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Research participants are partners in discovery at the NIH Clinical Center, the largest research hospital in America. Clinical research is medical research involving people The Clinical Center provides hope through pioneering clinical research to improve human health. We rapidly translate scientific observations and laboratory discoveries into new ways to diagnose, treat and prevent disease. More than 500,000 people from around the world have participated in clinical research since the hospital opened in 1953. We do not charge patients for participation and treatment in clinical studies at NIH. In certain emergency circumstances, you may qualify for help with travel and other expenses Read more , to see if clinical studies are for you.

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The National Institutes of Health (NIH) Clinical Center Search the Studies site is a registry of publicly supported clinical studies conducted mostly in Bethesda, MD.

Treatment Research

Scientists have developed a strategy for treating cancer that takes advantage of tumors’ ability to rapidly evolve and turns it against them. It involves intentionally making some tumor cells resistant to a specific treatment from the get-go.

In late 2023, FDA announced it was investigating instances of second cancers following treatment with CAR T-cell therapies. In this Q&A, NCI’s Dr. Stephanie Goff explains what’s known about the issue, stressing that second cancers “of any kind are rare.”

Scientists have been searching for ways to make immune checkpoint inhibitors work for more patients. In two trials, researchers explored a possible role for JAK inhibitors, which dampen chronic inflammation.

A new cellular immunotherapy approach shrank tumors in 3 of 7 patients with metastatic colon cancer, in a small NCI clinical trial. Normal white blood cells from each patient were genetically engineered to produce receptors that recognize and attack their specific cancer cells.

When it comes to cancer drugs, researchers are moving away from a paradigm called the maximum tolerated dose. Instead, they’re focusing more on identifying doses that produce fewer side effects but are still effective against a person’s cancer.

Reshaping the cancer clinical trials infrastructure to overcome key bottlenecks will involve embracing technology and collaboration, and inviting innovation, explain NCI Director Dr. W. Kimryn Rathmell and NCI Special Advisor Dr. Shaalan Beg.

In a new study in mice, researchers showed they could enhance radiation therapy by boosting levels of the BAMBI protein in MDSC immune cells in the tumor microenvironment. After radiation, T cells flooded into the tumor and killed tumors elsewhere in the body.

In a clinical trial, people being treated for cancer who participated in virtual mind–body fitness classes were less likely to be hospitalized, and had shorter stays when they were hospitalized, than people who did not take the classes.

NCI’s James H. Doroshow, M.D., reflects on the accomplishments of NCI-MATCH, a first-of-its-kind precision medicine cancer trial, and gives an overview of three new successor trials: ComboMATCH, MyeloMATCH, and iMATCH.

A new study, conducted largely in mice, may help explain why a currently used molecular marker—called mismatch repair deficiency—doesn’t always work to predict which patients will respond to immunotherapies called immune checkpoint inhibitors.

New approach may increase the effectiveness of T-cell-based immunotherapy treatments against solid tumors.

A cancer-infecting virus engineered to tamp down a tumor’s ability to suppress the immune system shrank tumors in mice, a new study shows. The modified oncolytic virus worked even better when used along with an immune checkpoint inhibitor.

Despite recommendations, a new analysis shows few people with cancer undergo germline testing to learn if their cancer may have been caused by gene changes inherited from a parent. Germline testing can help doctors determine the best treatments for a patient and help identify people whose family members may be at higher risk of cancer.

ComboMATCH will consist of numerous phase 2 cancer treatment trials that aim to identify promising drug combinations that can advance to larger, more definitive clinical trials.

A new study has compared three formulations of an mRNA vaccine designed to treat cancers caused by human papillomavirus (HPV) infections. All three vaccines showed promise in mice.

Researchers have identified a mechanism by which cancer cells develop specific genetic changes needed to become resistant to targeted therapies. They also showed that this process, called non-homologous end-joining (NHEJ), can potentially be disrupted.

For some people with cancer, is 6 months of immunotherapy the only treatment they might ever need? Or 4 weeks of immunotherapy followed by minor surgery? Results from several small clinical trials suggest these scenarios may be bona fide possibilities.

Two research teams have developed ways of overcoming barriers that have limited the effectiveness of CAR T-cell therapies, including engineering ways to potentially make them effective against solid tumors like pancreatic cancer and melanoma.

In people with cancer treated with immune checkpoint inhibitors, a rare, but often fatal, side effect is inflammation in the heart, called myocarditis. Researchers have now identified a potential chief cause of this problem: T cells attacking a protein in heart cells called α-myosin.

Researchers have modified a chemo drug, once abandoned because it caused serious gut side effects, so that it is only triggered in tumors but not normal tissues. After promising results in mice, the drug, DRP-104, is now being tested in a clinical trial.

Two research teams have developed a treatment approach that could potentially enable KRAS-targeted drugs—and perhaps other targeted cancer drugs—flag cancer cells for the immune system. In lab studies, the teams paired these targeted drugs with experimental antibody drugs that helped the immune system mount an attack.

Inflammation is considered a hallmark of cancer. Researchers hope to learn more about whether people with cancer might benefit from treatments that target inflammation around tumors. Some early studies have yielded promising results and more are on the horizon.

NCI researchers are developing an immunotherapy that involves injecting protein bits from cytomegalovirus (CMV) into tumors. The proteins coat the tumor, causing immune cells to attack. In mice, the treatment shrank tumors and kept them from returning.

FDA has approved the combination of the targeted drugs dabrafenib (Tafinlar) and trametinib (Mekinist) for nearly any type of advanced solid tumor with a specific mutation in the BRAF gene. Data from the NCI-MATCH trial informed the approval.

People with cancer who take immunotherapy drugs often develop skin side effects, including itching and painful rashes. New research in mice suggests these side effects may be caused by the immune system attacking new bacterial colonies on the skin.

Researchers have developed tiny “drug factories” that produce an immune-boosting molecule and can be implanted near tumors. The pinhead-sized beads eliminated tumors in mice with ovarian and colorectal cancer and will soon be tested in human studies.

