Researchers with the National Institutes of Health (NIH) have started an adaptive Phase III trial, designed to determine the safety and efficacy of three immune modulator drugs in treating adult patients hospitalized with COVID-19. According to the team, the study centers around the immune response known as cytokine storm, in which a patient’s immune system releases high large of amounts of proteins that trigger inflammation, which can lead to acute respiratory distress syndrome and other potentially life-threatening complications.
The goal of the trial is to ascertain if modulating this extreme immune response can help reduce the need for ventilators and reduce the length of hospital stays that COVID-19 patients must indures. Known as “ACTIV-1 Immune Modulators,” the trial reportedly will determine if these specific therapies can quell an overwhelmed immune system and restore balance.
“This is the fifth master protocol to be launched under the ACTIV [Accelerating COVID-19 Therapeutic Interventions and Vaccines] partnership in an unprecedented timeframe, and focuses efforts on therapies that hold the greatest promise for treating COVID-19,” said NIH director Francis Collins. “Immune modulators provide another treatment modality in the ACTIV therapeutic toolkit to help manage the complex, multi-system conditions that can be caused by this very serious disease.”
Trial administrators expect to enroll more than 2,000 hospitalized adults with moderate to severe COVID-19 at medical facilities in the US and Latin America. The National Center for Advancing Translational Sciences (NCATS), part of NIH, will coordinate and oversee the trial; the Biomedical Advanced Research and Development Authority (BARDA) of the US Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, will offer funding support.
BARDA’s Clinical Studies Network will be responsible for operationalizing the trial through a task order awarded to contract research organization (CRO) Technical Resources International Inc.
ACTIV-1 IM is a randomized, placebo-controlled trial that uses an adaptive master protocol. Master protocols reportedly allow coordinated, efficient evaluation of multiple investigational agents as they become available, which enables flexibility needed to weed out drugs that do not demonstrate effectiveness, identify those that do in a short time frame and rapidly incorporate additional experimental agents into the trial.
The ACTIV public-private partnership selected three agents for the study from a pool of more 130 immune modulators based on several factors, including relevance to COVID-19, strong evidence for use against inflammatory reaction and cytokine storm and availability for large-scale clinical studies. The initial agents are:
- infliximab (REMICADE), developed by Janssen Research & Development, LLC., one of the Janssen Pharmaceutical Companies of Johnson & Johnson
- abatacept (ORENCIA), developed by Bristol Myers Squibb
- Cenicriviroc (CVC), an investigational late-stage agent developed by AbbVie.
Trial participants also will receive doses of remdesivir, currently widely considered the standard of care treatment for patients hospitalized with COVID-19. Additionally, convalescent plasma and dexamethasone may be permitted by the site investigator and in accordance with national guidelines.
Patients will be randomly assigned to receive a placebo or one of the immune modulators as an add-on treatment. The trial will study the different combination treatment regimens with respect to illness severity, recovery speed, mortality and hospital resource utilization.
Enrollment has launched, and the trial is anticipated to last about six months. Researchers expect results to be made available shortly after the trial is completed, possibly sooner
The protocol team chair is William Powderly, director of the Institute for Clinical and Translational Sciences and co-director of the Division of Infectious Diseases at Washington University School of Medicine in St. Louis. NCATS’ Clinical and Translational Science Awards (CTSA) Program and the Trial Innovation Network reportedly will play a key role in adding US study sites and enrolling patients, including those from communities disproportionately affected by COVID-19.
“The CTSA Program’s nimbleness and innovation in conducting clinical trials—along with the network’s extensive capacity and broad geographical reach—have positioned it to rapidly implement this important trial,” said NCATS director Christopher Austin. “The innovative trial design will allow efficient evaluation of three different potential COVID-19 treatments concurrently, delivering new possible treatments for patients more quickly and valuable insights into the science of clinical translation.”
NIH announced the ACTIV initiative in April 2020 to develop a national research response to prioritize and speed the development of the most promising COVID-19 treatments and vaccines. Coordinated by the Foundation for the National Institutes of Health, ACTIV brings together partners from government, industry, academia and non-profit organizations.