Some clinical trials compare interventions that are already available to each other. When a new product or approach is being studied, it is not usually known whether it will be helpful, harmful, or no different than available alternatives (including no intervention). The investigators try to determine the safety and efficacy of the intervention by measuring certain outcomes in the participants. For example, investigators may give a drug or treatment to participants who have high blood pressure to see whether their blood pressure decreases.

Clinical trials used in drug development are sometimes described by phase. These phases are defined by the Food and Drug Administration (FDA).

Some people who are not eligible to participate in a clinical trial may be able to get experimental drugs or devices outside of a clinical trial through expanded access. See more information on expanded access from the FDA .

In an observational study, investigators assess health outcomes in groups of participants according to a research plan or protocol. Participants may receive interventions (which can include medical products such as drugs or devices) or procedures as part of their routine medical care, but participants are not assigned to specific interventions by the investigator (as in a clinical trial). For example, investigators may observe a group of older adults to learn more about the effects of different lifestyles on cardiac health.

Every clinical study is led by a principal investigator, who is often a medical doctor. Clinical studies also have a research team that may include doctors, nurses, social workers, and other health care professionals.

Clinical studies can be sponsored, or funded, by pharmaceutical companies, academic medical centers, voluntary groups, and other organizations, in addition to Federal agencies such as the National Institutes of Health, the U.S. Department of Defense, and the U.S. Department of Veterans Affairs. Doctors, other health care providers, and other individuals can also sponsor clinical research.

Clinical studies can take place in many locations, including hospitals, universities, doctors' offices, and community clinics. The location depends on who is conducting the study.

The length of a clinical study varies, depending on what is being studied. Participants are told how long the study will last before they enroll.

In general, clinical studies are designed to add to medical knowledge related to the treatment, diagnosis, and prevention of diseases or conditions. Some common reasons for conducting clinical studies include:

• Evaluating one or more interventions (for example, drugs, medical devices, approaches to surgery or radiation therapy) for treating a disease, syndrome, or condition
• Finding ways to prevent the initial development or recurrence of a disease or condition. These can include medicines, vaccines, or lifestyle changes, among other approaches.
• Evaluating one or more interventions aimed at identifying or diagnosing a particular disease or condition
• Examining methods for identifying a condition or the risk factors for that condition
• Exploring and measuring ways to improve the comfort and quality of life through supportive care for people with a chronic illness

Participating in Clinical Studies

A clinical study is conducted according to a research plan known as the protocol. The protocol is designed to answer specific research questions and safeguard the health of participants. It contains the following information:

• The reason for conducting the study
• Who may participate in the study (the eligibility criteria)
• The number of participants needed
• The schedule of tests, procedures, or drugs and their dosages
• The length of the study
• What information will be gathered about the participants

Clinical studies have standards outlining who can participate. These standards are called eligibility criteria and are listed in the protocol. Some research studies seek participants who have the illnesses or conditions that will be studied, other studies are looking for healthy participants, and some studies are limited to a predetermined group of people who are asked by researchers to enroll.

Eligibility. The factors that allow someone to participate in a clinical study are called inclusion criteria, and the factors that disqualify someone from participating are called exclusion criteria. They are based on characteristics such as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions.

Informed consent is a process used by researchers to provide potential and enrolled participants with information about a clinical study. This information helps people decide whether they want to enroll or continue to participate in the study. The informed consent process is intended to protect participants and should provide enough information for a person to understand the risks of, potential benefits of, and alternatives to the study. In addition to the informed consent document, the process may involve recruitment materials, verbal instructions, question-and-answer sessions, and activities to measure participant understanding. In general, a person must sign an informed consent document before joining a study to show that he or she was given information on the risks, potential benefits, and alternatives and that he or she understands it. Signing the document and providing consent is not a contract. Participants may withdraw from a study at any time, even if the study is not over. See the Questions to Ask section on this page for questions to ask a health care provider or researcher about participating in a clinical study.

Institutional review boards. Each federally supported or conducted clinical study and each study of a drug, biological product, or medical device regulated by FDA must be reviewed, approved, and monitored by an institutional review board (IRB). An IRB is made up of doctors, researchers, and members of the community. Its role is to make sure that the study is ethical and that the rights and welfare of participants are protected. This includes making sure that research risks are minimized and are reasonable in relation to any potential benefits, among other responsibilities. The IRB also reviews the informed consent document.

In addition to being monitored by an IRB, some clinical studies are also monitored by data monitoring committees (also called data safety and monitoring boards).

Various Federal agencies, including the Office of Human Subjects Research Protection and FDA, have the authority to determine whether sponsors of certain clinical studies are adequately protecting research participants.

Typically, participants continue to see their usual health care providers while enrolled in a clinical study. While most clinical studies provide participants with medical products or interventions related to the illness or condition being studied, they do not provide extended or complete health care. By having his or her usual health care provider work with the research team, a participant can make sure that the study protocol will not conflict with other medications or treatments that he or she receives.

Participating in a clinical study contributes to medical knowledge. The results of these studies can make a difference in the care of future patients by providing information about the benefits and risks of therapeutic, preventative, or diagnostic products or interventions.

Clinical trials provide the basis for the development and marketing of new drugs, biological products, and medical devices. Sometimes, the safety and the effectiveness of the experimental approach or use may not be fully known at the time of the trial. Some trials may provide participants with the prospect of receiving direct medical benefits, while others do not. Most trials involve some risk of harm or injury to the participant, although it may not be greater than the risks related to routine medical care or disease progression. (For trials approved by IRBs, the IRB has decided that the risks of participation have been minimized and are reasonable in relation to anticipated benefits.) Many trials require participants to undergo additional procedures, tests, and assessments based on the study protocol. These requirements will be described in the informed consent document. A potential participant should also discuss these issues with members of the research team and with his or her usual health care provider.

Anyone interested in participating in a clinical study should know as much as possible about the study and feel comfortable asking the research team questions about the study, the related procedures, and any expenses. The following questions may be helpful during such a discussion. Answers to some of these questions are provided in the informed consent document. Many of the questions are specific to clinical trials, but some also apply to observational studies.

• What is being studied?
• Why do researchers believe the intervention being tested might be effective? Why might it not be effective? Has it been tested before?
• What are the possible interventions that I might receive during the trial?
• How will it be determined which interventions I receive (for example, by chance)?
• Who will know which intervention I receive during the trial? Will I know? Will members of the research team know?
• How do the possible risks, side effects, and benefits of this trial compare with those of my current treatment?
• What will I have to do?
• What tests and procedures are involved?
• How often will I have to visit the hospital or clinic?
• Will hospitalization be required?
• How long will the study last?
• Who will pay for my participation?
• Will I be reimbursed for other expenses?
• What type of long-term follow-up care is part of this trial?
• If I benefit from the intervention, will I be allowed to continue receiving it after the trial ends?
• Will results of the study be provided to me?
• Who will oversee my medical care while I am participating in the trial?
• What are my options if I am injured during the study?
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Healthy Living with Diabetes

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How can I plan what to eat or drink when I have diabetes?

How can physical activity help manage my diabetes, what can i do to reach or maintain a healthy weight, should i quit smoking, how can i take care of my mental health, clinical trials for healthy living with diabetes.

Healthy living is a way to manage diabetes . To have a healthy lifestyle, take steps now to plan healthy meals and snacks, do physical activities, get enough sleep, and quit smoking or using tobacco products.

Healthy living may help keep your body’s blood pressure , cholesterol , and blood glucose level, also called blood sugar level, in the range your primary health care professional recommends. Your primary health care professional may be a doctor, a physician assistant, or a nurse practitioner. Healthy living may also help prevent or delay health problems  from diabetes that can affect your heart, kidneys, eyes, brain, and other parts of your body.

Making lifestyle changes can be hard, but starting with small changes and building from there may benefit your health. You may want to get help from family, loved ones, friends, and other trusted people in your community. You can also get information from your health care professionals.

What you choose to eat, how much you eat, and when you eat are parts of a meal plan. Having healthy foods and drinks can help keep your blood glucose, blood pressure, and cholesterol levels in the ranges your health care professional recommends. If you have overweight or obesity, a healthy meal plan—along with regular physical activity, getting enough sleep, and other healthy behaviors—may help you reach and maintain a healthy weight. In some cases, health care professionals may also recommend diabetes medicines that may help you lose weight, or weight-loss surgery, also called metabolic and bariatric surgery.

Choose healthy foods and drinks

There is no right or wrong way to choose healthy foods and drinks that may help manage your diabetes. Healthy meal plans for people who have diabetes may include

• dairy or plant-based dairy products
• nonstarchy vegetables
• protein foods
• whole grains

Try to choose foods that include nutrients such as vitamins, calcium , fiber , and healthy fats . Also try to choose drinks with little or no added sugar , such as tap or bottled water, low-fat or non-fat milk, and unsweetened tea, coffee, or sparkling water.

Try to plan meals and snacks that have fewer

• foods high in saturated fat
• foods high in sodium, a mineral found in salt
• sugary foods , such as cookies and cakes, and sweet drinks, such as soda, juice, flavored coffee, and sports drinks

Your body turns carbohydrates , or carbs, from food into glucose, which can raise your blood glucose level. Some fruits, beans, and starchy vegetables—such as potatoes and corn—have more carbs than other foods. Keep carbs in mind when planning your meals.

You should also limit how much alcohol you drink. If you take insulin  or certain diabetes medicines , drinking alcohol can make your blood glucose level drop too low, which is called hypoglycemia . If you do drink alcohol, be sure to eat food when you drink and remember to check your blood glucose level after drinking. Talk with your health care team about your alcohol-drinking habits.

Find the best times to eat or drink

Talk with your health care professional or health care team about when you should eat or drink. The best time to have meals and snacks may depend on

• what medicines you take for diabetes
• what your level of physical activity or your work schedule is
• whether you have other health conditions or diseases

Ask your health care team if you should eat before, during, or after physical activity. Some diabetes medicines, such as sulfonylureas  or insulin, may make your blood glucose level drop too low during exercise or if you skip or delay a meal.

Plan how much to eat or drink

You may worry that having diabetes means giving up foods and drinks you enjoy. The good news is you can still have your favorite foods and drinks, but you might need to have them in smaller portions  or enjoy them less often.

For people who have diabetes, carb counting and the plate method are two common ways to plan how much to eat or drink. Talk with your health care professional or health care team to find a method that works for you.

Carb counting

Carbohydrate counting , or carb counting, means planning and keeping track of the amount of carbs you eat and drink in each meal or snack. Not all people with diabetes need to count carbs. However, if you take insulin, counting carbs can help you know how much insulin to take.

Plate method

The plate method helps you control portion sizes  without counting and measuring. This method divides a 9-inch plate into the following three sections to help you choose the types and amounts of foods to eat for each meal.

• Nonstarchy vegetables—such as leafy greens, peppers, carrots, or green beans—should make up half of your plate.
• Carb foods that are high in fiber—such as brown rice, whole grains, beans, or fruits—should make up one-quarter of your plate.
• Protein foods—such as lean meats, fish, dairy, or tofu or other soy products—should make up one quarter of your plate.

If you are not taking insulin, you may not need to count carbs when using the plate method.

Work with your health care team to create a meal plan that works for you. You may want to have a diabetes educator  or a registered dietitian  on your team. A registered dietitian can provide medical nutrition therapy , which includes counseling to help you create and follow a meal plan. Your health care team may be able to recommend other resources, such as a healthy lifestyle coach, to help you with making changes. Ask your health care team or your insurance company if your benefits include medical nutrition therapy or other diabetes care resources.

Talk with your health care professional before taking dietary supplements

There is no clear proof that specific foods, herbs, spices, or dietary supplements —such as vitamins or minerals—can help manage diabetes. Your health care professional may ask you to take vitamins or minerals if you can’t get enough from foods. Talk with your health care professional before you take any supplements, because some may cause side effects or affect how well your diabetes medicines work.

Research shows that regular physical activity helps people manage their diabetes and stay healthy. Benefits of physical activity may include

• lower blood glucose, blood pressure, and cholesterol levels
• better heart health
• healthier weight
• better mood and sleep
• better balance and memory

Talk with your health care professional before starting a new physical activity or changing how much physical activity you do. They may suggest types of activities based on your ability, schedule, meal plan, interests, and diabetes medicines. Your health care professional may also tell you the best times of day to be active or what to do if your blood glucose level goes out of the range recommended for you.

Do different types of physical activity

People with diabetes can be active, even if they take insulin or use technology such as insulin pumps .

Try to do different kinds of activities . While being more active may have more health benefits, any physical activity is better than none. Start slowly with activities you enjoy. You may be able to change your level of effort and try other activities over time. Having a friend or family member join you may help you stick to your routine.

The physical activities you do may need to be different if you are age 65 or older , are pregnant , or have a disability or health condition . Physical activities may also need to be different for children and teens . Ask your health care professional or health care team about activities that are safe for you.

Aerobic activities

Aerobic activities make you breathe harder and make your heart beat faster. You can try walking, dancing, wheelchair rolling, or swimming. Most adults should try to get at least 150 minutes of moderate-intensity physical activity each week. Aim to do 30 minutes a day on most days of the week. You don’t have to do all 30 minutes at one time. You can break up physical activity into small amounts during your day and still get the benefit. 1

Strength training or resistance training

Strength training or resistance training may make your muscles and bones stronger. You can try lifting weights or doing other exercises such as wall pushups or arm raises. Try to do this kind of training two times a week. 1

Balance and stretching activities

Balance and stretching activities may help you move better and have stronger muscles and bones. You may want to try standing on one leg or stretching your legs when sitting on the floor. Try to do these kinds of activities two or three times a week. 1

Some activities that need balance may be unsafe for people with nerve damage or vision problems caused by diabetes. Ask your health care professional or health care team about activities that are safe for you.

Stay safe during physical activity

Staying safe during physical activity is important. Here are some tips to keep in mind.

Drink liquids

Drinking liquids helps prevent dehydration , or the loss of too much water in your body. Drinking water is a way to stay hydrated. Sports drinks often have a lot of sugar and calories , and you don’t need them for most moderate physical activities.

Avoid low blood glucose

Check your blood glucose level before, during, and right after physical activity. Physical activity often lowers the level of glucose in your blood. Low blood glucose levels may last for hours or days after physical activity. You are most likely to have low blood glucose if you take insulin or some other diabetes medicines, such as sulfonylureas.

Ask your health care professional if you should take less insulin or eat carbs before, during, or after physical activity. Low blood glucose can be a serious medical emergency that must be treated right away. Take steps to protect yourself. You can learn how to treat low blood glucose , let other people know what to do if you need help, and use a medical alert bracelet.

Avoid high blood glucose and ketoacidosis

Taking less insulin before physical activity may help prevent low blood glucose, but it may also make you more likely to have high blood glucose. If your body does not have enough insulin, it can’t use glucose as a source of energy and will use fat instead. When your body uses fat for energy, your body makes chemicals called ketones .

High levels of ketones in your blood can lead to a condition called diabetic ketoacidosis (DKA) . DKA is a medical emergency that should be treated right away. DKA is most common in people with type 1 diabetes . Occasionally, DKA may affect people with type 2 diabetes  who have lost their ability to produce insulin. Ask your health care professional how much insulin you should take before physical activity, whether you need to test your urine for ketones, and what level of ketones is dangerous for you.

Take care of your feet

People with diabetes may have problems with their feet because high blood glucose levels can damage blood vessels and nerves. To help prevent foot problems, wear comfortable and supportive shoes and take care of your feet  before, during, and after physical activity.

If you have diabetes, managing your weight  may bring you several health benefits. Ask your health care professional or health care team if you are at a healthy weight  or if you should try to lose weight.

If you are an adult with overweight or obesity, work with your health care team to create a weight-loss plan. Losing 5% to 7% of your current weight may help you prevent or improve some health problems  and manage your blood glucose, cholesterol, and blood pressure levels. 2 If you are worried about your child’s weight  and they have diabetes, talk with their health care professional before your child starts a new weight-loss plan.