Women are more likely than men to experience severe side effects from cancer treatments such as chemotherapy, targeted therapy, and immunotherapy, a new study finds. Researchers hope the findings will increase awareness of the problem and help guide patient care.

Research to improve CAR T-cell therapy is progressing rapidly. Researchers are working to expand its use to treat more types of cancer and better understand and manage its side effects. Learn how CAR T-cell therapy works, which cancers it’s used to treat, and current research efforts.

Experts say studies are needed on how to best transition telehealth from a temporary solution during the pandemic to a permanent part of cancer care that’s accessible to all who need it.

Removing immune cells called naive T cells from donated stem cells before they are transplanted may prevent chronic graft-versus-host disease (GVHD) in people with leukemia, a new study reports. The procedure did not appear to increase the likelihood of patients’ cancer returning.

A specific form of the HLA gene, HLA-A*03, may make immune checkpoint inhibitors less effective for some people with cancer, according to an NCI-led study. If additional studies confirm the finding, it could help guide the use of these commonly used drugs.

The success of mRNA vaccines for COVID-19 could help accelerate research on using mRNA vaccine technology to treat cancer, including the development of personalized cancer vaccines.

Aneuploidy—when cells have too many or too few chromosomes—is common in cancer cells, but scientists didn’t know why. Two new studies suggest that aneuploidy helps the cells survive treatments like chemotherapy and targeted therapies.

New research suggests that fungi in the gut may affect how tumors respond to cancer treatments. In mice, when bacteria were eliminated with antibiotics, fungi filled the void and impaired the immune response after radiation therapy, the study found.

FDA has approved belumosudil (Rezurock) for the treatment of chronic graft-versus-host disease (GVHD). The approval covers the use of belumosudil for people 12 years and older who have already tried at least two other therapies.

In lab studies, the antibiotic novobiocin showed promise as a treatment for cancers that have become resistant to PARP inhibitors. The drug, which inhibits a protein called DNA polymerase theta, will be tested in NCI-supported clinical trials.

A drug called avasopasem manganese, which has been found to protect normal tissues from radiation therapy, can also make cancer cells more vulnerable to radiation treatment, a new study in mice suggests.

While doctors are familiar with the short-term side effects of immune checkpoint inhibitors, less is known about potential long-term side effects. A new study details the chronic side effects of these drugs in people who received them as part of treatment for melanoma.

Cholesterol-lowering drugs known as PCSK9 inhibitors may improve the effectiveness of cancer immune checkpoint inhibitors, according to studies in mice. The drugs appear to improve the immunotherapy drugs’ ability to find tumors and slow their growth.

Researchers have developed a nanoparticle that trains immune cells to attack cancer. According to the NCI-funded study, the nanoparticle slowed the growth of melanoma in mice and was more effective when combined with an immune checkpoint inhibitor.

A comprehensive analysis of patients with cancer who had exceptional responses to therapy has revealed molecular changes in the patients’ tumors that may explain some of the exceptional responses.

Researchers are developing a new class of cancer drugs called radiopharmaceuticals, which deliver radiation therapy directly and specifically to cancer cells. This Cancer Currents story explores the research on these emerging therapies.

FDA has recently approved two blood tests, known as liquid biopsies, that gather genetic information to help inform treatment decisions for people with cancer. This Cancer Currents story explores how the tests are used and who can get the tests.

Cancer cells with a genetic feature called microsatellite instability-high (MSI-high) depend on the enzyme WRN to survive. A new NCI study explains why and reinforces the idea of targeting WRN as a treatment approach for MSI-high cancer.

Efforts to contain the opioid epidemic may be preventing people with cancer from receiving appropriate prescriptions for opioids to manage their cancer pain, according to a new study of oncologists’ opioid prescribing patterns.

The gene-editing tool CRISPR is changing the way scientists study cancer, and may change how cancer is treated. This in-depth blog post describes how this revolutionary technology is being used to better understand cancer and create new treatments.

FDA’s approval of pembrolizumab (Keytruda) to treat people whose cancer is tumor mutational burden-high highlights the importance of genomic testing to guide treatment, including for children with cancer, according to NCI Director Dr. Ned Sharpless.

Patients with acute graft-versus-host disease (GVHD) that does not respond to steroid therapy are more likely to respond to the drug ruxolitinib (Jakafi) than other available treatments, results from a large clinical trial show.

NCI is developing the capability to produce cellular therapies, like CAR T cells, to be tested in cancer clinical trials at multiple hospital sites. Few laboratories and centers have the capability to make CAR T cells, which has limited the ability to test them more broadly.

An experimental drug may help prevent the chemotherapy drug doxorubicin from harming the heart and does so without interfering with doxorubicin’s ability to kill cancer cells, according to a study in mice.

In people with blood cancers, the health of their gut microbiome appears to affect the risk of dying after receiving an allogeneic hematopoietic stem cell transplant, according to an NCI-funded study conducted at four hospitals across the globe.

A novel approach to analyzing tumors may bring precision cancer medicine to more patients. A study showed the approach, which analyzes gene expression using tumor RNA, could accurately predict whether patients had responded to treatment with targeted therapy or immunotherapy.

Bone loss associated with chemotherapy appears to be induced by cells that stop dividing but do not die, a recent study in mice suggests. The researchers tested drugs that could block signals from these senescent cells and reverse bone loss in mice.

Some experts believe that proton therapy is safer than traditional radiation, but research has been limited. A new observational study compared the safety and effectiveness of proton therapy and traditional radiation in adults with advanced cancer.

In people with cancer, the abscopal effect occurs when radiation—or another type of localized therapy—shrinks a targeted tumor but also causes untreated tumors in the body to shrink. Researchers are trying to better understand this phenomenon and take advantage of it to improve cancer therapy.

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Study designs: Part 1 – An overview and classification

Priya ranganathan.

Department of Anaesthesiology, Tata Memorial Centre, Mumbai, Maharashtra, India

Rakesh Aggarwal

1 Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

There are several types of research study designs, each with its inherent strengths and flaws. The study design used to answer a particular research question depends on the nature of the question and the availability of resources. In this article, which is the first part of a series on “study designs,” we provide an overview of research study designs and their classification. The subsequent articles will focus on individual designs.

