April 19, 2021
Using an ACTIV master protocol, the trial will focus on potential interventions for mild-to-moderate illness
The National Institutes of Health will fund a large, randomized, placebo controlled Phase 3 clinical trial to test several existing prescription and over-the-counter medications for people to self-administer to treat symptoms of COVID-19. Part of the Accelerating COVID 19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership, the ACTIV-6 trial aims to provide evidence-based treatment options for the majority of adult patients with COVID-19 who have mild-to-moderate symptoms and are not sick enough to be hospitalized. NIH will provide an initial investment of $155 million in funding for the trial.
“While we’re doing a good job with treating hospitalized patients with severe disease, we don’t currently have an approved medication that can be self-administered to ease symptoms of people suffering from mild disease at home, and reduce the chance of their needing hospitalization,” said NIH Director Francis S. Collins, M.D., Ph.D. “ACTIV-6 will evaluate whether certain drugs showing promise in small trials can pass the rigor of a larger trial.”
Several drugs currently are recommended for the treatment of hospitalized patients with moderate to severe COVID-19, including the antiviral drug remdesivir, the anti-inflammatory baricitinib, and corticosteroids. Additionally, the U.S. Food and Drug Administration authorized emergency use of intravenous monoclonal antibodies in non-hospitalized patients with mild to moderate COVID-19 who are at high risk for severe disease. However, medications that can be self-administered at home to reduce COVID-19 symptoms are critically needed.
The ACTIV-6 protocol will explore a pool of up to seven drugs approved by FDA for other conditions — an approach called drug repurposing — and test their safety and effectiveness in treating mild to moderate COVID-19. Because the drugs under consideration already have been tested in humans, repurposing could deliver COVID-19 treatment options sooner. Drugs will be administered orally or by inhaler and will be easy for participants to take at home. Participants will be assigned randomly to receive either a placebo or one of the treatments, which will be sent to them by mail.
Enrollment is expected to open in a few weeks to up to 13,500 participants who are at least 30 years old, have tested positive for SARS-CoV-2 infection and have experienced two or more mild-to-moderate symptoms of COVID-19 for no more than seven days. Researchers plan to assess changes in patients’ symptoms over a 14-day period, as well as hospitalizations and deaths over a 28-day period. They also will assess long-term COVID-19-related symptoms at 90 days after treatment begins. The list of drugs that will be added to the study arms is still being finalized. All the drugs will have established safety records and early indications from smaller or less controlled studies of effectiveness against COVID-19.
The trial will focus on enrollment of people within minority, rural and other communities that are significantly affected by COVID-19 but lack access to major academic medical centers, where large clinical trials usually take place.
With funding provided by the American Rescue Plan Act, NIH’s National Center for Advancing Translational Sciences (NCATS) will oversee the trial. The Duke Clinical Research Institute, Durham, North Carolina, an NCATS-funded Clinical and Translational Science Awards (CTSA) Program hub, will serve as the clinical coordinating center, and the Vanderbilt Institute for Clinical and Translational Research CTSA Program hub at Vanderbilt University Medical Center, Nashville, Tennessee, will serve as the trial’s data coordinating center.
To expedite enrollment in ACTIV-6, NCATS and its Duke-Vanderbilt Trial Innovation Center will partner with the Patient-Centered Outcomes Research Institute (PCORI), an independent nonprofit research funding organization. PCORnet, the National Patient-Centered Clinical Research Network, which is funded by PCORI, will support the ACTIV-6 governance and operations. In addition, PCORnet sites will enroll participants from a broad range of communities.
“Getting approval for a new drug to come to market usually takes years,” said Joni Rutter, Ph.D., NCATS acting director. “By leveraging drug repurposing and existing national clinical trial networks, ACTIV-6 aims to speed the delivery of definitive answers about available drugs that could help people manage COVID-19 symptoms at home.”
Media Contact: NCATS Information Officer, email@example.com
Questions & Answers
How are drugs selected for this trial?
The selection process for ACTIV trials is described in detail in “Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines — Selecting Compounds for Clinical Evaluation in Coronavirus Disease 2019 Clinical Trials.” For ACTIV-6, compounds were selected based on a number of factors, including known safety profiles, route of administration (oral drugs were prioritized for ACTIV-6), early clinical and real-world evidence of effectiveness in treating COVID-19, and level of public and scientific interest. See the article and supplemental content for more details.
The first round of ACTIV-6 agent prioritization ended in April 2021. Four agents received high priority rankings and three of these agents — ivermectin, fluvoxamine and fluticasone — currently are being tested in ACTIV-6.
A second round to prioritize additional potential treatment candidates for ACTIV-6 was held in October 2021 so that replacement drugs will be available in the event that the ongoing arms are stopped early for safety or futility (e.g., lack of effect). Drug combinations — such as fluvoxamine/fluticasone and ivermectin/fluvoxamine — were considered in the second round of agent prioritization for ACTIV-6.
What drugs currently are being studied in ACTIV-6?
Enrollment is open to test the safety and effectiveness of ivermectin, fluvoxamine and fluticasone in treating mild to moderate COVID-19 symptoms at home. Agent prioritization is ongoing, and additional study arms may open. For the latest information on the drugs being studied, visit the ACTIV website.
If the drugs to be tested in ACTIV-6 are approved already by the FDA and show some evidence of efficacy in COVID-19, why is a randomized, controlled clinical trial necessary?
Anecdotal evidence and small observational studies are not enough to determine if a treatment is effective at relieving symptoms in mild to moderate COVID-19. Robust data from randomized, placebo-controlled clinical trials like ACTIV-6 are necessary for the FDA to approve the use of one or more of the ACTIV-6 drugs as a COVID-19 treatment and to inform specific, evidence-based guidance on how to effectively use the drugs as a COVID-19 treatment. See the Coronavirus Disease 2019 (COVID-19) Treatment Guidelines for more information about ivermectin (page 125) and fluvoxamine (page 228).
Is ivermectin a safe treatment for COVID-19?
NIH’s COVID-19 Treatment Guidelines Panel has determined that data are currently insufficient to recommend either for or against the use of ivermectin for treatment of COVID-19. Results from adequately powered, well-designed and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19. Ivermectin is not authorized or approved by the FDA for prevention or treatment of COVID-19.
When will results from ACTIV-6 be available?
Enrollment is underway and results will be available shortly after the trial is completed — approximately 2 years — or possibly sooner, if analysis conducted during the trial indicates that one or more of the drugs is beneficial. When possible, interim results will be shared with other investigators or made public so that access to beneficial drugs can be accelerated.
About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.
NIH…Turning Discovery Into Health®