You may be able to reach and maintain a healthy weight by

• following a healthy meal plan
• consuming fewer calories
• being physically active
• getting 7 to 8 hours of sleep each night 3

If you have type 2 diabetes, your health care professional may recommend diabetes medicines that may help you lose weight.

Online tools such as the Body Weight Planner  may help you create eating and physical activity plans. You may want to talk with your health care professional about other options for managing your weight, including joining a weight-loss program  that can provide helpful information, support, and behavioral or lifestyle counseling. These options may have a cost, so make sure to check the details of the programs.

Your health care professional may recommend weight-loss surgery  if you aren’t able to reach a healthy weight with meal planning, physical activity, and taking diabetes medicines that help with weight loss.

If you are pregnant , trying to lose weight may not be healthy. However, you should ask your health care professional whether it makes sense to monitor or limit your weight gain during pregnancy.

Both diabetes and smoking —including using tobacco products and e-cigarettes—cause your blood vessels to narrow. Both diabetes and smoking increase your risk of having a heart attack or stroke , nerve damage , kidney disease , eye disease , or amputation . Secondhand smoke can also affect the health of your family or others who live with you.

If you smoke or use other tobacco products, stop. Ask for help . You don’t have to do it alone.

Feeling stressed, sad, or angry can be common for people with diabetes. Managing diabetes or learning to cope with new information about your health can be hard. People with chronic illnesses such as diabetes may develop anxiety or other mental health conditions .

Learn healthy ways to lower your stress , and ask for help from your health care team or a mental health professional. While it may be uncomfortable to talk about your feelings, finding a health care professional whom you trust and want to talk with may help you

• lower your feelings of stress, depression, or anxiety
• manage problems sleeping or remembering things
• see how diabetes affects your family, school, work, or financial situation

Ask your health care team for mental health resources for people with diabetes.

Sleeping too much or too little may raise your blood glucose levels. Your sleep habits may also affect your mental health and vice versa. People with diabetes and overweight or obesity can also have other health conditions that affect sleep, such as sleep apnea , which can raise your blood pressure and risk of heart disease.

NIDDK conducts and supports clinical trials in many diseases and conditions, including diabetes. The trials look to find new ways to prevent, detect, or treat disease and improve quality of life.

What are clinical trials for healthy living with diabetes?

Clinical trials—and other types of clinical studies —are part of medical research and involve people like you. When you volunteer to take part in a clinical study, you help health care professionals and researchers learn more about disease and improve health care for people in the future.

Researchers are studying many aspects of healthy living for people with diabetes, such as

• how changing when you eat may affect body weight and metabolism
• how less access to healthy foods may affect diabetes management, other health problems, and risk of dying
• whether low-carbohydrate meal plans can help lower blood glucose levels
• which diabetes medicines are more likely to help people lose weight

Find out if clinical trials are right for you .

Watch a video of NIDDK Director Dr. Griffin P. Rodgers explaining the importance of participating in clinical trials.

What clinical trials for healthy living with diabetes are looking for participants?

You can view a filtered list of clinical studies on healthy living with diabetes that are federally funded, open, and recruiting at www.ClinicalTrials.gov . You can expand or narrow the list to include clinical studies from industry, universities, and individuals; however, the National Institutes of Health does not review these studies and cannot ensure they are safe for you. Always talk with your primary health care professional before you participate in a clinical study.

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

NIDDK would like to thank: Elizabeth M. Venditti, Ph.D., University of Pittsburgh School of Medicine.

• Introduction
• Conclusions
• Article Information

Peak respiratory severity was classified by an ordinal scale as follows: (1) no oxygen therapy; (2) standard-flow oxygen therapy (<30 L/min); (3) high-flow nasal cannula (≥30 L/min) or noninvasive ventilation; (4) invasive mechanical ventilation; and (5) death.

A, 177 RSV-A sequences from adults aged 18 years and older hospitalized within the Investigating Respiratory Viruses in the Acutely Ill Network of 25 hospitals in 20 US States (tips color coded by State) and 68 contextual sequences from outside the United States collected between January and March 2020, available on Global Initiative on Sharing All Influenza Data. B, 32 RSV-B sequences from adults aged 18 years and older hospitalized within the Investigating Respiratory Viruses in the Acutely Ill Network of 25 hospitals in 20 US States (tips color coded by State) with 46 contextual sequences from outside the United States collected between January and March 2020, available on Global Initiative on Sharing All Influenza Data.

eAppendix 1. Investigators and Collaborators

eTable 1. Underlying Medical Conditions Obtained Through Medical Record Review

eTable 2. Characteristics and In-Hospital Outcomes of Adults Aged ≥18 Years Hospitalized With Coinfections of RSV, SARS-CoV-2, or Influenza

eTable 3. Components of Composite in-Hospital Outcomes Among Adults Aged ≥18 Years Hospitalized With RSV, COVID-19, or Influenza by Vaccination Status

eTable 4. Severity of RSV-Associated Hospitalizations vs COVID-19-Associated Hospitalizations, by Vaccination Status, Among US Adults Aged ≥60 Years

eTable 5. Severity of RSV-Associated Hospitalizations vs Influenza-Associated Hospitalizations, by Vaccination Status, Among US Adults Aged ≥60 Years

eFigure 1. RSV Testing Among Adults Aged ≥18 Years Hospitalized With Acute Respiratory Illness (ARI)

eFigure 2. Adults Aged ≥18 Years Hospitalized With RSV, COVID-19, or Influenza

eFigure 3. Frequency of Adults Aged ≥18 Years Hospitalized With RSV, COVID-19, or Influenza Disease by Admission Week

eFigure 4. Frequency of Adults Aged ≥18 Years Hospitalized With RSV, COVID-19, or Influenza Disease by Admission Week and US Department of Health and Human Services (HHS) Region

eAppendix 2. RSV Primer Pools

eAppendix 3. RSV Strain Names and GISAID Accession IDs

Data Sharing Statement

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Surie D , Yuengling KA , DeCuir J, et al. Severity of Respiratory Syncytial Virus vs COVID-19 and Influenza Among Hospitalized US Adults. JAMA Netw Open. 2024;7(4):e244954. doi:10.1001/jamanetworkopen.2024.4954

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Severity of Respiratory Syncytial Virus vs COVID-19 and Influenza Among Hospitalized US Adults

• 1 Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
• 2 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
• 3 Department of Internal Medicine, University of Michigan, Ann Arbor
• 4 Department of Microbiology and Immunology, University of Michigan, Ann Arbor
• 5 Baylor Scott & White Health, Temple, Texas
• 6 Texas A&M University College of Medicine, Temple
• 7 Baylor College of Medicine, Temple, Texas
• 8 Department of Medicine, Intermountain Medical Center, Murray, Utah and University of Utah, Salt Lake City
• 9 Department of Emergency Medicine, University of Colorado School of Medicine, Aurora
• 10 University of Iowa, Iowa City
• 11 Department of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
• 12 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
• 13 Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
• 14 Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
• 15 Department of Emergency Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle
• 16 Department of Emergency Medicine, University of Washington, Seattle
• 17 Department of Medicine, Baystate Medical Center, Springfield, Massachusetts
• 18 School of Public Health, University of Michigan, Ann Arbor
• 19 Department of Medicine, Oregon Health and Sciences University, Portland
• 20 Department of Medicine, Emory University, Atlanta, Georgia
• 21 Department of Medicine, Cleveland Clinic, Cleveland, Ohio
• 22 Department of Emergency Medicine, Stanford University School of Medicine, Stanford, California
• 23 Department of Medicine, University of California, Los Angeles
• 24 Department of Medicine, University of Miami, Miami, Florida
• 25 Department of Medicine, Washington University in St Louis, St Louis, Missouri
• 26 Department of Medicine, The Ohio State University, Columbus
• 27 Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
• 28 Baylor Scott &White Health, Dallas, Texas
• 29 Texas A&M University College of Medicine, Dallas
• 30 Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan
• 31 Division of Infectious Diseases, Henry Ford Health, Detroit, Michigan
• 32 Department of Emergency Medicine, University of Arizona, Tucson
• 33 Yale University School of Medicine, New Haven, Connecticut
• 34 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
• 35 Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee
• 36 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
• 37 Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
• 38 Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee
• 39 Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

Question   How does disease severity of respiratory syncytial virus (RSV) compare with COVID-19 and influenza among adults hospitalized with these infections?

Findings   In this cohort study of 7998 hospitalized adults aged 18 years and older in 20 US states during February 2022 to May 2023, RSV disease severity was similar to unvaccinated patients hospitalized with COVID-19 or influenza, but substantially more severe than vaccinated patients hospitalized with COVID-19 or influenza disease.

Meaning   These findings suggest that before RSV vaccine introduction in the US, RSV disease was at least as severe as COVID-19 or influenza among unvaccinated patients and more severe than COVID-19 or influenza among vaccinated patients hospitalized with those diseases.

Importance   On June 21, 2023, the Centers for Disease Control and Prevention recommended the first respiratory syncytial virus (RSV) vaccines for adults aged 60 years and older using shared clinical decision-making. Understanding the severity of RSV disease in adults can help guide this clinical decision-making.

Objective   To describe disease severity among adults hospitalized with RSV and compare it with the severity of COVID-19 and influenza disease by vaccination status.

Design, Setting, and Participants   In this cohort study, adults aged 18 years and older admitted to the hospital with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 US states from February 1, 2022, to May 31, 2023. Clinical data during each patient’s hospitalization were collected using standardized forms. Data were analyzed from August to October 2023.

Exposures   RSV, SARS-CoV-2, or influenza infection.

Main Outcomes and Measures   Using multivariable logistic regression, severity of RSV disease was compared with COVID-19 and influenza severity, by COVID-19 and influenza vaccination status, for a range of clinical outcomes, including the composite of invasive mechanical ventilation (IMV) and in-hospital death.

Results   Of 7998 adults (median [IQR] age, 67 [54-78] years; 4047 [50.6%] female) included, 484 (6.1%) were hospitalized with RSV, 6422 (80.3%) were hospitalized with COVID-19, and 1092 (13.7%) were hospitalized with influenza. Among patients with RSV, 58 (12.0%) experienced IMV or death, compared with 201 of 1422 unvaccinated patients with COVID-19 (14.1%) and 458 of 5000 vaccinated patients with COVID-19 (9.2%), as well as 72 of 699 unvaccinated patients with influenza (10.3%) and 20 of 393 vaccinated patients with influenza (5.1%). In adjusted analyses, the odds of IMV or in-hospital death were not significantly different among patients hospitalized with RSV and unvaccinated patients hospitalized with COVID-19 (adjusted odds ratio [aOR], 0.82; 95% CI, 0.59-1.13; P  = .22) or influenza (aOR, 1.20; 95% CI, 0.82-1.76; P  = .35); however, the odds of IMV or death were significantly higher among patients hospitalized with RSV compared with vaccinated patients hospitalized with COVID-19 (aOR, 1.38; 95% CI, 1.02-1.86; P  = .03) or influenza disease (aOR, 2.81; 95% CI, 1.62-4.86; P  < .001).

Conclusions and Relevance   Among adults hospitalized in this US cohort during the 16 months before the first RSV vaccine recommendations, RSV disease was less common but similar in severity compared with COVID-19 or influenza disease among unvaccinated patients and more severe than COVID-19 or influenza disease among vaccinated patients for the most serious outcomes of IMV or death.

Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of severe respiratory disease in adults. An estimated 60 000 to 160 000 RSV-associated hospitalizations and 6000 to 10 000 deaths occur each year among adults aged 65 years and older in the US. 1 - 6 In May 2023, the US Food and Drug Administration approved 2 RSV vaccines for use in adults aged 60 years and older. 7 On June 21, 2023, the Centers for Disease Control and Prevention recommended these new RSV vaccines for adults aged 60 years and older with decisions on whether to be vaccinated based on shared clinical decision-making between patient and health care practitioner. 7 Understanding the severity of RSV disease in adults can help guide this clinical decision-making.

Disease severity from an infection can be affected by host immunity, pathogen virulence, as well as use of therapeutics targeting either the host response or the pathogen. 8 Vaccination strengthens host immunity against infection and its sequelae and has been shown to attenuate both COVID-19 and influenza disease severity. 9 - 11 Because vaccines against COVID-19 and influenza are routinely used by adults in the US, a comparison of disease severity caused by RSV with that of COVID-19 or influenza, by vaccination status, could be useful for framing the potential benefits of RSV vaccination, which may include reduction in disease severity, as observed with COVID-19 and influenza vaccination.

We assessed disease severity among adults hospitalized in the US with RSV during the 16 months immediately preceding recommendations by the Advisory Committee on Immunization Practices for RSV vaccine use. To provide context for the observed severity of RSV disease in hospitalized patients, we compared it with the severity of adults hospitalized with COVID-19 and influenza disease, stratified by vaccination status, during the same period.

This cohort study was determined to be public health surveillance, with a waiver of ethics board review and participant informed consent by each participating institution and the CDC and was conducted consistent with applicable federal law and CDC policy (45 CFR part 46.102(l)(2), 21 CFR part 56; 42 USC §241(d); 5 USC §552a; 44 USC §3501, et seq). This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

We prospectively enrolled patients admitted to any of 25 hospitals in 20 US states within the Investigating Respiratory Viruses in the Acutely Ill (IVY) Network. The IVY Network has been continuously conducting observational analyses on respiratory viruses since 2019, is funded by CDC, is coordinated by Vanderbilt University Medical Center, and includes enrolling centers geographically dispersed throughout the continental US (eAppendix 1 in Supplement 1 ). 10 - 13 Enrollment of patients with influenza and COVID-19 began in 2019 and 2020, respectively. Enrollment of patients with RSV began on February 1, 2022. The current analysis included patients enrolled between February 1, 2022, and May 31, 2023, which was the 16 months preceding recommendations for adult RSV vaccines in the US. This analysis expands on information previously published, which was limited to adults aged 60 years and older by assessing different clinical outcomes, stratified by vaccination status, as well as differences by virus subtype and phylogeny among all adults aged 18 years and older hospitalized within the IVY Network during same period. 14

Hospital admissions at each site were reviewed daily and assessed for eligibility. Hospitalized adults aged 18 years and older with symptoms or signs compatible with acute respiratory illness (ARI) who underwent clinical testing for RSV, SARS-COV-2, or influenza as standard of care were eligible for enrollment. ARI was defined as presence of at least 1 of the following: fever, cough, dyspnea, chest imaging findings consistent with pneumonia, or hypoxemia (ie, an oxygen saturation as measured by pulse oximetry <92% or supplemental oxygen use for patients without chronic oxygen needs, or escalation of oxygen therapy for patients who receive chronic supplemental oxygen). Nasal specimens were also obtained from enrolled patients and tested at a central laboratory (Vanderbilt University Medical Center) by reverse transcription–polymerase chain reaction (RT-PCR) for RSV, SARS-CoV-2, and influenza. Patients with nasal specimens with positive test results for RSV, SARS-CoV-2 or influenza within 10 days of illness onset and 3 days of hospital admission, based on either clinical or central laboratory testing, were included.

Medical records were reviewed by trained personnel who abstracted demographic and clinical data, including in-hospital outcomes within 28 days of admission. Patients (or proxies) were interviewed for information on race, ethnicity, current illness, COVID-19 and influenza vaccination status, residence in a long-term care facility, and health care utilization in the previous year. Race and ethnicity were categorized as Black or African American, non-Hispanic; Hispanic or Latino, any race; White, non-Hispanic; other race, non-Hispanic (includes Asian, Native American or Alaska Native, and Native Hawaiian or Other Pacific Islander); and other (includes patients who self-reported their race and ethnicity as other and those for whom race and ethnicity were unknown). Data on race and ethnicity were collected because the association between respiratory viral infection and severe outcomes may vary by race or ethnicity.