INTRODUCTION

Research study design is a framework, or the set of methods and procedures used to collect and analyze data on variables specified in a particular research problem.

Research study designs are of many types, each with its advantages and limitations. The type of study design used to answer a particular research question is determined by the nature of question, the goal of research, and the availability of resources. Since the design of a study can affect the validity of its results, it is important to understand the different types of study designs and their strengths and limitations.

There are some terms that are used frequently while classifying study designs which are described in the following sections.

A variable represents a measurable attribute that varies across study units, for example, individual participants in a study, or at times even when measured in an individual person over time. Some examples of variables include age, sex, weight, height, health status, alive/dead, diseased/healthy, annual income, smoking yes/no, and treated/untreated.

Exposure (or intervention) and outcome variables

A large proportion of research studies assess the relationship between two variables. Here, the question is whether one variable is associated with or responsible for change in the value of the other variable. Exposure (or intervention) refers to the risk factor whose effect is being studied. It is also referred to as the independent or the predictor variable. The outcome (or predicted or dependent) variable develops as a consequence of the exposure (or intervention). Typically, the term “exposure” is used when the “causative” variable is naturally determined (as in observational studies – examples include age, sex, smoking, and educational status), and the term “intervention” is preferred where the researcher assigns some or all participants to receive a particular treatment for the purpose of the study (experimental studies – e.g., administration of a drug). If a drug had been started in some individuals but not in the others, before the study started, this counts as exposure, and not as intervention – since the drug was not started specifically for the study.

Observational versus interventional (or experimental) studies

Observational studies are those where the researcher is documenting a naturally occurring relationship between the exposure and the outcome that he/she is studying. The researcher does not do any active intervention in any individual, and the exposure has already been decided naturally or by some other factor. For example, looking at the incidence of lung cancer in smokers versus nonsmokers, or comparing the antenatal dietary habits of mothers with normal and low-birth babies. In these studies, the investigator did not play any role in determining the smoking or dietary habit in individuals.

For an exposure to determine the outcome, it must precede the latter. Any variable that occurs simultaneously with or following the outcome cannot be causative, and hence is not considered as an “exposure.”

Observational studies can be either descriptive (nonanalytical) or analytical (inferential) – this is discussed later in this article.

Interventional studies are experiments where the researcher actively performs an intervention in some or all members of a group of participants. This intervention could take many forms – for example, administration of a drug or vaccine, performance of a diagnostic or therapeutic procedure, and introduction of an educational tool. For example, a study could randomly assign persons to receive aspirin or placebo for a specific duration and assess the effect on the risk of developing cerebrovascular events.

Descriptive versus analytical studies

Descriptive (or nonanalytical) studies, as the name suggests, merely try to describe the data on one or more characteristics of a group of individuals. These do not try to answer questions or establish relationships between variables. Examples of descriptive studies include case reports, case series, and cross-sectional surveys (please note that cross-sectional surveys may be analytical studies as well – this will be discussed in the next article in this series). Examples of descriptive studies include a survey of dietary habits among pregnant women or a case series of patients with an unusual reaction to a drug.

Analytical studies attempt to test a hypothesis and establish causal relationships between variables. In these studies, the researcher assesses the effect of an exposure (or intervention) on an outcome. As described earlier, analytical studies can be observational (if the exposure is naturally determined) or interventional (if the researcher actively administers the intervention).

Directionality of study designs

Based on the direction of inquiry, study designs may be classified as forward-direction or backward-direction. In forward-direction studies, the researcher starts with determining the exposure to a risk factor and then assesses whether the outcome occurs at a future time point. This design is known as a cohort study. For example, a researcher can follow a group of smokers and a group of nonsmokers to determine the incidence of lung cancer in each. In backward-direction studies, the researcher begins by determining whether the outcome is present (cases vs. noncases [also called controls]) and then traces the presence of prior exposure to a risk factor. These are known as case–control studies. For example, a researcher identifies a group of normal-weight babies and a group of low-birth weight babies and then asks the mothers about their dietary habits during the index pregnancy.

Prospective versus retrospective study designs

The terms “prospective” and “retrospective” refer to the timing of the research in relation to the development of the outcome. In retrospective studies, the outcome of interest has already occurred (or not occurred – e.g., in controls) in each individual by the time s/he is enrolled, and the data are collected either from records or by asking participants to recall exposures. There is no follow-up of participants. By contrast, in prospective studies, the outcome (and sometimes even the exposure or intervention) has not occurred when the study starts and participants are followed up over a period of time to determine the occurrence of outcomes. Typically, most cohort studies are prospective studies (though there may be retrospective cohorts), whereas case–control studies are retrospective studies. An interventional study has to be, by definition, a prospective study since the investigator determines the exposure for each study participant and then follows them to observe outcomes.

The terms “prospective” versus “retrospective” studies can be confusing. Let us think of an investigator who starts a case–control study. To him/her, the process of enrolling cases and controls over a period of several months appears prospective. Hence, the use of these terms is best avoided. Or, at the very least, one must be clear that the terms relate to work flow for each individual study participant, and not to the study as a whole.

Classification of study designs

Figure 1 depicts a simple classification of research study designs. The Centre for Evidence-based Medicine has put forward a useful three-point algorithm which can help determine the design of a research study from its methods section:[ 1 ]

Classification of research study designs

• Does the study describe the characteristics of a sample or does it attempt to analyze (or draw inferences about) the relationship between two variables? – If no, then it is a descriptive study, and if yes, it is an analytical (inferential) study
• If analytical, did the investigator determine the exposure? – If no, it is an observational study, and if yes, it is an experimental study
• If observational, when was the outcome determined? – at the start of the study (case–control study), at the end of a period of follow-up (cohort study), or simultaneously (cross sectional).

In the next few pieces in the series, we will discuss various study designs in greater detail.

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Clinical Trials – Information for Participants

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What are clinical trials?

Clinical trials are research studies that look at ways to prevent, detect, or treat diseases and conditions. They are critical to understanding and treating mental illnesses. Clinical trials are the primary way researchers determine if a new treatment is safe and effective in people.

