NIH Launches Long-Term COVID Clinical Trials Through RECOVER Initiative, Opening Enrollment

News release

Monday 31 July 2023

Today, the National Institutes of Health launched and is opening enrollment for Phase 2 clinical trials that will evaluate at least four potential treatments for prolonged COVID, with additional clinical trials to test at least seven more treatments expected in the coming months. Treatments will include drugs, biologics, medical devices and other therapies. The trials are designed to evaluate multiple treatments simultaneously to more quickly identify those that are effective. Part of the NIH Researcher in the COVID to Enhance Recovery (RECOVER) Initiative, the trials were based on findings from other RECOVER research over the past two years and focus on several of the symptoms described as most burdensome by people experiencing prolonged COVID. With its complementary research efforts, RECOVER has positioned NIH to design and conduct trials that have the potential to provide long-term COVID patients experiencing varying symptoms with relief faster than any individual study can alone.

“We know that when patients are suffering, we can never move fast enough,” said Acting NIH Director Lawrence A. Tabak, DDS, Ph.D. “NIH is committed to a highly coordinated and scientifically rigorous approach to finding treatments that will provide relief to the millions of people living with prolonged COVID.”

RECOVER is a large, nationwide research program designed to understand, treat and prevent protracted COVID-19, which is characterized by long-term symptoms following infection with SARS-CoV-2, the virus that causes COVID-19. The initial phase of the initiative involved launching large multi-site observational studies that examined and followed people through their experiences with COVID-19 to find out why some people develop long-term symptoms while others make a full recovery. These studies are ongoing and have recruited more than 24,000 participants to date. Researchers are also analyzing 60 million electronic health records and conducting more than 40 pathobiological studies on how COVID-19 affects different body tissues and organs. Data gathered from these efforts helped shape the development of phase 2 clinical trials, which test the safety and effectiveness of treatments typically in groups of 100-300 participants.

“Hundreds of RECOVER researchers and research participants are working hard to uncover the biological causes of prolonged COVID. The condition affects nearly every body system and presents with more than 200 symptoms,” said Walter J. Koroshetz, MD, director of the NIH’s National Institute of Neurological Disorders and Stroke, and co-leader of the RECOVER Initiative. “Recognizing that more than one solution is likely needed, we have taken the lessons learned from RECOVER participants to design rigorous clinical trial platforms that will identify treatments for people with different symptom clusters for to improve their functioning and well-being.”

The trials launched today will focus on viral persistence and cognitive dysfunction using “platform protocols“, a term used to describe the adaptive design of these trials.

RECOVER-VITAL will initially focus on a treatment aimed at SARS-CoV-2 persistence, which can occur if the virus stays in the body and causes the immune system not to function properly or damages the organs. The first intervention will test a longer dose regimen of the antiviral agent PAXLOVID (nirmatrelvir and ritonavir) than is used to treat acute COVID to see if it improves symptoms in patients with long-standing COVID. PAXLOVID is supplied by Pfizer, Inc., New York City, and is currently approved for the treatment of mild to moderate COVID-19 in adults who are at high risk of progression to severe COVID-19, including hospitalization or death. The first trial pages have been activated and are signing up.

RECOVER-NEURO will examine available interventions for cognitive dysfunction related to prolonged COVID, including brain fog, memory problems, and difficulty with attention, clear thinking, and problem solving. Interventions under this protocol will include a web-based brain training program called BrainHQ, developed by Posit Science Corporation in San Francisco, which has been used to improve cognitive function; PASC-Cognitive Recovery, a web-based goal management exercise program developed by Mount Sinai Health System, New York City, which has been used to improve executive function; and a device used for home-based transcranial direct current stimulation developed by Soterix Medical, Inc., Woodbridge, New Jersey, which has been shown to aid brain activity and blood flow. Trial pages are currently being activated.