The enrollment period for this analysis was prior to the availability of RSV vaccines; hence all patients with RSV infection were unvaccinated. Vaccination status for COVID-19 and influenza were obtained from electronic medical records (EMRs), state or jurisdictional registries, and by self-report. Final vaccination status was determined by combining data from verified documented sources (EMR and registry data) as well as plausible self-report based on date of vaccination. 13 For this analysis, enrolled patients were excluded if they had confirmed or inconclusive laboratory test results indicating coinfection or possible coinfection with RSV, SARS-CoV-2, or influenza; had unknown vaccination status for COVID-19 or influenza when hospitalized with the respective virus; had only 1 mRNA vaccine (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) dose or 1 recombinant S protein vaccine (NVX-CoV2373 [Novavax]) dose when hospitalized with COVID-19; had unknown in-hospital outcomes; or were identified as ineligible for enrollment after data cleaning.

Patients were classified into 2 COVID-19 vaccination groups: unvaccinated, defined as no prior receipt of COVID-19 vaccination; and vaccinated, if they had received at least a primary COVID-19 vaccine series or bivalent COVID-19 vaccine dose at least 7 days before illness onset (eMethods in Supplement 1 ). Patients who received bivalent COVID-19 vaccination may have previously received 1 to 5 doses of the original (ancestral strain) monovalent vaccines. Influenza vaccination status was classified into 2 groups: unvaccinated, defined as no receipt of influenza vaccine during the current season based on admission date or vaccinated, if they had received the current season’s influenza vaccination at least 14 days before illness onset.

Disease severity was characterized using clinical data during the patient’s hospital admission, beginning at initial hospital presentation, and ending at the earliest of hospital discharge, patient death, or the end of hospital day 28. Using these data, we created 6 nonmutually exclusive in-hospital outcomes: (1) supplemental oxygen therapy, defined as supplemental oxygen at any flow rate and by any device for patients not receiving chronic oxygen therapy or with escalation of oxygen therapy for patients receiving chronic oxygen therapy; (2) respiratory failure treated with advanced respiratory support, defined as a composite of new receipt of high-flow nasal cannula (HFNC), noninvasive ventilation (NIV) or invasive mechanical ventilation (IMV); (3) acute organ failure, defined as a composite of respiratory failure (new receipt of HFNC, NIV, or IMV), cardiovascular failure (use of vasopressors), or kidney failure (new receipt of kidney replacement therapy); (4) intensive care unit (ICU) admission; (5) hospital-free days to day 28, which is an ordinal composite of in-hospital death and hospital length of stay, defined as the number of days alive and out of the hospital between admission and 28 days later, with in-hospital death coded as −1 15 ; and (6) a composite of IMV or death (eMethods in Supplement 1 ).

In addition to these nonmutually exclusive outcomes, we also generated mutually exclusive outcome categories based on a hierarchy of respiratory disease severity. An ordinal outcome, peak respiratory disease severity, was constructed with the following 5 categories: no oxygen therapy, standard-flow oxygen therapy, HFNC or NIV, IMV, and death. Each patient was classified into 1 category based on the highest category achieved during the hospitalization through day 28.

Nasal swabs were obtained from enrolled patients and tested for RSV, SARS-CoV-2, and influenza by RT-PCR at a central laboratory (Vanderbilt University Medical Center, Nashville, Tennessee) (eMethods in Supplement 1 ). Viral whole genome sequencing was performed at the University of Michigan on specimens with positive results by central RT-PCR testing for RSV, SARS-CoV-2, or influenza (eMethods in Supplement 1 and eAppendix 2 in Supplement 2 ). Maximum likelihood phylogenetic trees were generated using IQ-TREE with a GTR model and visualized and annotated using ggtree. 16 Strain names and Global Initiative on Sharing All Influenza Data accession identifications are provided in eAppendix 3 Supplement 3 .

Demographics, clinical characteristics, and outcomes of enrolled patients were described by infecting virus (RSV, SARS-CoV-2, influenza) as well as by viral subtype (A and B subtypes for RSV; Omicron sublineages BA.1, BA.2, BA.4/5, BQ.1, and XBB.1.5 for SARS-CoV-2; and influenza A[H3N2] and A[H1N1]) and vaccination status (unvaccinated or vaccinated against COVID-19 or influenza). In-hospital outcomes were compared between patients hospitalized with RSV, COVID-19, and influenza disease among enrolled patients. A series of multivariable regression models were used to compare outcomes of patients hospitalized with RSV disease with 4 comparator groups: (1) patients hospitalized with COVID-19 without prior COVID-19 vaccination (unvaccinated COVID-19 group), (2) patients hospitalized with COVID-19 and previous COVID-19 vaccination (vaccinated COVID-19 group), (3) patients hospitalized with influenza disease without prior vaccination with the current season’s influenza vaccine (unvaccinated influenza group), and (4) patients hospitalized with influenza with receipt of the current season’s influenza vaccine (vaccinated influenza group). Models were adjusted for age, sex, self-reported race and ethnicity, number of organ systems with a chronic medical condition (eTable 1 in Supplement 1 ), and geographic region (US Department of Health and Human Services Region). Dichotomous outcomes were analyzed with multivariable logistic regression models. Ordinal outcomes, including hospital-free days and peak respiratory disease severity, were analyzed with multivariable proportional odds models. Because of the potential for type I error owing to multiple comparisons, findings from secondary analyses should be interpreted as exploratory. Statistical significance was indicated by a 2-sided P  < .05.

In a sensitivity analysis, we repeated the severity comparisons for RSV, COVID-19, and influenza while restricting the population to adults aged 60 years and older. Currently, RSV vaccines are only recommended for adults aged 60 years and older, although adults of different ages may be considered in the future. Thus, we reported results for adults of all ages (≥18 years) as the primary analysis and results for adults aged 60 years and older as a secondary analysis.

Only patients with complete data for models were analyzed; missing data were not imputed. The numbers of patients with missing data were reported. All analyses were conducted using SAS software version 9.4 (SAS Institute). Data were analyzed from August to October 2023.

Between February 1, 2022 and May 31, 2023, a total of 9117 adults aged 18 years and older hospitalized with ARI had laboratory-confirmed RSV, SARS-CoV-2, or influenza based on either clinical or central laboratory testing and were enrolled. This included 34 patients (0.5%) identified with RSV after central testing of 6759 enrolled patients who did not undergo clinical testing for RSV (eFigure 1 in Supplement 1 ). Among 9117 patients with clinical or central laboratory-confirmed RSV, SARS-CoV-2, or influenza infection, 1119 were excluded from this analysis primarily due to confirmed coinfection (200 patients) (eTable 2 in Supplement 1 ), possible coinfection (376 patients), patients with COVID-19 with only 1 mRNA or 1 recombinant S protein vaccine dose (230 patients), unknown COVID-19 or influenza vaccination history (198 patients), or unknown clinical outcomes (70 patients) (eFigure 2 in Supplement 1 ). The final sample included 7998 adults (median [IQR] age, 67 [54-78] years; 4047 [50.6%] female).

Among 7998 included patients with test results positive for RSV, COVID-19, or influenza, 484 (6.1%) were hospitalized with RSV, 6422 (80.3%) were hospitalized with COVID-19, and 1092 (13.7%) were hospitalized with influenza. Peak hospitalizations for both RSV and influenza occurred during November to December 2022, whereas high numbers of COVID-19 hospitalizations occurred throughout the analysis period (eFigure 3 and eFigure 4 in Supplement 1 ).

Adults hospitalized with RSV were younger than those hospitalized with COVID-19 (median [IQR] age, 65 [53-75] years vs 68 [56-78] years; P  = .002), with no difference compared with those hospitalized with influenza disease (median [IQR] age, 64 [50-74] years; P  = .09) ( Table 1 ). A higher percentage of patients hospitalized with RSV had an ethnicity and race described as non-Hispanic Black compared with those hospitalized with COVID-19 (23.8% vs 19.4%; P  < .01), but this percentage was similar among influenza patients (115 patients [23.8%] vs 271 patients [27.9%]; P  = .34). Patients hospitalized with RSV and COVID-19 had similar proportions of underlying immunocompromising conditions (99 patients [20.5%] vs 1135 patients [17.7%]; P  = .12), but patients with RSV were more likely to have immunocompromising conditions than influenza patients (149 patients [13.6%]; P  < .001). Chronic cardiovascular and pulmonary conditions were common among patients with each of the viruses. Patients hospitalized with RSV were more likely to self-report dyspnea than patients with either COVID-19 (385 patients [79.6%] vs 3916 patients [61.0%]; P  < .001) or influenza (788 patients [72.2%]; P  = .002). Of 6422 patients with COVID-19, 5000 (77.9%) were classified as vaccinated and were a median (IQR) of 259 days (152-407) days from last COVID-19 vaccination. Of 1092 patients with influenza, 393 (36.0%) had received seasonal influenza vaccination.

Overall, most outcomes revealed disease severity among patients with RSV that was not significantly different from patients with unvaccinated COVID-19 and influenza and substantially higher than patients with vaccinated COVID-19 and influenza ( Table 2 ). For example, the outcome of IMV or death was experienced by 58 of 484 patients with RSV (12.0%); 201 of 1422 unvaccinated patients with COVID-19 (14.1%) (adjusted odds ratio [aOR], 0.82; 95% CI, 0.59-1.13); 458 of 5000 vaccinated patients with COVID-19 (9.2%) (aOR, 1.38; 95% CI, 1.02-1.86); 72 of 699 unvaccinated patients with influenza (10.3%) (aOR, 1.20; 95% CI, 0.82-1.76); and 20 of 393 vaccinated patients with influenza (5.1%) (aOR, 2.81; 95% CI, 1.62-4.86). Patients with RSV were more than twice as likely to receive advanced respiratory support than vaccinated patients with COVID-19 (aOR, 2.03; 95% CI, 1.64-2.51) or vaccinated patients with influenza (aOR, 2.71; 95% CI, 1.89-3.87). Frequencies and proportions of each outcome and their components are shown in eTable 3 in Supplement 1 .

Similar results were found when comparing RSV disease severity with COVID-19 and influenza disease among adults aged 60 years and older (eTable 4 and eTable 5 in Supplement 1 ).

When evaluating peak respiratory disease severity, patients with RSV had higher overall severity compared with the unvaccinated COVID-19 group (aOR, 1.54; 95% CI, 1.27-1.86) and the unvaccinated influenza group (aOR, 1.48; 95% CI, 1.18-1.85) and substantially higher overall disease severity compared with the vaccinated COVID-19 group (aOR, 2.16; 95% CI, 1.82-2.57) and the vaccinated influenza group (aOR, 2.40; 95% CI, 1.83-3.14) ( Figure 1 ).

Of 368 patients with RSV subtype identified, 250 (67.9%) were subtype A and 118 (32.1%) were subtype B. Whole-genome sequencing of RSV subtypes A and B found that lineages circulating during the period of this analysis derived from lineages circulating in early 2020 (before the COVID-19 pandemic in the US) ( Figure 2 ). Clinical outcomes were overall similar between RSV subtype A and B ( Table 3 ). All patients hospitalized with COVID-19 had SARS-CoV-2 Omicron lineages. Among 3466 patients with identified SARS-CoV-2 lineages, BA.1 was the least frequent Omicron lineage (217 patients [6.3%]) but demonstrated the greatest severity ( Table 3 ). Among 649 patients hospitalized with influenza infection and identified subtype, influenza A(H3N2) predominated during the analysis period (474 patients [73.0%]) and had lower or similar severity than influenza A(H1N1) ( Table 3 ).

In this prospective, multicenter cohort study of adults hospitalized in 20 US states during the 16 months preceding the firstUS adult RSV vaccination recommendation, the frequency of RSV hospitalizations was substantially lower than for COVID-19 and influenza; RSV hospitalizations were approximately one-fourteenth as common as COVID-19 hospitalizations and one-half as common as influenza hospitalization. Disease severity of RSV was similar to COVID-19 and influenza among unvaccinated patients and higher than COVID-19 and influenza among vaccinated patients hospitalized with those diseases for the critical outcomes of ICU admission and IMV or death. RSV genomes sequenced from this cohort derived from early 2020 lineages, suggesting the virus circulating during the period of this analysis was similar to RSV that circulated before the COVID-19 pandemic. This evaluation of RSV epidemiology during a period of endemic COVID-19 demonstrates that RSV is a serious respiratory infection in adults, and especially older adults. 14 Newly approved RSV vaccines for adults aged 60 years and older have the potential to reduce this severity, similar to attenuation of disease severity achieved with COVID-19 and influenza vaccination, as previously reported 9 - 11 and also observed in this analysis.

Although several studies have previously compared severity of RSV with influenza disease, strengths of this analysis include comparisons of RSV (which was not vaccine preventable during the period of this analysis) with unvaccinated COVID-19 and influenza disease to separate the association of vaccination in attenuating disease severity from the direct effects of the pathogen. By stratifying our COVID-19 and influenza populations by vaccination status, we show that critical outcomes of ICU admission and IMV or death occurred in a similar proportion of unvaccinated adults hospitalized with RSV compared with unvaccinated adults hospitalized with COVID-19 or influenza. Although outcome definitions varied across studies and analyses were not stratified by vaccination status in prior studies, most prior work suggested RSV disease was more severe than influenza disease among hospitalized adults, including use of supplemental oxygen, IMV, or ICU admission. 17 - 20

Three prior studies have compared RSV disease severity with COVID-19 and suggested lower severity for RSV compared with COVID-19. 19 , 21 , 22 However, 2 of these studies 19 , 21 were conducted using data from 2020, when COVID-19 vaccines were not available and Omicron lineages were not in circulation. Between 2020 and 2022 to 2023, the clinical manifestations of COVID-19 evolved considerably due to the emergence of the Omicron variant, increases in population-level immunity from both vaccination and infection, and improvements in clinical care, including increases in use of antiviral treatments. 23 , 24 As a consequence, the severity of COVID-19 has declined, and the severity of RSV disease is now relatively high compared with COVID-19 from Omicron lineages.

An additional strength of this analysis is that respiratory specimens were obtained from participants, which allowed for subsequent characterization into subtypes by RT-PCR and into lineages based on whole genome sequencing. RSV A and B subtypes have been shown to cocirculate, although 1 subtype often predominates in each season. 25 There are limited data comparing severity between RSV A and B subtypes in adults. Our findings demonstrate very similar patient characteristics and clinical outcomes between RSV A and B subtypes, consistent with studies from before the COVID-19 pandemic. 26 , 27 Similar to prior work during the 2022 RSV surge, we demonstrated expected RSV genomic divergence from early 2020 lineages, suggesting that the severity of RSV disease observed in this analysis is unlikely to have resulted from major genomic changes in RSV during the COVID-19 pandemic. 28

The high disease severity observed among older adults without previous RSV vaccination in this analysis is important to guide decision-making for RSV vaccination in this population. Both clinical trials that led to Food and Drug Administration approval of RSV vaccines for adults aged 60 years and older showed moderate to high efficacy of RSV vaccination against lower respiratory tract disease, which is in the causal pathway leading to severe disease. 29 , 30 Although additional studies are needed to assess the protection of these vaccines against severe respiratory disease in older adults, our results suggest that there is a burden of disease beyond prevention of RSV hospitalization—the reduction of in-hospital RSV disease severity—that could occur with RSV vaccination, as shown for COVID-19 and influenza vaccination in both previous studies and this analysis. 9 - 11

This analysis is subject to limitations. First, it is possible that RSV was preferentially detected among patients who were more severely ill and therefore more likely to receive clinical testing for RSV at participating hospitals and be subsequently enrolled. However, most enrolled patients had nasal swabs tested at a central laboratory for RSV, SARS-CoV-2, and influenza, lessening the potential bias of detecting RSV among patients who were more severely ill based on clinical testing only. During the period of this analysis, we enrolled 6759 adults aged 18 years and older hospitalized with ARI who did not have clinical testing for RSV; only 34 (0.5%) of these patients had a positive RSV test result based on central testing, suggesting the number of undetected RSV hospitalizations was likely low. Second, treatment with antiviral and immunomodulatory medications was not considered in analyses. Quantifying the effect of treatment on observed severity and accounting for it in severity comparisons is complicated by several factors, including that there are currently no routine treatments available RSV; indications for COVID-19 inpatient treatment is often based on severity, making it difficult to disentangle the associations between treatment and observed severity; and COVID-19 treatment practice varied considerably during the analysis period. We presented respiratory virus groups (RSV, COVID-19, and influenza) stratified by vaccination status without stratification or adjustment for acute treatments; the presented severity levels for COVID-19 and influenza represent a mix of patients who did and did not receive antiviral and immunomodulatory treatments.