Clinical trials can study:

• New drugs or combinations of drugs.
• New medical procedures (such as a new blood test or scan).
• New medical devices (such as a  brain stimulation device ).
• New therapies or behavioral interventions, which help people change their behaviors, thoughts, and feelings to improve their mental health
• New ways to prevent health conditions or find a disease early, sometimes even before symptoms occur.

Watch these videos to learn more about clinical trials

Why are clinical trials important.

Clinical trials are the foundation of most medical advances. Without clinical trials, many of the medical treatments and cures we have today wouldn’t exist.

By testing new treatments and interventions in a carefully designed and controlled way, researchers learn more about the underlying mechanisms of disease and develop new ways to diagnose, treat, and prevent illness.

The results of clinical trials help inform medical decision-making and provide evidence-based information about the benefits and risks of different treatments or interventions. Researchers and doctors use this information to decide which treatments should be recommended and which require more study.

Why should I participate in a clinical trial?

People volunteer for clinical trials for many reasons. Some people join clinical trials to help doctors and researchers learn more about a disease and improve health care. Other people, such as those with health conditions, join to try treatments that aren’t widely available.

Researchers usually study people who have a specific health condition. Researchers sometimes need to compare data from volunteers with no health conditions to data from people with specific health conditions so they can use that information to learn more about the disease.

Participating in a clinical trial is entirely up to you. If you volunteer for a clinical trial and later decide it’s not right for you, you can withdraw anytime.

Clinical Research Trials and You: Questions and Answers

Find more information about the risks and benefits of joining a clinical trial, how your safety is protected, and what happens when a clinical trial ends.

Download this free fact sheet about clinical trials

What is it like to participate in a clinical trial?

During a clinical trial, you will see a team of researchers, sometimes called a study team, clinical trial team, or clinical research team, who will monitor your health closely.

You may have more tests and medical exams than you would if you were getting mental health care but not participating in a clinical trial. The study team may also ask you to do other tasks, such as keeping a log about your health or filling out forms about how you feel.

Clinical trials occur in medical centers, doctors’ offices, and community-based organizations nationwide. You may need to travel or stay in a hospital to participate in a clinical trial.

Are clinical trials safe?

Clinical trials are generally safe. Though there are risks to participating in clinical research, clinical trials are designed to minimize risks and keep you safe.

Before a clinical trial can start, it must be reviewed and approved by an institutional review board (IRB) for U.S.-based studies or an independent ethics committee outside the U.S. This review ensures that it is safe and that the potential benefits of the trial are worth the potential risks. The study team will also make sure you meet certain requirements and that it is safe for you to participate.

Clinical studies might make you feel a little uncomfortable for a short time, but how much risk you face depends on the type of study you join. For instance, if you are participating in a study testing a new drug, the medication might make you feel sick or tired when you first start taking it. In some studies, instead of trying a new medicine, you might take computer-based tests or have a non-invasive magnetic resonance imaging (MRI) done, which carries different risks. The research team and the IRB continuously monitor studies to ensure ongoing safety.

Speak with the study team to understand the risks involved in a particular study. Potential risks are included in the informed consent process, and the research team will be able to explain anything you don’t understand.

Are clinical trials paid?

Some clinical trials pay participants, including some trials that take place at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD.

The amount of money you get paid depends on things like how long the trial takes, how much time you need to give, and what kind of trial it is. Sometimes, the trial may also cover your travel, lodging, and food costs. Not all clinical trials are paid, and you should consider all aspects of the study, including risks and benefits, before making a final decision.

How do I find a clinical trial?

The National Institute of Mental Health (NIMH) is the lead federal agency for research on mental disorders. NIMH supports clinical trials at the NIH campus in Bethesda, MD and across the United States.

Find a study at the NIH campus

NIMH researchers conduct many clinical trials at the NIH Clinical Center  . Located on the NIH campus in Bethesda, Maryland, the Clinical Center is the largest research hospital in the world.

Learn more about how to join an NIMH clinical trial at the NIH Clinical Center. These studies enroll volunteers from the local area and across the nation.

Find NIMH clinical trials for adults and children that are currently accepting volunteers:

• Join a Research Study: Adults
• Join a Research Study: Children
• Frequently Asked Questions About Participating in NIMH Research Studies for Adults & Children

You can also subscribe to receive  email updates   about clinical trials conducted at NIH.

Find other studies around the United States

NIMH also funds many studies that are currently recruiting people around the country on different mental health disorders, including:

• Anxiety Disorders
• Attention-Deficit/Hyperactivity Disorder (ADHD)
• Autism Spectrum Disorder (ASD)
• Bipolar Disorder
• Borderline Personality Disorder
• Eating Disorders
• Generalized Anxiety Disorder
• Obsessive-Compulsive Disorder (OCD)
• Panic Disorder
• Post-Traumatic Stress Disorder (PTSD)
• Schizophrenia
• Social Anxiety Disorder
• Studies Recruiting Only Men
• Studies Recruiting Only Women
• Conditions Related to Mental Disorders

Other ways to find a clinical trial

• Search  clinicaltrials.gov   , a database of privately and publicly funded clinical studies conducted worldwide.
• Talk to your health care provider  about studies that may be right for you. You can also learn about studies in newspapers, TV, or online.
• Join a national registry of research volunteers , such as  ResearchMatch   . ResearchMatch is a nonprofit program funded by NIH that helps connect people interested in research studies with researchers from medical centers across the United States.
• Join the  NIH  All of Us  Research Program   ,  which is enrolling a large group of people that reflects the diversity of the United States. The program aims to build a diverse database that can inform thousands of studies on various health conditions.

How do I sign up to participate in a clinical trial?

After you find a clinical trial you're interested in, contact the study team to learn more about it. You can usually find the study teams’ contact information in the trial’s description. The staff can give you information that will help you decide whether to participate.

Check out this resource from the U.S. Department of Health and Human Services (HHS) for a list of specific questions to ask about volunteering for a research study  .

Let your health care provider know if you decide to join a clinical trial. They may want to talk to the study team to help coordinate your care and ensure the trial is safe for you.