Additional trials, based on the platform protocols below, which are still under review, will be launched in the coming months:

RECOVER SLEEP will test interventions for changes in sleep patterns or ability to sleep after having COVID-19. A trial for hypersomnia, or excessive daytime sleepiness, will test two wakefulness-promoting drugs compared to a placebo control. Another trial for sleep disorders, such as trouble falling or staying asleep, will test other interventions designed to improve sleep quality to see if those interventions can help regulate sleep patterns in adults with long-term COVID.

RECOVER-AUTONOMIC will investigate interventions to help treat symptoms associated with problems in the autonomic nervous system, which controls a range of body functions, including heart rate, breathing and digestive system activity. The initial trial will focus on postural orthostatic tachycardia syndrome (POTS), a disorder with a range of symptoms including irregular heartbeat, dizziness and fatigue, and will have multiple study arms. The first arm will evaluate a treatment used for immune disorders versus a placebo. The second arm will evaluate a drug currently used to treat chronic heart failure in people with an elevated heart rate against a placebo. Participants within each arm will then be randomized to receive either more intensive coordinated care that does not involve additional medication, or usual care.

A fifth platform protocol focusing on exercise intolerance and fatigue is being developed with input from the patient community and scientific experts.

All trials are designed to individually and collectively accelerate the identification of safe and effective treatments for some of the most debilitating symptoms of prolonged COVID. Study interventions were reviewed by teams of scientists and patient representatives and approved by NIH leadership based on ideas submitted through a May 2022 request for applications.

“Clinical trials to test effective treatments and interventions are a core component of the government-wide response to protracted COVID,” said Adm. Rachel L. Levine, MD, Assistant Secretary for Health, Department of Health and Human Services. “Together with appropriate supports and services, access to clinical care, and updated information about what we know about prolonged COVID-19, we can work toward relief for individuals and families most affected.”

RECOVER is committed to enrolling a study population that is inclusive and representative of the communities most affected by prolonged COVID. Campuses will partner with local communities to raise awareness of lingering COVID and offer opportunities to participate in the RECOVER clinical trials. Researchers developed the trials with extensive feedback from patient representatives, experts in symptom areas and proposed interventions, and after reviewing hundreds of proposals.

A data and safety monitoring committee consisting of an independent group of experts will monitor participant safety throughout the trial and make recommendations.

“Our patient and community representatives have provided critical input to help us ensure that the results of these trials are applicable to people across the country and become available as soon as possible,” said Kanecia Zimmerman, MD, Ph.D., MPH, Principal Investigator of the RECOVER Clinical Trials Data Coordinating Center, Duke Clinical Research Institute, Durham, North Carolina.

Trials will continue to launch and enroll participants on an ongoing basis. Enrollment will take place at clinical research sites throughout the United States. A track record for signing up different participants was a key criterion for choosing the venue. These trials will follow a traditional clinical trial recruitment strategy in that sites will contact their patients and community residents to enroll in the trials.

Those interested in learning more about the RECOVER trial should visit https://trials.recovercovid.org/.

About RECOVER: The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative is a $1.15 billion effort, including support through the American Rescue Plan Act of 2021, that seeks to identify how people recover from COVID-19, and who is at risk of developing post-acute sequelae of SARS-CoV-2 (PASC). Researchers are also working with patients, clinicians and communities across the United States to identify strategies to prevent and treat the long-term effects of COVID – including prolonged COVID. For more information, please visit recovercovid.org.

HHS Long COVID Coordination: This work is part of National research action plana broader government-wide effort in response Presidential Memorandum directs the Secretary of the Department of Health and Human Services to initiate a full and effective response to protracted COVID. Led by Assistant Secretary of Health Admiral Rachel Levine, the plan and its companion Services and support for long-term effects of COVID-19 The report lays the groundwork for advancing progress in the prevention, diagnosis, treatment and delivery of services for people experiencing prolonged COVID.

About the National Institutes of Health (NIH):NIH, the nation’s medical research agency, includes 27 institutes and centers and is part of the US Department of Health and Human Services. NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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