In this cohort study among adults hospitalized in the US during the 16 months preceding recommendations for the first adult RSV vaccines, RSV disease severity was similar to severity of COVID-19 and influenza disease among unvaccinated patients and substantially higher than COVID-19 and influenza disease among vaccinated patients. Severity of RSV disease among adults may be important to consider as RSV vaccine policy evolves.

Accepted for Publication: February 6, 2024.

Published: April 4, 2024. doi:10.1001/jamanetworkopen.2024.4954

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Surie D et al. JAMA Network Open .

Corresponding Author: Diya Surie, MD, Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS H18-6, Atlanta, GA 30329 ( [email protected] ).

Author Contributions: Ms Yuengling and Dr Zhu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Surie, DeCuir, Brown, Gibbs, Khan, Bender, Wilson, Qadir, Casey, Rice, Halasa, Grijalva, Lewis, Ellington, McMorrow, Martin, Self.

Acquisition, analysis, or interpretation of data: Surie, Yuengling, DeCuir, Zhu, Lauring, Gaglani, Ghamande, Peltan, Brown, Ginde, Martinez, Mohr, Hager, Ali, Prekker, Gong, Mohamed, N. Johnson, Srinivasan, Steingrub, Leis, Khan, Hough, Bender, Duggal, Bendall, Wilson, Qadir, Chang, Mallow, Kwon, Exline, Shapiro, Columbus, Vaughn, Ramesh, Mosier, Safdar, Casey, Talbot, Rice, Halasa, Chappell, Baughman, Womack, Swan, C. Johnson, Lwin, Lewis, Ellington, McMorrow, Martin, Self.

Drafting of the manuscript: Surie, Hager, Khan, Shapiro, Casey, Halasa, Self.

Critical review of the manuscript for important intellectual content: Surie, Yuengling, DeCuir, Zhu, Lauring, Gaglani, Ghamande, Peltan, Brown, Ginde, Martinez, Mohr, Gibbs, Hager, Ali, Prekker, Gong, Mohamed, N. Johnson, Srinivasan, Steingrub, Leis, Khan, Hough, Bender, Duggal, Bendall, Wilson, Qadir, Chang, Mallow, Kwon, Exline, Columbus, Vaughn, Ramesh, Mosier, Safdar, Talbot, Rice, Chappell, Grijalva, Baughman, Womack, Swan, C. Johnson, Lwin, Lewis, Ellington, McMorrow, Martin, Self.

Statistical analysis: Yuengling, DeCuir, Zhu, Bender, C. Johnson, Lwin.

Obtained funding: Surie, Talbot, Halasa, McMorrow, Martin, Self.

Administrative, technical, or material support: Surie, Lauring, Martinez, Mohr, Hager, Ali, Prekker, Gong, Steingrub, Bender, Duggal, Wilson, Qadir, Mallow, Kwon, Exline, Vaughn, Mosier, Safdar, Baughman, Womack, Ellington, McMorrow, Martin, Self.

Supervision: Surie, Gaglani, Ghamande, Gibbs, Hager, Gong, N. Johnson, Srinivasan, Bender, Mallow, Kwon, Exline, Vaughn, Talbot, Halasa, McMorrow, Martin, Self.

Conflict of Interest Disclosures: Dr Lauring reported receiving personal fees from Roche outside the submitted work. Dr Gaglani reported receiving grants from the Centers for Disease Control and Prevention (CDC), Abt Associates, and Westat; personal fees from the CDC; and serving as cochair for the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics, Infectious Diseases and Immunization Committee outside the submitted work. Dr Peltan reported receiving grants from Janssen Pharmaceuticals and Regeneron outside the submitted work. Dr Brown reported having a patent for an airway device with royalties paid from ReddyPort. Dr Ginde reported receiving grants from the National Institutes of Health (NIH), Department of Defense (DOD), Faron Pharmaceuticals, AbbVie, and Biomeme and personal fees from SeaStar outside the submitted work. Dr Gibbs reported receiving grants from NIH and grants from DOD outside the submitted work. Dr Hager reported receiving grants from NIH outside the submitted work. Dr Gong reported receiving grants from NIH and personal fess from Philips outside the submitted work. Dr N. Johnson reported receiving grants from NIH and serving on an advisory board for Neuroptics outside the submitted work. Dr Khan reported receiving grants from Dompe Pharmaceuticals, 4D Medical, Eli Lilly, and United Therapeutics outside the submitted work. Dr Hough reported receiving grants from NIH outside the submitted work. Dr Duggal reported receiving grants from NIH and personal fees from ALung Technologies outside the submitted work. Dr Wilson reported receiving grants from NIH outside the submitted work. Dr Chang reported receiving personal fees from PureTech Health outside the submitted work. Dr Mallow reported receiving personal fees from Medical Legal Consulting outside the submitted work. Dr Vaughn reported receiving grants from CDC outside the submitted work. Dr Ramesh reported receiving personal fees from Moderna, Pfizer, and AstraZeneca outside the submitted work. Dr Safdar reported receiving grants from CDC, National Heart, Lung, and Blood Institute (NHLBI), and Comprehensive Research Associates outside the submitted work. Dr Casey reported receiving personal fees from Fisher & Paykel outside the submitted work. Dr Rice reported receiving grants from NIH NHLBI and personal fees from Cumberland Pharmaceuticals and Sanofi outside the submitted work. Dr Halasa reported receiving grants from Sanofi, Quidel, and Merck outside the submitted work. Dr Chappell reported receiving grants from Merck and research support from CDC, NIH, and DOD outside the submitted work. Dr Grijalva reported receiving grants from NIH, CDC, Agency for Healthcare Research and Quality (AHRQ), and Food and Drug Administration and personal fees from Merck and Syneos Health outside the submitted work. Dr Martin reported receiving grants from Merck outside the submitted work. No other disclosures were reported.

Funding/Support: This work was funded by the CDC (contract No. 75D30122C12914 and 75D30122C14944; paid to Vanderbilt University Medical Center).

Role of the Funder/Sponsor: Investigators from CDC were involved in all aspects of the analysis, including the design and conduct of the activity, collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The CDC had the right to control decisions about publication via the CDC publication clearance process.

Group Information: The investigators and collaborators of the Investigating Respiratory Viruses in the Acutely Ill (IVY) Network are listed in eAppendix 1 in Supplement 1 .

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

Data Sharing Statement: See Supplement 4 .

Additional Contributions: We gratefully acknowledge all the participants and data contributors, including laboratories for generating the genetic sequence and metadata and sharing via the Global Initiative on Sharing All Influenza Data Initiative, on which some of these results are based.

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A Global Perspective on the Pharmaceutical Industry

• Leading in Healthcare Through Project Management
• Global Clinical Research: The Process from Start to Finish
• New Frontier in Patient Recruitment

• Study protocol
• Open access
• Published: 10 April 2024

A ustralasian M alignant PL eural E ffusion (AMPLE)-4 trial: study protocol for a multi-centre randomised trial of topical antibiotics prophylaxis for infections of indwelling pleural catheters

• Estee P. M. Lau   ORCID: orcid.org/0000-0003-0972-1210 1 , 2 ,
• Matthew Ing 1 , 3 , 4 ,
• Sona Vekaria 4 , 5 ,
• Ai Ling Tan 1 ,
• Chloe Charlesworth 4 ,
• Edward Fysh 3 , 6 , 7 ,
• Ranjan Shrestha 8 ,
• Elaine L. C. Yap 9 ,
• Nicola A. Smith 10 ,
• Benjamin C. H. Kwan 11 , 12 ,
• Tajalli Saghaie 13 , 14 ,
• Bapti Roy 15 ,
• John Goddard 16 , 17 ,
• Sanjeevan Muruganandan 18 ,
• Arash Badiei 19 , 20 ,
• Phan Nguyen 19 , 20 ,
• Mohamed Faisal Abdul Hamid 21 ,
• Vineeth George 22 , 23 ,
• Deirdre Fitzgerald 24 ,
• Nick Maskell 25 ,
• David Feller-Kopman 26 ,
• Kevin Murray 27 ,
• Aron Chakera 28 , 3 &
• Y C Gary Lee 1 , 3 , 4  

Trials volume  25 , Article number:  249 ( 2024 ) Cite this article

Metrics details

Malignant pleural effusion (MPE) is a debilitating condition as it commonly causes disabling breathlessness and impairs quality of life (QoL). Indwelling pleural catheter (IPC) offers an effective alternative for the management of MPE. However, IPC-related infections remain a significant concern and there are currently no long-term strategies for their prevention. The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a multicentre randomised trial that evaluates the use of topical mupirocin prophylaxis ( vs no mupirocin) to reduce catheter-related infections in patients with MPE treated with an IPC.

A pragmatic, multi-centre, open-labelled, randomised trial. Eligible patients with MPE and an IPC will be randomised 1:1 to either regular topical mupirocin prophylaxis or no mupirocin (standard care). For the interventional arm, topical mupirocin will be applied around the IPC exit-site after each drainage, at least twice weekly. Weekly follow-up via phone calls or in person will be conducted for up to 6 months. The primary outcome is the percentage of patients who develop an IPC-related (pleural, skin, or tract) infection between the time of catheter insertion and end of follow-up period. Secondary outcomes include analyses of infection (types and episodes), hospitalisation days, health economics, adverse events, and survival. Subject to interim analyses, the trial will recruit up to 418 participants.

Results from this trial will determine the efficacy of mupirocin prophylaxis in patients who require IPC for MPE. It will provide data on infection rates, microbiology, and potentially infection pathways associated with IPC-related infections.

Ethics and dissemination

Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000005920). Results will be published in peer-reviewed journals and presented at scientific conferences.

Trial registration

Australia New Zealand Clinical Trial Registry ACTRN12623000253606. Registered on 9 March 2023.

Peer Review reports

Malignant pleural effusion (MPE) is a significant healthcare problem [ 1 ]. It is a common complication of advanced cancer, most frequently in lung and breast cancers [ 2 , 3 ], and its presence usually signifies incurable metastatic disease. The prognosis of patients with MPE is poor, with a median life expectancy ranging from 4 to 12 months [ 4 ], and the management of MPE remains palliative in nature. MPE causes disabling breathlessness that is debilitating and is associated with poor quality of life (QoL). Therefore, the primary goal of therapy is to provide effective control of symptoms with minimal interventions.

Indwelling pleural catheter (IPC) is an ambulatory drainage device for MPE patients that permits fluid evacuation at home, avoiding hospital visits. Multiple randomised studies have proven that IPC is significantly superior to conventional talc slurry pleurodesis for the management of MPE in reducing the need for further invasive pleural interventions and hospitalisation days while providing equivalent benefits in relieving breathlessness and QoL [ 5 , 6 , 7 ]. IPC is now established as one of the first-line management options for MPE in recent guidelines [ 8 , 9 ].

Despite the advantages of IPC, there exists a 10–20% associated complication rate [ 10 ], with IPC-related infection being clinicians’ biggest hesitation in adopting IPC use. IPC-related infections usually develop after 6 weeks post-insertion [ 11 ] and include infections of the pleural cavity/fluid, catheter tract (i.e. tunnel infections), and skin at the exit-site (i.e. cellulitis). The incidences of IPC-related infections varied among studies and was reported to be as high as 25% [ 7 ]. The largest multi-centre study and a recent review of IPC-related pleural infections found Staphylococcus aureus as the most common causative organism [ 12 , 13 ].

IPCs share many similarities with peritoneal dialysis (PD) catheters which are also frequently complicated by peritonitis and exit-site infections (ESIs). The use of topical antibiotics (especially mupirocin) to reduce PD-related infections have been a subject of several recent studies. Mupirocin is a topical antibiotic with excellent activity against gram-positive organisms and is an attractive prophylactic option for S. aureus -related infections [ 14 ].

Several studies demonstrated significant reduction in peritonitis and ESIs attributed to S. aureus or Gram-positive organisms when mupirocin was applied around the catheter exit site [ 15 , 16 , 17 , 18 , 19 ]. A meta-analysis [ 20 ] also found that mupirocin prophylaxis reduced the rate of S. aureus peritonitis and ESIs by 66% and 62% respectively. In a prospective controlled study [ 21 ], mupirocin reduced the overall incidence of peritonitis by 61% and ESI by 55%. Specifically, S. aureus peritonitis was cut by 100% and ESI by 65%. The International Society for Peritoneal Dialysis (ISPD) guidelines now recommend a daily application of topical mupirocin around the catheter exit-site as prophylaxis for peritoneal dialysis patients [ 22 , 23 ].

To date, no long-term preventative approaches exist for IPC-related infections, which are significant events to cancer patients and delay oncologic treatments. Management of infection requires hospitalisations with associated costs. Having a prophylactic antibiotic to reduce/prevent infection is an attractive option, but whether the use of mupirocin prophylaxis can be extrapolated to IPC infections is unknown. Patients undergoing PD and those with MPE differ in underlying comorbidities and frequencies of fluid exchanges/drainages and are exposed to different sources of infection. Results of mupirocin use in PD cannot be directly extrapolated to MPE patients with an IPC without a randomised clinical trial. Our pilot study [ 24 ] established the safety and feasibility of mupirocin prophylaxis in patients with malignant effusions, and the AMPLE-4 trial represents the next step to investigate the efficacy.

Study design

The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a pragmatic, multi-centre, open-labelled, 1:1 randomised study to evaluate the use of regular prophylactic topical mupirocin ( vs no mupirocin) to reduce catheter-related infections in patients fitted with an IPC for MPE.

Study setting

This trial will be conducted at tertiary centres across Australia, New Zealand, and Asia, and new enrolling sites will be updated regularly on the trial registration website (URL: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12623000253606 ). This trial will include 418 patients with MPEs, who require an IPC randomised 1:1 to either topical mupirocin or no topical mupirocin (standard care) (Fig.  1 ).

Study flow chart. ECOG, Eastern Cooperative Oncology Group; IPC, indwelling pleural catheter; MPE, malignant pleural effusion

Participant screening, selection, and recruitment

The site principal investigator or designated site research staff will screen patients with symptomatic MPE for when an IPC is planned for treatment. Potential participants will be approached about the study and be provided with the participant information and consent form to read and to ask questions to the study team. They will also be given time to discuss the study with family and carers and their general practitioner, if needed. Eligible participants will be offered trial entry and will be enrolled after providing informed consent. The site principal investigator will be aware of their dual role as the patients’ primary physician and as a clinical researcher and where this patient dependency can be a potential conflict. Enrolment and screening logs will be maintained.

Inclusion criteria

Patients who require insertion of an IPC for control of MPE can be considered for inclusion. MPE is defined if cancer cells are identified in the pleural fluid or pleural biopsy or is a large exudative effusion without other causes in a patient with advanced disseminated malignancy.

Exclusion criteria

Exclusion criteria includes age < 18 years, allergy to mupirocin, ipsilateral pleural infection within past 3 months, and inability to consent or comply with the protocol.

Topical mupirocin arm

For those assigned to the topical mupirocin (interventional) arm, topical mupirocin 2% (cream or ointment) will be applied around the exit-site of the IPC for an area approximately 3 cm in diameter. An information sheet with a picture of how to apply mupirocin will be provided to patients/carers. The antibiotic should be applied within 48 h of IPC insertion and thereafter following each drainage but at least twice weekly (with dressing change) until IPC is removed or the end of this study.

No topical mupirocin (standard care) arm

Patients assigned to the standard care arm will be managed in the conventional manner with the usual education and care of the IPC and without topical mupirocin prophylaxis.