How can I learn more about participating in a clinical trial?

Federal resources

• Clinical Trials  : The National Institute on Aging offers articles about how clinical trials work and how to participate about clinical trials.
• NIH Clinical Research Trials and You  : Answers from the NIH to many common questions about participating in a clinical trial
• Clinical Trials  (MedlinePlus - also en español)  : Information about clinical trial protocols and institutional review boards
• Federal Government Health Insurance Programs  : Information about federal programs that help pay the costs of care in clinical trials
• NIH Clinical Research Trials and You: Personal Stories  : Stories about volunteers and researchers
• Videos sobre la investigación clínica  : Spanish-language videos about participating in research
• What is a clinical trial?   
• Should I participate in a clinical trial? What’s in it for me? 
• What should I know to participate in a clinical trial? 
• HHS: Human Research Volunteer Informational videos  : Basic information about research, including questions to ask and what to think about when deciding whether to participate in a study

Last reviewed : April 2024

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• Published: 14 September 2024

Short-term efficacy of photobiomodulation in early and intermediate age-related macular degeneration: the PBM4AMD study

• Marco Nassisi   ORCID: orcid.org/0000-0002-9354-9005 1 , 2 ,
• Claudia Mainetti 1 ,
• Giorgia Rosapia Paparella 2 ,
• Luca Belloni Baroni 2 ,
• Paolo Milella 2 ,
• Gaia Leone 1 ,
• Davide Galli 1 ,
• Francesco Pozzo Giuffrida   ORCID: orcid.org/0000-0002-2309-8157 2 ,
• Laura Dell’Arti 1 ,
• Chiara Mapelli 1 ,
• Giuseppe Casalino 1 &
• Francesco Viola 1 , 2  

Eye ( 2024 ) Cite this article

1 Altmetric

Metrics details

• Retinal diseases
• Therapeutics

This independent prospective study evaluated the short-term effects and safety of photobiomodulation (PBM) in early and intermediate age-related macular degeneration.

patients were treated with PBM in one eye. Functional parameters and drusen volume were measured at one (W4), three- (W12) and six-months (W24) after PBM.

The study included 38 subjects who completed the PBM protocol. Two patients developed macular neovascularization during the study period. Best corrected visual acuity improved from 77.82 ± 5.83 ETDRS letters at baseline to 82.44 ± 5.67 at W12 ( p  < 0.01), then declined to 80.05 ± 5.79 at W24 ( p  < 0.01 vs. baseline). Low luminance visual acuity showed a similar pattern, improving from 61.18 ± 8.58 ETDRS letters at baseline to 66.33 ± 8.55 at W12 ( p  < 0.01), and decreasing to 62.05 ± 9.71 at W24 ( p  = 0.02). Contrast sensitivity improved at W12 (20.11 ± 9.23 ETDRS letters, p  < 0.01), but returned to baseline by W24 (16.45 ± 9.12, p  = 0.5). Scotopic microperimetry showed a decrease in mean absolute retinal sensitivity from 9.24 ± 3.44 dB to 7.47 ± 4.41 dB at W24 ( p  < 0.01), while relative sensitivity decreased only at W24 ( p  = 0.04). Drusen volume decreased at W4 (0.018 ± 0.009 mm3, p  < 0.01) and W12 (0.017 ± 0.009 mm3, p  < 0.01), with a slight increase at W24 (0.019 ± 0.012 mm3, p  = 0.154).

Conclusions

PBM resulted in temporary improvements in visual function and a reduction in drusen volume, but these effects were not sustained at six months. The long-term efficacy and impact on disease progression are uncertain, necessitating further research to confirm these findings and determine optimal patient selection.

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The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study – 6 month results

Introduction.

Age-related macular degeneration (AMD) is a progressive and chronic retinal disease that primarily affects the macula, leading to irreversible central vision loss in the elderly population of developed countries. In 2020, AMD affected an estimated 196 million people worldwide [ 1 , 2 , 3 ]. The early and intermediate stages of AMD are characterized by the presence of drusen, while advanced stages involve macular neovascularization (MNV) and/or geographic atrophy (GA) [ 4 , 5 ]. Current treatments target exudative MNV, and aim to slow the progression of atrophy in the absence of MNV [ 6 , 7 ]. Unfortunately, no treatment options are currently available for the earlier stages of AMD [ 4 , 8 ]. However, treating these earlier stages could potentially prevent or delay the irreversible central vision impairment observed in the late stages of the disease. Photobiomodulation (PBM) is a therapeutic approach that involves modulating cellular pathways using specific wavelengths of light that can be absorbed by photosensitive molecules [ 9 ]. Near-infrared (NIR) light, within the wavelength range of 500–1000 nm, is hypothesized to stimulate cytochrome C-oxidase in the mitochondria, leading to increased mitochondrial replication and density, enhanced cellular metabolic rate, and heightened antioxidant activity. PBM has demonstrated benefits in various diseases including orthodontic and dermatological conditions [ 10 , 11 , 12 , 13 , 14 , 15 ]. Although a few clinical trials have explored the use of PBM in early and intermediate AMD, with promising safety and visual outcome results, the efficacy and prognostic factors associated with PBM therapy remain to be determined [ 16 , 17 , 18 , 19 ]. In this independent, prospective, monocentric interventional cohort study, we aim to evaluate the short-term efficacy and safety of PBM in eyes with early or intermediate AMD and identify potential prognostic factors linked to treatment outcomes.

The study was an independent, prospective, monocentric interventional cohort study. Consecutive patients with early or intermediate AMD were recruited at the Ophthalmology Unit of the IRCCS Ca’ Granda Foundation Ospedale Maggiore Policlinico, Milan, Italy, between January and April 2022. Eligible subjects had early or intermediate AMD [ 20 ], were aged ≥ 55 years, and had a best corrected visual acuity (BCVA) between 0 and 1 LogMAR.