Clinical care

Participants in both arms will be managed by their own clinical teams and receive all other medical treatments (including chemotherapy and radiotherapy) as deemed clinically appropriate. Patients’ medical care, including IPC care and oncology management, will be directed by their attending physicians, as per standard practice in the treatment hospital, regardless of study group allocation. This includes the frequency of drainage, drainage device (suction bottle or drainage bag), and administration of talc pleurodesis via IPC. All patients will receive standard education on IPC aftercare, have access to support services (e.g. direct phone line), and receive usual care from their attending physicians. Decision of IPC removal is made by the physicians in-charge.

Monitoring and follow-up

Potential participants, as part of the informed consent process, will have the study procedures and follow-up plan discussed in detail.

All patients (or their carers/nurses) will be contacted by phone every week to assess for clinical outcomes, compliance, or adverse events until death or end of 6-month follow-up period (Table  1 ). Frequency of the phone review will decrease to monthly once the IPC is removed. If the patient is attending hospital visits for other reasons, then the telephone review may be replaced by face-to-face assessment.

Where participants do not answer follow-up calls/attend planned study visits, the research staff will contact them again or book an additional visit if required. If the patient is an inpatient, the visit will be carried out in the hospital, if appropriate.

Data on primary and secondary endpoints will be captured weekly (monthly if IPC is removed) from catheter insertion until death or end of 6-month follow-up period. Outcomes will be reported as mean or median, as appropriate.

Primary endpoint

The primary outcome is the percentage of patients who developed an IPC-related infection from catheter insertion until death or end of 6-month follow-up period. IPC-related infection can be any one of the following:

Pleural infection: presence of pus and/or bacteria (by Gram stain or culture) in pleural fluid plus a clinical picture compatible with infection (e.g. fever, leucocytosis, raised inflammatory markers).

Catheter tract infection: signs of inflammation along the tract usually with swelling and significant tenderness plus a clinical presentation compatible with infection.

Cellulitis at exit-site: signs of inflammation clinically warranting systemic antibiotic treatment as determined by the attending physician.

Secondary endpoints

Infection will be analysed:

As the total number of episodes for all patients in each group;

As percentage of patients and as total number of episodes—each adjusted for number of days IPC is in situ for each patient;

As each of the individual types of infection;

Time to first episode of infection; and

For organism(s) causing infection (e.g. S. aureus  vs  others)

Hospital days will be analysed:

As total days in hospital (for any reasons)

As days related to IPC-related infections, similar to methods used in prior AMPLE trials [6, 25]. All records of hospitalisation will be reviewed by an independent investigator.

Adverse and serious adverse events will be recorded as in previous AMPLE trials [6, 25]. Definitions for adverse and serious adverse events are listed under adverse events section in the protocol.

Resources used associated with antibiotics use and IPC-related infections will be obtained from discharge letters and hospital in-patient enquiry coding. In-/out-patient management of any related complications will be captured from hospital records or self-reports from patients and will include treatments, imaging, and other interventions related to the adverse events. An experienced health economist will oversee this study aspect.

Survival will be measured from randomisation to death or end of study follow-up.

Sample size

This study will enrol 418 patients to detect a difference in IPC-related infection rate between the treatment arms. The difference that we wish to detect is 10% in the topical mupirocin prophylaxis arm (i.e. a relative reduction in infection rates of 50%) vs 20% in the no topical mupirocin prophylaxis (standard care) arm (based on previous studies) [ 7 , 15 , 16 , 17 , 18 , 25 ]. Previous randomised clinical trials (RCTs) reported a pleural infection rate of ~ 10% [ 7 , 25 ]. Incidences of tract infection and cellulitis (combined) are often similar to the pleural infection rates in published papers. Hence, we estimated a 20% incidence for overall IPC-related infections. In the RCTs investigating mupirocin prophylaxis in PD patients, a two-third reduction in infection rates ( vs control arms) were commonly reported [ 15 , 16 , 17 ]. To be conservative, we therefore estimated an incidence of 10% in our treatment arm. The sample size calculation was carried out using an anticipated chi square test to compare these proportions, assuming a 5% significance level and a power of 80%. To achieve this, we would need 199 patients per group (with an additional 5% to allow for dropouts based on previous AMPLE trial [ 6 ]), giving a total of 418 patients.

Randomisation

Participants will be randomised 1:1 to either topical mupirocin or no topical mupirocin (standard care). Randomisation will include minimisation for (i) cancer type (mesothelioma vs non-mesothelioma), (ii) known presence of trapped lung ( vs not), (iii) ECOG performance status (≤ 2 vs  ≥ 3), and (iv) current immunosuppression (or chemotherapy) vs not. The Griffith Randomisation Service by the Griffith University, Queensland, Australia, provides the randomisation setup via their automated web portal. The site principal investigator or designated site research staff screening patients will be able to generate the allocation sequence using the automated centralised randomisation system, enrol participants, and assign participants to interventions based on the randomisation.

Data management and safety

All procedures for the handling and analysis of data will be conducted using GCP ICH guidelines and the National Statement on Ethical Conduct in Human Research (2007) – Updated 2018 and in accordance with local policies and procedures.

Patient privacy and confidentiality will be maintained, as any information that identifies participants will be available only at the enrolment study site and only to designated study investigators, all of whom will either have signed a confidentiality agreement or be employees of the hospital.

Data collected will be stored in line with the Australian Code for the Responsible Conduct of Research for clinical trials and local policy guidelines for research data archiving. Access to the final trial dataset will only be available to the research team at the lead site.

Audits, if any, are usually carried out by an independent compliance monitoring officer.

Statistical plan

Data will be analysed on an intention-to-treat basis and per protocol basis. All participants, excluding those who withdrew prior to the randomisation intervention, will be included in the intention-to-treat analyses and analysed according to their randomised assignment. Per-protocol analyses will be performed in participants who have had at least one week of mupirocin application vs those who did not have any. Sensitivity analysis, e.g. with multiple imputation, will be carried out whenever appropriate, to account for missing data. The primary outcome will be analysed using chi-square test and subsequent logistic regression analyses allowing adjustments for minimisation variables. A secondary analysis of the primary outcome will utilise the time to event data, where cumulative incidence plots will be presented, and the log-rank statistic used to compare the treatment groups. In addition, Cox regression models will be used to calculate cause specific hazard ratios adjusted for minimisation variables. A competing risk analysis will also be performed to account for the competing risk of death in estimation of event rates. For binary or continuous secondary outcomes, inter-group differences will be examined using chi-square tests or two sample t -tests respectively, with additional logistic and linear regression analyses adjusting for minimisation variables. Adverse and serious adverse events will be reported in descriptive figures. Data analysts will be masked to the assigned groups, where appropriate.

An interim analysis is planned after 100 patients have been enrolled and completed follow-up. The purpose is to (i) assess the rate of recruitment and determine the feasibility of fulfilling the enrolment target and (ii) futility—observe the actual incidence of event rates in the control group to ensure the study is adequately powered to detect a clinically meaningful difference. We would determine if the conditional power based on the trend observed at the interim analysis decreases to less than 0.2. The need for further interim analysis will be assessed accordingly, and any decision to terminate the trial will be made by the trial steering committee.

The trial has been approved (as of 20 December 2023) by the following committees:

Sir Charles Gairdner Osborne Park Healthcare Group Human Research Ethics Committee (HREC) for Australian public hospitals, Australia

St John of God Health Care Ethics Committee for Midland Hospital, Western Australia

Universiti Kebangsaan Malaysia Research Ethics Committee for University Kebangsaan Malaysia Medical Centre, Malaysia

Northern B Health and Disability Ethics Committee for hospitals in New Zealand

Macquarie University Human Research Ethics Committee, Medical Sciences, Australia

Study investigators will ensure that any amendments to the protocol is approved by the ethics committee and signed by any patients subsequently entering into the trial and those currently in the study, if affected by the amendment.

Trial monitoring and oversight

The trial steering committee (TSC) will be responsible for the supervision of the trial in all its aspects. It will be responsible for ensuring the completion of the trial to clinical and ethical standards. Members of the TSC include an independent chairperson, independent member(s), chief investigator and selected investigators, a consumer representative, and the trial coordinator(s). The TSC will monitor site recruitment and review any recommendations received from the data and safety monitoring board (DSMB). The DSMB ensures the safety of study participants through monitoring of ethical conduct of the study and study procedures, reviewing adverse events, and considering new data (recently published studies) that may determine the validity of study continuation. The DSMB includes an independent chairperson and other independent members, one of whom is a statistician.

Sponsorship

The study is sponsored by the Institute for Respiratory Health, a not-for-profit organisation. Contact details: Mr Bi Lam, Finance Manager, Level 2, 6 Verdun Street, Nedlands WA 6009.

t|+ 61 8 6151 0877 e| [email protected].

Adverse events

All adverse events relating to the study, serious and non-serious, will be fully documented according to the ‘Adverse Event Reporting’ Section of the Investigator Site File. An adverse event is defined as any untoward medical occurrence, including an exacerbation of a pre-existing condition in a patient in a clinical investigation who received an experimental procedure. The event does not necessarily have to have a causal relationship with this treatment. A serious adverse event is defined as any adverse event/adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, and results in persistent or significant disability of incapacity.

All adverse events relating to and occurring during the course of the clinical study (i.e. from signing the informed consent until death or the end of the study follow-up period, whichever comes first) will be collected, documented, and reported to the DSMB. Events will also be reported if a causal link (relatedness) between the adverse event and the study is suspected but not confirmed.

Plans for dissemination

Results from this study will be published in peer-reviewed journals and presented at national and international conferences. Authorship eligibility guidelines will be discussed during the TSC meetings.

This is the first randomised trial to investigate a long-term preventative strategy for IPC-related infections. It is designed to be pragmatic, with few exclusion criteria to ensure that the results are generalisable. Whether the benefits of topical mupirocin prophylaxis in the context of peritoneal dialysis can be extrapolated to IPC for MPE patients requires robust examination. The presence of a control group in AMPLE-4 will provide insight into the potential efficacy of mupirocin prophylaxis in reducing IPC-related infections in patients with MPE.

The primary outcome of AMPLE-4, which includes all three types of IPC-related infections (pleural, tract and skin), will provide a more comprehensive understanding of the actual IPC-related infection rate, as existing literature mainly focussed on reporting IPC-related pleural infections, with catheter tract infections and cellulitis being less well documented. Furthermore, the findings from this study will enhance our understanding of the microbiology and potentially infection pathways associated with IPC-related infections, bridging knowledge gaps which are crucial for advancing the field.

Trial status

Protocol version: Version 2.00/16.10.23.

Date recruitment began: 21.07.23.

Estimated recruitment completion date: end of March 2026.

Availability of data and materials

Investigators at the lead site will have access to the final trial dataset. Supporting data including standard operating procedures, details of data management procedures, case report forms, and datasets generated and/or analysed during the current study will be available to the scientific community with as few restrictions as possible, while retaining exclusive use until publication of major outcomes. Data requests from qualified researchers should be made to YCGL ([email protected]).

Abbreviations

Exit-site infection

Data and safety monitoring board

Indwelling pleural catheter

International Society for Peritoneal Dialysis

Malignant pleural effusion

Peritoneal dialysis

Quality of life

Trial steering committee

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Acknowledgements

The design of this trial incorporated input and feedback from the Pleural Consumer Reference Group.

This study has received funding from the Cancer Council of Western Australia. YCGL is a leadership fellow of the National Health & Medical Research Council, Australia.

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Authors and affiliations.

Pleural Medicine Unit, Institute for Respiratory Health, Perth, Australia

Estee P. M. Lau, Matthew Ing, Ai Ling Tan & Y C Gary Lee

School of Medical and Health Sciences, Edith Cowan University, Perth, Australia

Estee P. M. Lau

Medical School, Faculty of Health & Medical Sciences, University of Western Australia, Perth, Australia

Matthew Ing, Edward Fysh, Aron Chakera & Y C Gary Lee

Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia

Matthew Ing, Sona Vekaria, Chloe Charlesworth & Y C Gary Lee

Department of Pharmacy, Sir Charles Gairdner Hospital, Perth, Australia

Sona Vekaria

Department of Respiratory Medicine, St John of God Hospital Midland, Perth, Australia

Edward Fysh

Curtin University Medical School, Perth, Australia

Department of Respiratory Medicine, Fiona Stanley Hospital, Perth, Australia

Ranjan Shrestha

Department of Respiratory Medicine, Middlemore Hospital, Auckland, New Zealand

Elaine L. C. Yap

Department of Respiratory Medicine, Wellington Regional Hospital, Wellington, New Zealand

Nicola A. Smith

Department of Respiratory and Sleep Medicine, The Sutherland Hospital, Sydney, Australia

Benjamin C. H. Kwan

University of New South Wales, Sydney, Australia

Department of Respiratory Medicine, Concord Repatriation General Hospital, Concord, NSW, Australia

Tajalli Saghaie

Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia

Department of Respiratory and Sleep Medicine, Westmead Hospital, Sydney, Australia

Department of Respiratory Medicine, Sunshine Coast University Hospital, Birtinya, QLD, Australia

John Goddard

Griffith University, Brisbane, QLD, Australia

Department of Respiratory Medicine, Northern Health, Epping, VIC, Australia

Sanjeevan Muruganandan

Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia

Arash Badiei & Phan Nguyen

Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia

Respiratory Unit, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

Mohamed Faisal Abdul Hamid

Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, NSW, Australia

Vineeth George

Hunter Medical Research Institute, Newcastle, Australia

Department of Respiratory Medicine, Tallaght University Hospital, Dublin, Ireland

Deirdre Fitzgerald

Academic Respiratory Unit, Bristol Medical School, University of Bristol, Bristol, UK

Nick Maskell

Department of Medicine, Section of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

David Feller-Kopman

School of Population and Global Health, University of Western Australia, Perth, Australia

Kevin Murray

Renal Unit, Sir Charles Gairdner Hospital, Perth, Australia

Aron Chakera

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Contributions

Conceptualisation: EPML, YCGL; funding acquisition: EPML, YCGL; methodology: EPML, YCGL, AC; project administration: ALT, MI, SV; data collection/enrolment: EPML, MI, ALT, CC, EF, RS, ELCY, NAS, BCHK, TS, BR, JG, SM, AB, PN, MFAH, VG, DF, NM, DFK, KM, AC, YCGL; data curation: ALT, MI; formal analysis: KM, YCGL; resources: YCGL; supervision: YCGL; protocol preparation (original draft): EPML, YCGL; all authors reviewed and approved final submission.

Corresponding author

Correspondence to Y C Gary Lee .

Ethics declarations

Ethics approval and consent to participate.

The trial has been approved by the relevant ethics committee for Sir Charles Gairdner Hospital, St John of God Midland, Sunshine Coast University, Fiona Stanley, John Hunter, Macquarie University, Northern Health, Royal Adelaide, St Vincent and Westmead Hospitals in Australia, University Kebangsaan Medical Centre in Malaysia, and Middlemore and Wellington Regional Hospitals in New Zealand. All participants will sign a consent form prior to enrolment in the study, including consent for publication of the anonymised data.

Consent for publication

All participants will sign a consent form prior to enrolment in the study, including consent for publication of the anonymised data. A copy of the consent form is available on request.

Competing interests

YCGL is an honorary consultant to Lung Therapeutics Ltd.