Exclusion criteria included any form of late AMD in the study eye, pupillary abnormalities, active or previous sensitivity to yellow/red/near-infrared light, a history of or current treatment for epilepsy, and the presence of other ocular pathologies (e.g glaucoma, vitreopathies, myopic maculopathy, other retinopathies, advanced cataract) that could affect the results and treatment effectiveness. Only one eye per patient was treated with NIR-PBM. Notably, the presence of MNV and/or complete retinal pigment epithelium and outer retinal atrophy (cRORA) in the fellow eye was not an exclusion criterion.

The study protocol was approved by the local ethics committee (Comitato Etico Milano Area 2, protocol n.3136 of the 12 th of November 2021) and adhered to the tenets of the Declaration of Helsinki. All patients provided informed consent after the study and its potential outcomes were explained to them.

A blood test to assess levels of triglycerides and cholesterol (total, low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol) was conducted at baseline.

Ophthalmic assessment

A complete ophthalmic assessment of the study eye was performed during the screening visit and at 1 month (W4), 3 months (W12), and 6 months (W24) after the initial application (baseline).

All subjects were assessed for BCVA and low luminance visual acuity (LLVA) using ETDRS charts at a distance of 4 meters (Precision Vision, Woodstock, IL, USA). For LLVA, a 2.0 log unit neutral density filter was applied in front of the patient’s best correction [ 21 ]. Contrast sensitivity (CS) was also assessed using Sloan charts (Precision Vision, Woodstock, IL, USA). Retinal sensitivity was recorded in scotopic conditions using MP-1S (Nidek Technologies) with a personalized map of 60 tested points after a 30-minute dark adaptation period. Mean absolute retinal sensitivity was determined by averaging the results of all tested points, while mean relative retinal sensitivity was calculated by averaging the results of all tested points, excluding the point at 0 dB.

Subjects were assessed with 20° × 20° high speed SD-OCT volume scans (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) consisting of 97 horizontal section scans (60 μm inter-scan distance, 30 frames averaged) and with 2 central (one vertical and one horizontal) 30° line scans, 30 times averaged in enhanced depth imaging (EDI) modality. Central retinal thickness (CRT) and drusen volume in the central millimeter (DV), 3 mm (DV3), and 6 mm (DV6) were automatically obtained with the machine’s software (Heidelberg Eye Explorer v1.10.4.0).

OCT images were also qualitatively assessed for the presence of subretinal drusenoid deposits (SDD), and hyperreflective retinal foci (HRF), as previously reported [ 22 ]. All qualitative and quantitative assessments were performed by two independent operators (LBB and GRP). In cases of disagreement, open adjudication was conducted between the two graders; unresolved cases were assessed by the head of the service (FV) who made the final decision.

Fundus autofluorescence (FAF) with a 488 nm wavelength (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) was also performed at the same visit.

Photobiomodulation

All included subjects were treated with PBM (Lumithera Valeda Light Delivery System, LumiThera Inc., Poulsbo, WA, USA) which delivers three different wavelengths in the NIR (850 nm), red (660 nm) and yellow (590 nm) ranges. Each session consists of four phases [ 17 ]: in the 1st and 3rd phases, the device delivers 35 s of pulsed yellow and NIR wavelengths while the patient’s eyes are open; in the 2nd and 4th phases, the device delivers 90 s of continuous red wavelength while the patient’s eyes are closed. Each session lasts a maximum of 5 min. Per the manufacturer’s instructions, all subjects received a total of 9 sessions (3 per week for 3 weeks, with a minimum of 24 h between consecutive applications). The first PBM application could be performed on the same day as the screening visit or within one week.

Statistical analyses

IBM Statistical Package for Social Science (SPSS) software (v. 21.0, IBM, Chicago, IL, USA) was used for statistical analysis.

The sample size was calculated for modifications in BCVA and relative retinal sensitivity. For BCVA, based on previous literature, an expected increase of 4 letters with a significance level of 5% and 80% power, assuming a standard deviation of the difference of 5 letters, yielded a required sample size of approximately 25 subjects. For relative retinal sensitivity, a hypothesized modification of 0.5 dB, with the same significance level and power, and assuming a standard deviation of the difference of 1 dB, resulted in a required sample size of approximately 34 subjects. Considering an estimated dropout rate of approximately 15%, the calculated sample size was adjusted to 40 patients. The normal distribution of all quantitative data was verified using the Shapiro-Wilk test; then, parametric or non-parametric tests were used accordingly for comparisons between different time points. The analysis of association between baseline variables and functional outcomes (if there was significant improvement) was performed at 90 days (i.e. BCVA, LLVA, CS) using a linear regression analysis with a stepwise procedure.

All data were presented as mean ± standard deviation. P-values were considered statistically significant if < 0.05.

We recruited 40 consecutive patients with early or intermediate AMD. Two patients did not complete the PBM protocol: one was lost to follow-up after three PBM applications and was unreachable; the other was hospitalized for a stroke between the screening and baseline visits. Both were excluded from the analysis.

The mean age of the 38 remaining subjects (24 females) was 78.5 ± 6.76 years. Hypercholesterolemia (≥200 mg/dl) was detected in 19 patients (50%) with an overall mean value of 198.68 ± 39,21 mg/dl. Average LDL and HDL levels were 139.22 ± 37.36 mg/dl and 59.46 ± 13.78 mg/dl, respectively. The mean level of triglycerides was 101.33 ± 39.99 mg/dl, with 2 patients having hypertriglyceridemia (≥200 mg/dl). Twenty-four patients (63,16%) were current or former smokers. No patients were taking Age-Related Eye Disease Studies (AREDS) supplements at the beginning of the study or during its duration.

No adverse events were reported during the intervention phase. Two subjects developed exudative macular type 3 neovascularization at W4 and W24 and were promptly treated with anti-VEGF intravitreal injections. These two patients were excluded from the analysis.

Functional analysis

Baseline mean BCVA (77.82 ± 5.83 ETDRS letters) improved significantly during the six-month follow-up period, peaking at W12 (82.44 ± 5.67 ETDRS letters, p  < 0.01). At W24, BCVA declined but remained significantly higher than baseline (80.05 ± 5.79 ETDRS letters, p  < 0.01).

Mean LLVA (61.18 ± 8.58 ETDRS letters at baseline) followed a similar trend, with the highest improvement at W12 (66.33 ± 8.55 ETDRS letters, p  < 0.01) and a slight decline at W24 (62.05 ± 9.71 ETDRS letters, p  = 0.02).

Mean CS (17 ± 9.30 ETDRS letters at baseline) improved at W12 (20.11 ± 9.23 ETDRS letters, p  < 0.01), but returned to baseline levels at W24 (16.45 ± 9.12 ETDRS letters, p  = 0.5).

For scotopic microperimetry, the mean absolute retinal sensitivity progressively decreased from 9.24 ± 3.44 dB to 7.47 ± 4.41 dB at W24 ( p  < 0.01). Mean relative retinal sensitivity (9.77 ± 3.05 dB) remained stable at W4 (9.21 ± 3.48 dB, p = 0.51) and W12 (9.25 ± 3.68 dB), but decreased at W24 (8.53 ± 3.73 dB, p  = 0.04). Table  1 .

Structural analysis

At baseline, HRF were present in 87% of patients, while SDD were present in 53% of patients.

Drusen volume was 0.021 ± 0.011 mm 3 in the central millimetre; DV3 was 0.165 ± 0.064 mm 3 and DV6 was 0.493 ± 0.114 mm 3 . DV significantly reduced at W4 (0.018 ± 0.009 mm 3 , p  < 0.01) and W12 (0.017 ± 0.009 mm 3 , p  < 0.01); however, at W24 it increased to 0.019 ± 0.012 mm 3 ( p  = 0.154). DV3 decreased at W4 (0.146 ± 0.056 mm 3 , p  < 0.01) and W12 (0.143 ± 0.054 mm 3 , p  < 0.01), but slightly increased at W24, remaining significantly lower than baseline (0.150 ± 0.068 mm 3 , p  = 0.03). DV6 also decreased from baseline at W4 (0.0459 ± 0.087 mm 3 , p  < 0.01), W12 (0.0455 ± 0.082 mm 3 , p  < 0.01), and W24 (0.0464 ± 0.102 mm 3 , p  < 0.01).

Post-hoc analysis with fellow eyes

In the subgroup of 18 patients with bilateral early or intermediate AMD, we compared treated and untreated eyes for each functional parameter. Treated eyes showed significant improvement in BCVA (from 77.67 ± 6.32 at baseline, to 82.18 ± 5.97 at W12 [ p  = 0.001] and 79.5 ± 6.44 at W24 [ p  = 0.096]) and, although temporarily, in LLVA (from 60.05 ± 12.49 at baseline, to 68.23 ± 6.78 at W12 [ p  < 0.001] and 63 ± 8.55 at W24 [ p  = 0.104]), and CS (from 18.33 ± 8.34 at baseline, to 21.06 ± 8.58 at W12 [ p  = 0.015] and 17.61 ± 8.84 at W24 [ p  = 0.460]). Untreated eyes showed no changes throughout the follow-up period (Fig.  1 ). Microperimetric assessment showed no differences between the two eyes. Mean absolute retinal sensitivity significantly decreased between baseline and W24 in both treated (8.8 ± 3.45 dB and 7.44 ± 4.8 dB, respectively, p  = 0.033) and untreated (8.33 ± 4.01 dB and 6.01 ± 3.79 dB, respectively, p  = 0.012) eyes (Fig.  1 ). Mean relative retinal sensitivity remained stable throughout the follow-up in both eyes (Fig.  1 ).

Best corrected visual acuity (top left), low luminance visual acuity (top middle), contrast sensitivity (top right), mean absolute scotopic retinal sensitivity (bottom left) and relative scotopic retinal sensitivity (bottom right) was compared between treated and untreated eyes.

Correlations

The difference in BCVA between W12 and baseline (ΔBCVA) was significantly correlated with baseline BCVA (standardized β coefficient = –0.613, p  < 0.001), baseline CS (β = 0.489, p  = 0.001) and triglyceride levels (β = –0.371, p  = 0.006) (Table  2 ).

Improvement in LLVA (ΔLLVA) at W12 was correlated only LDL levels (β = –0.452, p  = 0.006) (Table  2 ). Finally, ΔCS at W12 was correlated with DV6 (β = 0.335, p  = 0.040) and baseline LLVA (β = –0.323, p  = 0.047) (Table  2 ).

The objective of this study was to evaluate the effectiveness of PBM in the early and intermediate stages of dry AMD. Previous studies have reported the efficacy of PBM in limited patient populations with dry AMD, with only one being an independent study [ 17 , 18 , 19 ]. The PBM4AMD study is among the first independent investigations to introduce PBM in a hospital setting. All enrolled patients successfully completed the entire PBM cycle, which was well tolerated. Only two patients (5.2%) developed MNV during the course of the study (at 1 and 6 months, respectively). These patients were deemed at high risk for developing MNV prior to enrollment (i.e. exudative MNV in the fellow eye and the presence of imaging risk factors [ 22 ]). Therefore, these events were considered unrelated to PBM. Previous clinical studies using the same PBM instrument in AMD patients reported an incidence of MNV between 0 and 2.7% [ 17 , 18 , 19 ]. However, further studies with larger cohorts are necessary to definitively ascertain any potential association between the therapy and the onset of macular neovascularization.

Functional outcomes, including BCVA, LLVA, and CS, showed statistically significant improvements as early as 1 month after the intervention, with these improvements sustained over the following 2 months. These findings are consistent with previous studies demonstrating the clinical effectiveness of PBM in patients with dry AMD. The observed trend of BCVA improvement at 3 months, which diminishes at 6 months, aligns with previous research, suggesting the temporary nature of PBM’s effects and the potential need for reintervention [ 16 , 17 , 19 ]. Indeed, results from LIGHTSIGHT III demonstrated a sustained 5-letter improvement in BCVA after 1 year of repeated 4-month applications [ 15 ].