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Lau, E.P.M., Ing, M., Vekaria, S. et al. A ustralasian M alignant PL eural E ffusion (AMPLE)-4 trial: study protocol for a multi-centre randomised trial of topical antibiotics prophylaxis for infections of indwelling pleural catheters. Trials 25 , 249 (2024). https://doi.org/10.1186/s13063-024-08065-1

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Received : 20 December 2023

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DOI : https://doi.org/10.1186/s13063-024-08065-1

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• Mupirocin; Prophylaxis
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Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes

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• Published: 11 April 2024
• Volume 150 , article number  189 , ( 2024 )

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• Jie Tian 1   na1 ,
• Yong-Ping Song 2   na1 ,
• Gao-Chong Zhang 3   na1 ,
• Shu-Fang Wang 3 ,
• Xiao-Xiang Chu 3 ,
• Ye Chai 4 ,
• Chun-Ling Wang 5 ,
• Ai-Li He 6 ,
• Feng Zhang 7 ,
• Xu-Liang Shen 8 ,
• Wei-Hua Zhang 9 ,
• Lin-Hua Yang 10 ,
• Da-Nian Nie 11 ,
• Dong-Mei Wang 12 ,
• Huan-Ling Zhu 13 ,
• Da Gao 14 ,
• Shi-Feng Lou 15 ,
• Ze-Ping Zhou 16 ,
• Guo-Hong Su 17 ,
• Yan Li 18 ,
• Jin-Ying Lin 19 ,
• Qing-Zhi Shi 20 ,
• Gui-Fang Ouyang 21 ,
• Hong-Mei Jing 22 ,
• Sai-Juan Chen 1 ,
• Jian Li 1 &
• Jian-Qing Mi 1  

The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar–indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML).

In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR 4 ), molecular response 4.5 (MR 4.5 ), progression-free survival (PFS), overall survival (OS), and adverse events.

The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR 4 rates were similar in both arms. However, the 12-month cumulative rates of MR 4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively ( p  = 0.043). In core treatment since the 2-year analysis, the frequency of MR 4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm ( p  = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups.

The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

Avoid common mistakes on your manuscript.

Introduction

Chronic myeloid leukemia (CML) is characterized by the BCR::ABL1 oncoprotein, which produces a constitutively active tyrosine kinase that leads to pathogenesis (Heisterkamp et al. 1983 ). Tyrosine kinase inhibitors (TKIs) can inhibit the activity of the BCR::ABL1 fusion protein to trigger cell apoptosis. They have shown high rates of molecular responses and improved prognoses in patients with chronic phase (CP) of chronic myeloid leukemia (CML) (Hochhaus et al. 2020 ). The major molecular response (MMR) is recognized as the main optimal milestone of CML treatment (Deininger et al. 2020 ; Hochhaus et al. 2020 ). Nevertheless, a deep molecular response (DMR, molecular response 4 or better), particularly molecular response 4.5 (MR 4.5 ) or more, has been recently regarded as the gateway to treatment discontinuation and treatment-free remission (TFR) for patients with CP-CML, resulting in a low risk of progression (Deininger et al. 2020 ; Cortes et al. 2021 ). However, the rate of MR 4.5 is only 1–11% with TKIs in 1 year and 8–25% in 2 years (Hehlmann et al. 2014 ; Cortes et al. 2016 , 2018 ; Hochhaus et al. 2016a , b ; Hochhaus et al. 2016a , b ). Therefore, it is crucial to identify other methods to increase the proportion of deeper molecular responses.

Intravenous arsenic trioxide and oral tetra-arsenic tetrasulfide (As 4 S 4 ) have proven to be highly effective and safe and are used as a standard treatment for acute promyelocytic leukemia (APL) (Lu et al. 2002 ; Zhu et al. 2018 ). Based on in vitro data in the K562 cell line and CML primary cells from patients, arsenic can directly induce cell apoptosis and degrade BCR::ABL1 rather than inhibiting BCR::ABL1 activity as would a TKI (Li et al. 2002 ; Yin et al. 2004 ; Mao et al. 2010 ). Subsequently, additional results were observed in a mouse model of BCR::ABL -positive CML, where arsenic acted on BCR::ABL by directly binding the RING finger domain of c-CBL to inhibit its self-ubiquitination/degradation, while imatinib inhibits the PI3K/AKT/mTOR pathway (Zhang et al. 2009 ; Mao et al. 2010 ; Liu et al. 2014 ). The synergistic effect of the two drugs at the molecular level might be a promising approach to improving response rates in CML patients.

In addition, the realgar–indigo naturalis formula (RIF), an oral arsenic agent (As 4 S 4 )-containing formula, is convenient for managing medication and not inferior to intravenous arsenic trioxide (Zhu et al. 2018 ).

Based on these findings, this study aimed to determine if RIF plus imatinib led to a higher and deeper confirmed molecular response compared to imatinib monotherapy. This randomized controlled trial of arsenic combined with imatinib in CML treatment is the first of its kind and could potentially contribute to achieving higher TFR in CP .

Patient recruitment

Eligible patients for the trial were aged between 18 and 75 years and diagnosed with CP Ph-positive CML within 12 months prior to study entry. CP-CML was defined as the presence of less than 15% blasts, less than 20% basophils, and less than 30% blasts plus promyelocytes in peripheral blood and bone marrow, as well as a platelet count of less than 100 × 10 9 cells/L unrelated to therapy (Cortes et al. 2021 ). The participants did not harbor any extramedullary disease except for hepatosplenomegaly. Previous treatment for CML was excluded, with the exception of hydroxyurea and anagrelide. Further details on the inclusion and exclusion criteria are available in Online Resource 1. All participants provided written informed consent with documents approved by the institutional review board of each participating center, and the study was conducted following the Declaration of Helsinki.

Trial design and randomization

This was a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial, conducted in an outpatient setting. Participants who met the eligibility criteria were randomly assigned in a 1:1 ratio, using an interactive voice response system, to receive either RIF (provided by Yifan Pharmaceutical Co., Ltd.) in the combination with imatinib (Hansoh Pharma Co., Ltd.) or placebo (Yifan Pharmaceutical Co., Ltd.) plus imatinib. Stratified block randomization was applied according to the Sokal risk score (Sokal et al. 1984 ) at the time of diagnosis. The participants and study staff were blinded to the treatments in this double-blind trial.

Following randomization, all participants received imatinib daily. Participants assigned to the combination group received RIF, and those in the imatinib group received a placebo (RIF simulant) for 14 consecutive days every month. The total treatment duration was 12 months (a month defined as 28 days). After 12 months, all the participants received imatinib daily. The RIF (270 mg per tablet) contained realgar (As 4 S 4 , 30 mg per tablet), indigo naturalis (125 mg per tablet), Radix salviae miltiorrhizae (50 mg per tablet), Radix pseudostellariae (45 mg per tablet), and a collagen capsule (20 mg per tablet). Details of the treatment procedures, dose modifications, and laboratory assessments are provided in Online Resource 1.

Evaluation of efficacy

The primary endpoint was to compare the significant molecular response (MMR) (Hochhaus et al. 2020 ) rate at 6 months. MMR was defined as BCR::ABL1 IS transcript level of 0.1% or lower.

Secondary endpoints included MMR rates at 3, 9, and 12 months; molecular response 4 (MR 4 ) and MR 4.5 rates at 3, 6, 9, and 12 months; times to MMR, MR 4 , and MR 4.5 ; progression-free survival (PFS); and overall survival (OS). MR 4 and MR 4.5 were defined as BCR::ABL1 IS transcript levels ≤ 0.01% or ≤ 0.0032%, respectively (Cortes et al. 2021 ). Treatment failure was defined as no complete hematologic response and/or Ph +  > 95% at 3 months, BCR::ABL1  > 10% and/or Ph +  > 35% at 6 months, BCR::ABL1  > 1% and/or Ph +  > 0 at 12 months, and loss of complete hematologic remission, loss of complete cytogenetic response, loss of MMR, or clonal chromosomal abnormalities in Ph + cells at any time (Baccarani et al. 2013 ). PFS was defined as progression to the accelerated phase (AP), blastic phase (BP), or CML-related death at any time since randomization. OS was defined as the time from randomization to death caused by any cause at any time, including during follow-up and after discontinuation of the study treatment. Trial visits were conducted at screening, baseline, and 3, 6, 9, 12, 18, 24, 48, and 60 months.

Safety analysis

The safety analyses included all patients who received at least one dose of any study medication. The participants were analyzed according to the dose of any study drug administered at the start of treatment. Adverse events (AEs) were graded according to the Common Terminology Criteria for AEs (version 4.03) of the National Cancer Institute ( https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf ).

Statistical analysis

This study was designed to test the primary hypothesis that RIF plus imatinib for newly diagnosed CP-CML was superior to imatinib alone, with an estimation of increment by 12% of absolute improvement in MMR at 6 months , i.e., an estimated increase from 18% (imatinib) to 30% (combination treatment). The estimate of 18% of patients achieving an MMR at 6 months with imatinib was based on a previously reported, randomized, first-line study ( Cortes et al. 2018 ). The original sample size had been computed with a type 1 error rate of 0.05 and 80% power. We calculated that after adjusting for 20% dropout, the total planned sample size was 496 participants. However, only 191 participants were finally enrolled due to the COVID-19 pandemic in 2020.

All the efficacy analyses were performed based on the intention-to-treat (ITT) principle. In addition, a per-protocol (PP) analysis was conducted. Response rates were tested at a significance level of 0.05 using the chi-square test or Fisher’s exact test. Cumulative response rates, PFS, and OS were estimated using the Kaplan–Meier method, and groups were compared using the log-rank test. All reported P values were two-sided. Nominal two-sided P values were provided for descriptive purposes only, without multiplicity adjustment.

Safety was analyzed for all participants who received at least one dose of the assigned treatment. Data were analyzed using the SPSS software (version 25). The study was registered at www.chinadrugtrials.org.cn (number, CTR20170221).

Participants

From May 2017 to May 2020, 219 newly diagnosed CP-CML cases were assessed for eligibility at 21 study centers in China (Fig.  1 ). Of these, 191 underwent randomization and were included in the ITT population. The combination group (RIF plus imatinib) consisted of 96 patients who were assigned to this treatment arm and 95 were assigned to the imatinib group (placebo plus imatinib) . The two groups were well balanced in terms of sex, age, and Sokal score. The key baseline and clinical characteristics are summarized in Table  1 . In May 2020, because of the pandemic, the sponsor initiated the closure of the trial recruitment. This recommendation was approved by an independent data monitoring committee. Therefore, the current analysis is based on data collected up to November 11, 2022.

CONSORT diagram for this trial after a minimum follow-up of 5 years (data cutoff 11 November 2022). During the 12-month randomized, double-blind, placebo-controlled trial, all the patients remained unaware of their trial-group assignments. An analysis of BCR::ABL1 transcript level was performed every 3 months. Of the 219 patients with chronic myeloid leukemia who underwent screening, 191 were enrolled, 129 completed the trial and 159 completed a 5-year follow-up

A total of 157 participants (82.2%) completed the 12-month double-blind intervention (Table  2 ). The median dose was 1620 mg per day (range, 810–1890 mg, including 90–210 mg realgar) for RIF in the combination arm and 400 mg/day (range, 300–400 mg/day) for imatinib in both treatment arms. The median duration of treatment was 12.0 months (range, 1.1–12.0 months) for combination therapy and 12.0 months (range, 1.5–12.0 months) for imatinib. After 5 years, as of the data cutoff, 83.3% of combination-treated patients and 83.2% of imatinib-treated participants were still on follow-up (Table  2 and Supplementary Table S2 ). The median follow-up times were 51 months (range, 0–65 months) and 50 months (range, 0–65 months) for the RIF arm and 51 months (range, 2–65 months) for the imatinib arm at the time of analysis. The percentage of participants who continued imatinib treatment after the study was similar between the RIF group (46.9%, n  = 45) and the imatinib group (46.3%, n  = 44). Thirty-five participants in both study arms received other anti-CML drugs (Supplementary Table S2 ).

Primary endpoint

The rates of an MMR at 6 months in the ITT population were 11.5% in the combination arm and 12.6% in the imatinib arm ( p  =  0.828). In the PP population, the rate was 14.3% in the combination arm and 17.3% in the imatinib arm ( p  = 0.768). No statistically significant differences existed between the groups.

Secondary endpoints

In the ITT analysis, the rates of MMR at 3, 6, 9, and 12 months were similar between the two groups (Fig. S1 a), as well as the rates of MR 4 and MR 4.5 at 3, 6, 9, and 12 months (Fig. S1 b and c). No significant difference between MR 4 or MR 4.5 at 3, 6, or 9 months among patients of trial groups was observed. However, from the 9th month onward, there was increasingly improved efficacy with combination treatment compared with imatinib treatment (Fig. S1 and Fig.  2 ). Moreover, by 12 months, MR 4 was achieved/maintained in 20.8% of participants receiving combination treatment and in 12.6% of participants receiving imatinib ( p  = 0.129). The cumulative rate of MR 4.5 by 12 months was 10.3% higher with combination treatment than imatinib monotherapy (20.8% vs. 10.5%, respectively, p  =  0.043) in ITT populations ( Fig.  3 ).

Cumulative molecular response rates. The results in the intention-to-treat population were calculated by means of the Cochran–Mantel–Haenszel test, stratified according to the Sokal risk group, after the last patient had completed 12 cycles of therapy (with a 28-day duration for each cycle). Cumulative proportion of patients with a major molecular response (MMR; BCR::ABL IS  ≤ 0.1%), b molecular response 4 (MR 4 ; BCR::ABL IS  ≤ 0.01%), and c molecular response 4.5 (MR 4.5 ; BCR::ABL IS  ≤ 0.0032%) by 3, 6, 9, and 12 months is shown. IS international scale

Cumulative response rates over time. The percentages of patients with a major molecular response (MMR; BCR::ABL IS  ≤ 0.1%), b molecular response 4 (MR 4 ; BCR::ABL IS  ≤ 0.01%), and c molecular response 4.5 (MR 4.5 ; BCR::ABL IS  ≤ 0.0032%) by 1, 2, 3, 4, and 5 years are shown. IS international scale

In the PP analysis, the data of MMR and MR 4 showed no significant differences between the two groups (Fig. S2 ). However, the cumulative rate of MR 4.5 at 12 months in the combination treatment group was higher than in imatinib monotherapy one (32.3% vs. 14.9%, p  = 0.020) (Fig. S3 ).

At the data cutoff after 5 years, 45 (46.9%) and 44 (46.3%) participants in the combination and imatinib arms, respectively, remained on core treatment (without change to other anti-CML drugs); 79 (82.3%) and 80 (84.2%) randomized participants remained in the study (either on treatment or follow-up after discontinuation of study treatment; Supplementary Table S2 ). The cumulative rates of participants (ITT population) with responses in the final analysis (5 years follow-up) in the combination and imatinib arms were 72.9% and 76.8% for MMR ( p  = 0.209), 61.5% and 61.1% for MR 4 ( p  = 0.568), and 61.5% and 58.9% for MR 4.5 ( p  = 0.554), respectively (Fig.  3 ). In the 2-year analysis of participants on core treatment, the frequency of MR 4.5 in the combination arm tended to be higher compared with the imatinib arm (55.6% vs. 38.6%, p  =  0.063) .

By 5 years, PFS was 93.7% in the combination arm and 95.8% in the imatinib arm ( p  = 0.546, Fig.  4 ). Progression of CML to AP/BP was similar at 12 months, occurring in one participant in each group. One in the combination arm occurred at five months after randomization, and the other in the imatinib arm occurred at two months. Based on the data cutoff, the number of patients with AP/BP was six (6.3%) in the combination arm and four (4.2%) in the imatinib arm.

Kaplan–Meier curves for a overall survival (OS) and b progression-free survival (PFS) in both treatment arms. OS and PFS were calculated using patients on study treatment and in follow-up after discontinuation of randomly assigned treatment

By 5 years, the OS rate was not statistically significantly different between study groups (92.3% for combination therapy and 94.6% for imatinib, p  =  0.588 , Fig.  4 ). Based on the data cutoff, the number of deaths was seven in the combination arm and five in the imatinib arm, and the number of CML-related deaths was four and two, respectively (Supplementary Table S2 ).

The achievement of MR 4.5 by 12 months was also investigated using the Sokal score (Supplementary Fig. S4 ). A significant difference between combination- and imatinib-treated participants with confirmed molecular assessment was observed for MR 4.5 in the intermediate-risk group ( p  = 0.035, Supplementary Fig. S4 ). Five-year outcomes according to Sokal risk scores were also similar (Supplementary Table S3 ).

The safety population comprised 191 participants who received at least one dose of the study drug. Both trial treatments were safe and consistent with the known safety AE profiles. The overall rates of drug-related AEs associated with both treatments were similar (combination therapy, 96.9%; imatinib, 91.6%), and grade 3 or grade 4 events were observed (combination therapy, 35.4%; imatinib, 40.0%). Grade 3 or grade 4 non-hematological AEs were uncommon in all patients (6.3% in each group; Table  3 ). Of the nonhematologic adverse drug reactions occurring in the treated participants, the combination therapy, when compared with imatinib, was associated with higher incidences of diarrhea (27.1% vs. 14.7%, p  =  0.036), vomiting (26.0% vs. 17.9%, p  =  0.004), and nausea (34.4% vs. 17.9%, p  =  0.006) with significant difference between trial groups. These were primarily grade 1 or grade 2 events.

Diarrhea was frequently reported in the first month of treatment, and the median time to onset was 18 days (range: 1–294 days) in the combination arm compared with 35 days (range: 2–172 days) in the imatinib arm. Vomiting occurred frequently in the first 3 months after starting treatment in both groups, and the median time to onset was 7 days (range, 1–240 days) with the combination treatment and 18 days (range, 1–301 days) with imatinib. The median time to nausea onset was 6 days (range, 0–480 days) in the combination group and 2 days (range, 0–67 days) in the imatinib group.

Conversely, rash occurred less frequently with combination treatment than with imatinib, as did pruritus, muscle ache, bleeding, and muscle cramps; only muscle cramps (p  =  0.003) were significantly different between the trial groups.

Many participants in both arms experienced multiple cytopenia events (combination arm, 74.0%; imatinib arm, 65.3%). Grade 3 or grade 4 neutropenia occurred in 24.0% of the patients in the combination arm and 17.9% of the patients in the imatinib arm. However, the incidences of grade 3 or grade 4 anemia and thrombocytopenia were similar between the treatment arms (Table  3 ). The median time to onset of grade 3 or grade 4 hematologic AEs was 79 days (range, 35–104 days) for the combination treatment and 45 days (range, 29–70 days) for imatinib, with median durations of 28 and 21 days, respectively.

The most frequent biochemical abnormalities are listed in Table  3 . Grade 3 or grade 4 biochemical laboratory abnormalities were observed in 4.2% of the participants receiving combination therapy and 5.3% of those receiving imatinib. The grades at any level were similar in both groups . In the combination arm, the incidence of elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was more than two times than that in the imatinib arm (combination arm, 33.3%, and 31.3%; imatinib arm, 12.6%, and 10.5%, respectively, p  =  0.006 for ALT and p  <  0.001 for AST) ; however, with regard to grade 3 or grade 4 elevation of ALT and AST levels, no participant was found in the combination group, and only one case was observed in the imatinib group. Additional data are presented in Tables S3 and S4 .

Drug-related cardiac AEs such as prolonged QT interval, sinus bradycardia, and auricular premature beat, most presenting as grade 1 or grade 2, were experienced by 12 participants receiving combination therapy and 10 participants receiving imatinib. QT prolongation occurred only in the imatinib group (n = 4, one participant with grade 3). Additional data are available in Tables S4 and S5 in the Supplementary Appendix.

The causes of treatment discontinuation were AE, disease progression to AP/BP, loss to follow-up, and others (Table  2 ), with AE being the most prevalent reason (46.7%, n  = 28). Discontinuation of treatment caused by AEs was 12.5% in the combination arm and 12.6% in the imatinib arm and most frequently occurred within 6 months of treatment (Table  2 ). Serious AEs were uncommon in both arms. Of those participants who experienced dose interruptions and/or reductions for gastrointestinal symptoms, the rate was 8.3% for combination treatment and 2.1% for imatinib monotherapy (p  =  0.053); for hepatic toxic effects, it was higher on treatment among participants treated with combination therapy versus imatinib monotherapy (10.4% vs. 3.2%, p  =  0.046) (Table  3 ). Dose interruptions and/or reductions in hematological abnormalities were common in both groups (combination arm, 24.0%; imatinib arm, 22.1%). Most AEs were controllable, and most participants who experienced dose interruptions and/or reductions took the trial medication again. No new safety signals were observed in either group during the 5-year follow-up, and no participant died because of adverse events. Overall, the combination therapy was well tolerated and side effects were controllable.

Arsenic is a standard treatment agent for APL and has a long history of use in CML. It was the standard treatment for CML before the emergence of chemotherapy in the late nineteenth century (Forkner and Scott 1931 , Zhu et al. 2018 ). Our study was based on several previous studies that had confirmed the synergistic effects of RIF and imatinib in CML cells and mice (Li et al. 2002 ; Yin et al. 2004 ; Zhang et al. 2009 ; Mao et al. 2010 ). While As 4 S 4 triggers BCR::ABL1 degradation, imatinib inhibits its tyrosine kinase activity. The combination of these two agents was found to be able to lower protein and enzymatic activity levels of BCR::ABL (Yin et al. 2004 ). Arsenic considerably could upregulate c-CBL, which serves as an E3 ligase for several receptor/protein tyrosine kinases, including BCR::ABL , and mediate the ubiquitination and degradation of BCR::ABL (Mao et al. 2010 ).

In this randomized phase 3 trial, we compared the arsenic-containing combination therapy, RIF plus imatinib, with the current standard first-line therapy, imatinib, as an initial trial for newly diagnosed CP-CML. The recruitment of this study was terminated earlier than the initial design because of the coronavirus COVID-19 pandemic. Of the planned enrollment of 488 participants, only 191 participants were recruited; 157 participants reached the 12-month time point for analysis of the molecular response, and 159 participants were still on follow-up at 5 years.

In this trial, the primary endpoint of MMR at six months of combination therapy was similar to imatinib monotherapy based on the ITT population. The MMR rate in the imatinib arm at 12 months was 35.8%, which is consistent with that in other randomized trials (22–36.9%) (Kantarjian et al. 2010 ; Saglio et al. 2010 ; Wang et al. 2015 ; Cortes et al. 2018 ). No significant differences were observed in MMR and MR 4 rates between the two groups at any time within 12 months. However, there was a trend toward higher rates of achieving these endpoints with combination therapy compared to imatinib alone. A significant improvement in MR 4.5 with combination therapy versus imatinib was identified at 12 months (p  =  0.043), although the efficacy analyses were limited by early termination of recruitment. Moreover, at 2 years since randomization, 16.9% more participants who received combination therapy achieved MR 4.5 than those who received imatinib alone (55.6% vs. 38.6%). In recent years, several studies have confirmed that the depth of a patient’s molecular response is positively associated with the probability of TFR success and is essential for determining whether TFR is achieved (Hochhaus et al. 2017b , Takahashi et al. 2018a , b ; Takahashi et al. 2018a , b ). However, the 5-year MMR, MR 4 , and MR 4.5 rates were similar in the treatment groups. This could be owing to the longer duration of the effect by imatinib required against CML-initiating cells or alternative treatment with the second-generation TKIs after discontinuing the study treatment .

Current therapeutic aims are directed at achieving sufficient DMR to reduce the risks of blast crisis transformation and increase the rates of TFR, which have been extensively investigated and are now part of the management of CML patients (Deininger et al. 2020 ; Stuckey et al. 2020 ; Cortes et al. 2021 ; Krishnan et al. 2022 ). Etienne et al. reported that 233 patients treated with front-line imatinib who achieved MR 4.5 had better event-free survival and failure-free survival than those with a complete cytogenetic response and MMR status (Etienne et al. 2014 ). More consensus has been reached that sustained MR 4.5 is an ideal objectif and is associated with higher TFR rates than sustained MR 4 (Etienne et al. 2014 ; Branford 2020 ; Deininger et al. 2020 ; Cortes et al. 2021 ). In those trials on the second-generation TKIs in patients with newly diagnosed CP-CML, the cumulative rates of MR 4.5 by 12 months with dasatinib (DASISION trial), bosutinib (BFORE trial), nilotinib 300 mg twice daily, and nilotinib 400 mg twice daily (ENESTnd trial) were 5%, 6.4%, 7%, and 11%, respectively, and after 5 years were 33%, 46%, 52%, and 54%, respectively (Cortes et al. 2016 , 2018 ; Hochhaus et al. 2016a , b ; Brümmendorf et al. 2022 ), which were superior to that with imatinib. Although comparisons between trials should be considered with caution, the MR 4.5 rate with RIF plus imatinib (20.8% by 12 months) may be potentially equal to or even higher than observed with the second-generation TKIs. Several TKI discontinuation trials with limited long-term follow-ups have been reported. TFR rates in imatinib discontinuation studies for patients with a sustained MR 4.5 or better were estimated as 47%–65% at 12 months and 33%–64% at 24 months (Rousselot et al. 2014 ; Lee et al. 2016 ; Etienne et al. 2017 ); in dasatinib, discontinuation studies were 48% at 12 months and 46% at 24 months (Shah et al. 2020 ), and in nilotinib, discontinuation studies were 51.6–58% at 12 months and 49–53% at 24 months (Hochhaus et al. 2017a , b ; Mahon et al. 2018 ; Ross et al. 2018 ). Therefore, TKIs combined with RIF may be an efficacy treatment strategy for patients with CP-CML who would be willing to attempt discontinuation.

PFS and OS rates remain high and comparable between the trial groups (more than 90%). These results are consistent with the long-term outcomes in patients with newly diagnosed CP-CML who received the second-generation TKIs nilotinib, dasatinib, and bosutinib (Cortes et al. 2016 ; Hochhaus et al. 2016a , b ; Brümmendorf et al. 2022 ). Patients with CML treated with TKI can expect a near-normal life expectancy (Cortes et al. 2021 ).

Safety data were consistent with the known AE profiles of RIF in newly diagnosed patients with APL and imatinib in newly diagnosed patients with CP-CML (Preudhomme et al. 2010 ; Zhu et al. 2018 , Chen, Zhu et al. 2021). Most AEs occurred primarily during the first six months of treatment and were generally controllable, which is consistent with other trials (Zhu et al. 2018 , Chen et al. 2021 ). No severe adverse effects were observed at a cumulative dose of 105,840 mg realgar in this study. The predominant AEs of the RIF plus imatinib regimen were diarrhea, vomiting, nausea, edema, upper respiratory infection, cytopenia, and liver function abnormalities; most participants tolerated the regimen well and did not need to adjust the drug dose in our trial. The incidence and duration of hematological AEs in the two groups were similar, implying that RIF did not significantly increase hematological toxicity. The incidence of hepatotoxicity in the combination group was similar to that reported in other studies involving arsenic agents (Zhu et al. 2018 , Chen et al. 2021 ), though all being grade 1 or grade 2 in our trial. It has been reported that a small prolongation of the QTc interval occurred in patients who received arsenic trioxide, however, to a lesser extent in patients who received RIF, which is consistent with previous reports (Lo-Coco et al. 2013 ; Zhu et al. 2018 ).

The combination therapy was more toxic than imatinib alone regarding gastrointestinal side effects, such as diarrhea ( p  = 0.036), vomiting ( p  = 0.004), nausea ( p  = 0.006), and liver function abnormalities, including ALT ( p  = 0.006) and AST ( p  < 0.001), which led to temporary interruptions and/or reductions in the combination group (most cases stopped both RIF and imatinib) (Table S6 ). The rates of MMR and MR 4 in the combination group were lower than the imatinib group in the early stages of our trial; however, a reversal emerged in response between the trial groups at 9 months when AEs decreased. Furthermore, the difference between combination therapy and imatinib increased subsequently over time, and at 12 months, the MR 4.5 rate showed a significant increase in the combination arm (p  =  0.043). In addition, the reasons for the more frequent occurrence of muscle cramps (p  =  0.003), rash (p  =  0.086), pruritus, muscle ache, and bleeding with imatinib alone might be due to dose interruptions and/or reductions and gastrointestinal symptoms affecting drug absorption at the early stage in the combination group. This also supports our speculation that the time of occurrence of hematological AEs in the combination group lagged behind that in the imatinib group. Therefore, an early molecular response might not reflect the efficacy of the two arms well.

Limitations

This study had several limitations. First, the significant limitation of our study was low enrollment due to recruitment termination during the COVID-19 pandemic in early 2020, which underpowered the result. Second, our trial found a higher rate of achieving MR 4.5 in participants who received RIF plus imatinib than those who received imatinib monotherapy. Thus, in future, we could plan to design a trial to further evaluate RIF plus TKI for this index. Third, the follow-up time is a little short for TFR, which is another limitation of our trial, and we will continue to follow these patients for a long time.

In summary, there was no statistically significant difference in MMR rates between combination and imatinib arms at 6 months. However, we found that the combination regimen may increase the rates of MR 4.5 which are a prerequisite for TFR, than imatinib alone in participants with de novo CP-CML. In addition, the safety profile of combination treatment was similar to that of imatinib. As enrollment in this trial was terminated early, the efficacy of RIF with imatinib in this setting remains to be established.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgement

This trial (China drug trial number, CTR20170221) was supported by the health industry scientific research project of the National Health Commission (Numbered 201202003) and sponsored by Yifan Pharmaceutical Co., Ltd.

This study was sponsored by Yifan Pharmaceutical Co., Ltd.

Author information

The authors Jie Tian, Yong-Ping Song and Gao-Chong Zhang have contributed equally to this work.

Authors and Affiliations

State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Jie Tian, Sai-Juan Chen, Jian Li & Jian-Qing Mi

The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China

Yong-Ping Song

Yifan Research & Development, Hefei, Anhui, China

Gao-Chong Zhang, Shu-Fang Wang & Xiao-Xiang Chu

Lanzhou University Second Hospital, Lanzhou, Gansu, China

The Affiliated Huaian No 1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu, China

Chun-Ling Wang

The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China

Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China

Xu-Liang Shen

The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China

Wei-Hua Zhang

The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China

Lin-Hua Yang

The Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China

Da-Nian Nie

Hengshui People’s Hospital, Hengshui, Hebei, China

Dong-Mei Wang

West China Hospital of Sichuan University, Chengdu, Sichuan, China

Huan-Ling Zhu

The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China

The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

Shi-Feng Lou

The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

Ze-Ping Zhou

Cangzhou Central Hospital, Cangzhou, Hebei, China

Guo-Hong Su

The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China

The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China

Jin-Ying Lin

The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

Qing-Zhi Shi

Ningbo First Hospital, Ningbo, Zhejiang, China

Gui-Fang Ouyang

Peking University Third Hospital, Beijing, China

Hong-Mei Jing

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Contributions

All authors were accountable for all aspects of the work and reviewed and approved the final version of the manuscript. J-QM, G-CZ, and S-JC conceived and designed the data. S-JC provided the administrative support. J-QM, Y-PS, YC, C-LW, A-LH, FZ, X-LS, W-HZ, L-HY, D-NN, D-MW, H-LZ, DG, S-FL, Z-PZ, G-HS, YL, J-YL, Q-ZS, G-FO, and H-MJ provided the study materials of patients. JT, X-XC, G-CZ, J-QM, Y-PS, YC, C-LW, A-LH, FZ, X-LS, W-HZ, L-HY, D-NN, D-MW, H-LZ, DG, S-FL, Z-PZ, G-HS, YL, J-YL, Q-ZS, G-FO, and H-MJ collected and assembled the data. JT and JL involved in data analysis and interpreted the manuscript. JT and J-QM wrote the manuscript. S-FW, JL, J-QM, and S-JC revised the report.

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Correspondence to Sai-Juan Chen , Jian Li or Jian-Qing Mi .

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Tian, J., Song, YP., Zhang, GC. et al. Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes. J Cancer Res Clin Oncol 150 , 189 (2024). https://doi.org/10.1007/s00432-024-05700-x

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Evidence‐based medicine—When observational studies are better than randomized controlled trials

Jizzo r. bosdriesz.

1 ERA‐EDTA Registry, Department of Medical Informatics, Amsterdam Public Health Research Institute, Amsterdam UMC‐location AMC, University of Amsterdam, Amsterdam The Netherlands

Vianda S. Stel

Merel van diepen.

2 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden The Netherlands

Yvette Meuleman

Friedo w. dekker, carmine zoccali.