In a recent independent study, Benlhabib et al. reported a sustained 6-month gain of 5.5 ETDRS letters after a single PBM cycle [ 18 ]. The difference with our findings may be due to several factors: their study included only patients with central soft drusen, who might have experienced greater benefits due to drusen resorption over the long term [ 18 ] while our study included patients with early and intermediate AMD regardless of central involvement. Additionally, their study employed a different protocol spread over 5 weeks [ 18 ]. Further studies are needed to determine whether better patient selection or protocol modifications might enhance functional outcomes.

In addition to BCVA, our study evaluated LLVA and retinal sensitivity under scotopic conditions using microperimetry. LLVA is a good predictor of AMD progression, and scotopic microperimetry assesses rod function, which is primarily affected in this pathology. LLVA significantly increased (+4 ETDRS letters) after 3 months, further demonstrating PBM’s efficacy. However, absolute and relative mean retinal sensitivity under scotopic conditions declined and remained stable, respectively. Our cohort had a 53% prevalence of SDD, which are associated with a profound reduction in scotopic sensitivity [ 23 ]. It is plausible that rod function in these patients is already severely compromised, making recovery unlikely.

Drusen volume decreased significantly in all areas at 3 months, with a reduction of 0.022 mm 3 in the 6 mm ETDRS grid. None of the patients developed geographic atrophy (GA) due to drusen regression, suggesting that PBM may facilitate drusen material reabsorption and potentially slow disease progression. However, drusen growth and collapse are part of the disease’s natural history, possibly making our findings coincidental. Nevertheless, similar findings have been reported in previous PBM studies [ 17 , 18 , 19 ] whereas LIGHTSIGHT III found drusen volume remained stable over time, in contrast to growth in the control group [ 15 ].

Our study was the first to identify potential biomarkers for predicting functional outcomes. Baseline triglyceride and LDL levels were negative prognostic factors for increases in BCVA and LLVA, respectively. The relationship between blood lipid levels and AMD risk remains debated, with some evidence suggesting a protective role for triglycerides and LDL, while indicating a higher risk associated with HDL [ 24 ]. Further validation with larger sample sizes and more comprehensive lipid analyses is needed to draw clinically and prognostically relevant recommendations from our findings. Additionally, clarification of the relationship between lipid biomarkers and PBM efficacy is needed.

Baseline BCVA was inversely correlated with improvement in visual acuity at 3 months, indicating that patients with lower baseline BCVA were more responsive to PBM. However, all included patients had high visual acuity at baseline, which may have influenced this association due to the ceiling effect of current BCVA measuring techniques. The study also found a positive correlation between baseline DV and the increase in CS at 3 months, indicating that patients with higher baseline DV experienced greater reductions and improvements in retinal profile and photoreceptor functionality. The study’s limitations include the absence of a control group, precluding the exclusion of a placebo effect, and the lack of operator blinding. Additionally, the study reported only short-term results, leaving the long-term durability of PBM uncertain. These limitations should be considered when interpreting the results and drawing conclusions and a cautious and thoughtful approach is recommended in the analysis of the collected data. Nonetheless, the study’s strengths include its prospective design and comprehensive multimodal evaluation of patients in a specialized retinal pathology center.

In conclusion, this independent prospective study conducted in a hospital setting evaluated PBM for early and intermediate AMD. We observed temporary functional improvements and identified potential biomarkers associated with therapy outcomes. It is important to note that although statistically significant, the magnitude of functional improvement may not be clinically significant, especially for patients with already high visual acuity who may not perceive a qualitative difference. This also applies to the reduction of drusen volume, which still poses a risk for GA induction, not entirely ruled out in a short-term study.

The primary goal of treatment in early or intermediate AMD is to reduce the risk of developing late AMD. Based on the present results, PBM cannot be unequivocally interpreted as a treatment but rather as a potential temporary stabilization of the disease. In the context of stabilization, it may be necessary to perform multiple treatments to maintain the benefits provided. However, we still do not know the long-term safety implications of repeated applications, as there are currently no data extending beyond two years. PBM is registered as a medical device and is already available for application in private practices in several European countries; however, long-term efficacy and safety outcomes are still limited. Further independent studies are necessary to validate the current findings and to optimize patient selection for PBM.

What was known before:

Photobiomodulation (PBM) utilizes specific wavelengths of light, particularly near-infrared light, to modulate cellular pathways. Current hypotheses speculate that it promotes increased mitochondrial activity and cellular metabolism.

Age-related macular degeneration (AMD) is a chronic retinal disease causing irreversible central vision loss. Current treatments target advanced stages, but PBM, explored in clinical trials for early and intermediate AMD, shows promising safety and visual outcome results, with efficacy and prognostic factors still under investigation.

What this study adds:

The study demonstrated significant improvements in functional and structural outcomes, albeit temporary and of small magnitude.

The findings from this study provide valuable insights into the potential of PBM to stabilise early and intermediate stages of dry AMD.

The study’s outcomes underscore the importance of further research to validate and optimize patient selection for PBM therapy in AMD.

Data availability

Data supporting this study are available upon reasonable request to the corresponding author.

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Acknowledgements

This study was partially funded by Italian Ministry of Health, current research IRCCS.

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Ophthalmology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

Marco Nassisi, Claudia Mainetti, Gaia Leone, Davide Galli, Laura Dell’Arti, Chiara Mapelli, Giuseppe Casalino & Francesco Viola

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Marco Nassisi, Giorgia Rosapia Paparella, Luca Belloni Baroni, Paolo Milella, Francesco Pozzo Giuffrida & Francesco Viola

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Contributions

MN and FV conceptualized and designed the study, and supervised the research project. CM and DG led the data collection and management process. GRP, LBB, PM, GL, FPG, LDell’Arti, GC and CM were responsible for recruiting participants and managing the clinical aspects of the study. All authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

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Correspondence to Marco Nassisi .

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Nassisi, M., Mainetti, C., Paparella, G.R. et al. Short-term efficacy of photobiomodulation in early and intermediate age-related macular degeneration: the PBM4AMD study. Eye (2024). https://doi.org/10.1038/s41433-024-03326-4

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Received : 14 December 2023

Revised : 08 August 2024

Accepted : 04 September 2024

Published : 14 September 2024

DOI : https://doi.org/10.1038/s41433-024-03326-4

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