3 CNR‐IFC, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Calabria Italy

Kitty J. Jager

In evidence‐based medicine, clinical research questions may be addressed by different study designs. This article describes when randomized controlled trials (RCT) are needed and when observational studies are more suitable. According to the Centre for Evidence‐Based Medicine, study designs can be divided into analytic and non‐analytic (descriptive) study designs. Analytic studies aim to quantify the association of an intervention (eg, treatment) or a naturally occurring exposure with an outcome. They can be subdivided into experimental (ie, RCT) and observational studies. The RCT is the best study design to evaluate the intended effect of an intervention, because the randomization procedure breaks the link between the allocation of the intervention and patient prognosis. If the randomization of the intervention or exposure is not possible, one needs to depend on observational analytic studies, but these studies usually suffer from bias and confounding. If the study focuses on unintended effects of interventions (ie, effects of an intervention that are not intended or foreseen), observational analytic studies are the most suitable study designs, provided that there is no link between the allocation of the intervention and the unintended effect. Furthermore, non‐analytic studies (ie, descriptive studies) also rely on observational study designs. In summary, RCTs and observational study designs are inherently different, and depending on the study aim, they each have their own strengths and weaknesses.

SUMMARY AT A GLANCE

In evidence‐based medicine, clinical research questions may be addressed by different study designs. In this article, we explain that randomized controlled trials and observational study designs are inherently different, and depending on the study aim, they each have their own strengths and weaknesses.

1. INTRODUCTION

A lead editorial in the British Medical Journal by Dave Sackett defined evidence‐based medicine (EBM) as “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.” 1 In EBM, clinical research questions may be addressed by different study designs, each with their own merits and limitations. In the traditional hierarchy of study designs, the randomized controlled trial (RCT) is placed on top, followed by cohort studies, case‐control studies, case reports and case series. 2 However, the foremost consideration for the choice of study design should be the research question. For some research questions, an RCT might be the most suitable design, whereas for other research questions observational study designs are to be preferred.

According to the Centre for Evidence‐Based Medicine, clinical studies can be divided into analytic and non‐analytic studies. 3 The types of clinical studies (analytic vs non‐analytic studies) along with specific study designs and examples of research questions are given in Table ​ Table1. 1 . An analytic study aims to quantify the causal relationship between an intervention (eg, treatment) or a naturally occurring exposure (hereafter indicated as exposure) (eg, the presence of a disease) and an outcome. 3 , 4 To quantify the effect, it is necessary to compare the rates of the outcome in the intervention or exposed group, with that in a control group. Within analytic research, a further distinction can be made between experimental and observational analytic studies. 3 In experimental studies, that is, RCTs, the investigator intentionally manipulates the intervention by randomly allocating participants to the intervention or control group. 4 In contrast, in observational analytic studies, the intervention or exposure as well as the control group are simply measured (observed) without manipulation by the researcher. Non‐analytic or descriptive studies on the other hand aim to describe what is happening in a population (eg, the incidence or prevalence of a disease), without quantifying a causal relationship, using observational study designs. 3 , 4

Types of clinical studies with related study designs and examples

Abbreviations: ACE, angiotensin‐converting enzyme; AII, angiotensin‐II; CKD, chronic kidney disease; CRF, chronic renal failure; ESRD, end‐stage renal disease; PD, peritoneal dialysis; PRD, primary renal disease; RRT, renal replacement therapy.

This article aims to show when RCT are needed, and when observational studies are more suitable than RCT.

2. EXPERIMENTAL STUDIES

When the aim is to evaluate the intended effect of an intervention, the RCT is the gold standard (Figure ​ (Figure1A). 1A ). An intended effect is the outcome the person who prescribes the intervention intends to achieve. For example, a physician may prescribe a certain drug with the intention to prevent mortality. This is different from unintended effects, which will be discussed later in this article. 5 By the strength of the design, the evidence produced by a sufficiently powered RCT is highly convincing in determining the presence or absence of a causal relationship between an intervention and its intended effect on the outcome. 6 In an RCT, randomization is used to allocate participants to the intervention group or the control group (eg, without intervention, with a placebo or an alternative treatment). By randomization, one aims to prevent confounding by indication, also known as selection by prognosis. 7 Confounding by indication usually occurs when clinicians decide who will receive the intervention, as their opinion about the patient's prognosis guides their decision on treatment allocation. 8 For example, patients with more severe symptoms usually receive treatment that is more intensive. As a result, the group receiving more intensive treatment may have worse outcomes due to their worse prognosis at baseline. 9 Without randomization, the intervention and the control group will usually be different with respect to their baseline characteristics and their prognosis. Of note, randomization does not guarantee that the intervention and control group will be exactly the same in terms of baseline characteristics. However, randomization does ensure that any remaining differences between the intervention and control groups are determined by chance. 8

Outline of different analytic studies using A, an experimental study (randomized controlled trial) and B, C, D, an observational analytic study. Case‐mix* refers to differences in measured and unmeasured confounders between exposed and unexposed groups

An example of an RCT is the study by Bakris et al in which 11 506 patients with hypertension who were at high risk of cardiovascular events were randomly assigned to receive benazepril plus amlodipine or benazepril plus hydrochlorothiazide. 10 These patients were followed over time to assess the effect of these different anti‐hypertensive treatments (intervention) with respect to slowing the progression of chronic kidney disease (CKD) (intended outcome). The investigators found that the risk of progression was lower using a combination of benazepril plus amlodipine than with benazepril plus hydrochlorothiazide (hazard ratio [HR]: 0.52) (95% confidence interval [95% CI] 0.41‐0.65).

2.1. Limitations of RCT

Randomized controlled trials have several important limitations. First, the generalizability of their results is often limited due to sampling bias. This occurs when the study sample or the groups resulting from randomization are not representative of the source population they were drawn from. 7 , 11 This can be due to strict inclusion criteria. RCTs outside the field of nephrology often routinely exclude CKD patients and therefore the generalizability of their results to patients with CKD may be questionable. 12 Second, RCT are generally expensive to perform, 13 and therefore the study samples are often relatively small and their follow‐up relatively short. As a result, there might be substantial baseline differences remaining in the measured and unmeasured confounders between the two groups after randomization (although these differences are determined by chance). Third, for some research questions on the intended effect of an intervention, an RCT may be impossible, unfeasible or unnecessary. For instance, an RCT might be too costly, it might be unethical to randomize the intervention, or the health benefit of the treatment may be so dramatic that observational studies can demonstrate their effectiveness. These and other reasons are described in more detail elsewhere. 2 , 14 , 15

3. OBSERVATIONAL ANALYTIC STUDIES

In the above‐mentioned situations, when performing an RCT investigating the intended effect of an intervention is not possible or not justified, observational study designs, such as cohort studies (Figure ​ (Figure1B) 1B ) or case‐control studies are needed. 6 An observational study design may also be preferred for other reasons, such as the lack of generalizability in an RCT. Observational studies are also necessary to assess the effect of a naturally occurring exposure on an outcome (Figure ​ (Figure1C). 1C ). Please note that in observational analytic studies investigating the effect of an exposure there are no intended or unintended effects, just outcomes. 16

In cohort studies, participants are free of the outcome at study entry and are followed over time to assess who will develop the outcome and who will not. Cohort studies tend to be less costly to perform than RCTs, as they usually rely on less invasive and intensive methods of data collection. In addition, usually there are less ethical aspects to consider, since there is no intervention. However, a specific limitation of cohort studies is that they typically need to run for several years, and/or include many participants, in order to observe a sufficient number of occurrences of the (potentially rare) outcome. An example of a large cohort study, running for more than a decade, is the study by Wen et al. 17 They studied a large cohort of 462 293 adults to compare the all‐cause mortality risk (outcome) between different stages of CKD (naturally occurring exposure). They found the HR for all‐cause mortality to be lower in CKD stage 1 (HR: 1.8, 95% CI: 1.5‐2.2), stage 2 (HR: 1.7, 95% CI: 1.5‐1.9), and stage 3 (HR: 1.5, 95% CI: 1.4‐1.6) compared with CKD stage 4 (HR: 5.3, 95% CI: 4.5‐6.2) and stage 5 (HR: 9.1, 95% CI: 7.2‐11.4). 17

Case‐control studies are usually more efficient than cohort studies, because instead of selecting individuals on the basis of exposure or intervention, the selection of individuals is based on the outcome. Patients with a certain outcome (cases) are compared with a subset of individuals who did not develop the outcome (controls). 6 As a result, the number of included persons in the control group can be limited. The researchers may then use retrospective data to find out to what extent cases and controls were exposed to the exposure or intervention of interest. The main limitations of case‐control studies may include the difficulty in selecting an appropriate control group, and recall bias as data are always collected retrospectively. An example of a case‐control study is the study by Fored et al on the association between socio‐economic status (SES) (naturally occurring exposure) and chronic renal failure (CRF) (outcome). 18 They defined a source population from which they selected those with CRF as cases, and randomly selected a similar number of people without CRF as controls. They found that in families having a low SES, the risk of developing CRF was significantly higher (odds ratio [OR] = 1.6 [95% CI: 1.0‐2.6] for men and OR = 2.1 [95% CI: 1.1‐4.0] for women) than in families with a high SES.

The main drawback of observational analytic studies is that the intervention or exposure is not randomized, and therefore confounding by indication (in case of an intervention) or differences in case‐mix between the exposed and unexposed groups (in case of a naturally occurring exposure) are likely to exist. 6 This means that there are usually differences in measured and unmeasured confounders between the comparison groups. 11 As a result, any observed effect of the intervention or the exposure on the outcome might be due to these baseline differences. A variety of methods exists aiming to address confounding in observational analytic studies. The most commonly used methods are given in Box ​ Box1. 1 . However, in most cases, residual confounding remains and as a result, it is often not possible to draw firm conclusions about causality from observational analytic studies.

Methods used in observational analytic studies aiming to address confounding

4. STUDY OF UNINTENDED EFFECTS

Unintended effects are all effects on outcomes—harmful, harmless or even beneficial—that are produced by an intervention or treatment, that were not originally intended by the person who prescribed the intervention. 4 In the field of medicine, unintended effects can be side effects, and particularly the side effects of pharmaceutical agents are widely studied. Unintended effects of interventions may be relatively uncommon and often hard to predict, and they are therefore usually not considered in clinicians' decision‐making. 8 When clinicians do not know the unintended effects of an intervention, they cannot base their treatment allocation on these effects and therefore confounding by indication usually does not occur. 8 For this reason randomization is not needed, and thus observational analytic studies can be used to quantify the unintended effects of interventions (Figure ​ (Figure1D). 1D ). Because unintended effects may occur less frequently, these studies may require a large sample size and sometimes extended follow‐up. 8 In this perspective, RCTs are also less suitable as they normally include relatively small patient samples with relatively short follow‐up times, and have limited generalizability as a result of rigid in‐ and exclusion criteria. It should be noted; however, that once the occurrence of an unintended effect of a treatment is well known, physicians may take this into account in their treatment allocation, and consequently confounding by indication may occur. Also, in the situation that the treatment allocation by the physician is related to a certain variable (eg, patients with more severe symptoms receive more intensive treatment) and this specific variable is related to the unintended outcome (eg, patients with more severe symptoms may suffer more from unintended effects) confounding by indication will also occur. In this case, an RCT might be a more appropriate study design provided the unintended effect occurs with sufficient frequency.

Once a treatment has been introduced into clinical practice, one can study its unintended effects. To this end, pharmaceutical companies use so‐called post‐marketing surveillance, which is often mandated by the regulatory agencies, such as the American Food and Drug Administration, the European Medicines Agency and the Australian Therapeutic Goods Administration. To monitor the effectiveness and safety of drugs, and the occurrence of unintended effects, they rely on real‐world observational study designs. 19 Most unintended effects, especially those that are adverse and require medical attention, are first brought to attention in case reports. 20 However, some adverse effects might be very common, relatively benign, or only occur long after the treatment start, and not give rise to case reports, leading to underreporting. Therefore, more systematic surveillance systems that can link data from health‐care insurers and government agencies, and observational cohort studies might be employed. 20

An example of an observational study on unintended effects is the study by Kolesnyk et al, who assessed the unintended effects of using angiotensin‐converting enzyme (ACE) and angiotensin‐II (AII) inhibitors vs a control group without such medication on the peritoneal membrane function in a cohort of long‐term peritoneal dialysis (PD) patients. 21 The investigators found that ACE/AII inhibitors had a protective effect on peritoneal membrane function ( P  =.037). Because the ACE/AII inhibitors were prescribed with the aim to treat hypertension or heart failure, and not intended to prevent peritoneal membrane damage in PD, this is considered to be an unintended effect, albeit a beneficial one.

5. DESCRIPTIVE STUDIES

Observational study designs are also needed for non‐analytic studies (ie, descriptive studies). Such studies examine the frequency of risk factors, diseases or other health outcomes in a population, without assessing causal relationships. 4 Descriptive studies can for example be used to inform health‐care professionals and policymakers on the amount of public health resources needed. 22 For descriptive studies, one can use population statistics, or draw a sample from the population. In this article, we mainly focus on cross‐sectional descriptive studies and descriptive studies describing time trends. A more detailed description of types of descriptive studies can be found elsewhere. 23

Cross‐sectional descriptive studies can usually be implemented in a relatively short timeframe and with a reasonable budget. As the frequency of a disease may differ between groups and may depend on factors such as age and sex, it is common to standardize the results for these factors using a reference population. 24 An example is the study by Brück et al, which describes the prevalence of CKD in 13 European countries. 25 The CKD prevalence was age‐ and sex‐standardized to the population of the 27 Member States of the European Union to enable comparison between countries. The results of that study suggested substantial international differences in the prevalence of CKD across European countries, varying from 3% to 17% for CKD stages 1 to 5, and from 1% to 6% for CKD stages 3 to 5. 25 Descriptive studies may suffer from sampling bias due to their sample selection methods, which may hamper the generalizability of the results.

Other descriptive studies can describe (long‐term) time trends, for instance the incidence or prevalence of a disease. Insight into such trends may allow policymakers, health‐care practitioners and researchers to identify newly emerging health threats, to optimize future allocation of resources, initiate preventive efforts and monitor changes over time. 2 , 22 , 25 However, even if trends indicate favourable changes following preventive efforts, descriptive studies alone cannot establish causal links between prevention and outcome. Another caveat of studies investigating long‐term trends is that they need data collection over several years, preferably using the same methodology. An example of a descriptive study describing time trends is the one by Stel et al that made an international comparison of trends in the incidence of renal replacement therapy (RRT) for patients with end‐stage kidney disease (ESKD) by primary renal disease. 26 The incidence of RRT for ESKD due to diabetes mellitus or hypertension was found to strongly increase in Asia between 2005 and 2014, whereas both declined in Europe. Conversely, the incidence of RRT for ESKD due to glomerulonephritis was stable or decreased in all included countries.

6. CONCLUSIONS

The answer to the question “is an observational study better than an RCT?” depends on the research question at hand. There is not one overall gold standard study design for clinical research. With respect to analytic studies, the RCT is the best study design when it comes to evaluating the intended effect of an intervention. However, this type of research represents only a fraction of all clinical research. Observational analytic studies are most suitable if randomization of the intervention or exposure is not feasible or if the research question focuses on unintended effects of interventions. For non‐analytic or descriptive studies, observational study designs are also needed. We conclude that RCT and observational studies are inherently different, and each have their own strengths and weaknesses depending on the study question.

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.

ACKNOWLEDGEMENTS

The ERA‐EDTA Registry is funded by the ERA‐EDTA. This article was written by all the authors on behalf of the ERA‐EDTA Registry, which is an official body of the ERA‐EDTA.

Bosdriesz JR, Stel VS, van Diepen M, et al. Evidence‐based medicine—When observational studies are better than randomized controlled trials . Nephrology . 2020; 25 :737–743. 10.1111/nep.13742 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Jizzo R. Bosdriesz and Vianda S. Stel joint first authors.

Funding information The ERA‐EDTA Registry is funded by the ERA‐EDTA.