Virus World

Patients admitted with COVID-19 at select hospitals may now volunteer to enroll in a clinical trial to test the safety and efficacy of a potential new treatment for the disease. The Phase 3 randomized, controlled trial is known as ACTIV-3, and as a “master protocol,” it is designed to expand to test multiple different kinds of monoclonal antibody treatments. It also can enroll additional volunteers in the middle of the trial, if a specific investigational treatment shows promise. The new study is one of four ongoing or planned trials in the National Institutes of Health’s. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, a public-private partnership to speed development of the most promising treatments and vaccine candidates. It also is receiving support through Operation Warp Speed(link is external), the U.S. government’s multi-agency effort to develop, manufacture and distribute medical countermeasures to fight COVID-19.

The trial will take place at select hospitals around the world that are part of existing clinical trial networks. They include the lead network, the International Network of Strategic Initiatives in Global HIV Trials (INSIGHT), operated by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health. Collaborating clinical trial networks include the Prevention and Early Treatment of Acute Lung Injury network (PETAL) and Cardiothoracic Surgical Trials Network (CTSN), supported by the NIH’s National Heart, Lung and Blood Institute through the Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) program, and the U.S. Department of Veterans Affairs Medical Centers. ACTIV-3 uses an adaptive two-stage Phase 3 protocol design. The ACTIV-3 trial can be modified to test additional experimental therapeutics and flexibly allow novel therapeutics to enter at either stage 1 or stage 2. In addition, if a treatment appears to be safe and effective in the initial stage after review by an independent data and safety monitoring board (DSMB), the investigational therapeutic proceeds to stage 2 testing, where more volunteers are enrolled. If an investigational therapeutic is unsafe or not likely to be effective, it will be dropped...

The initial stage of the ACTIV-3 clinical trial aims to enroll approximately 300 volunteers who have been hospitalized with mild to moderate COVID-19 with fewer than 13 days of symptoms. Once their COVID-19 infections have been confirmed and they have consented to take part in the study, participants will be randomly assigned to receive either an intravenous (IV) infusion of LY-CoV555 or a saline placebo infusion. Participants also will receive standard care for COVID-19, including the antiviral remdesivir. After five days, participants’ symptoms will be assessed, as will their need for supplemental oxygen, mechanical ventilation, or other supportive care. Volunteers will be followed for 90 days after enrollment and will receive regular examinations and have blood samples taken periodically during this time to analyze their response to the investivational therapeutic. Data collected on the fifth day of the volunteers’ participation will determine whether the investigational therapeutic will be administered to a larger group of volunteers. If LY-CoV555 appears to be safe and appears to be effective, the trial will enroll an additional 700 participants. It also will begin enrolling more severely ill participants, such as those with organ failure requiring mechanical support, or COVID-19-associated dysfunction of organs other than the lungs. The primary endpoint of the trial is the participants’ sustained recovery for 14 days after release from the hospital. The principal investigator of ACTIV-3 is Jens Lundgren, M.D., of the University of Copenhagen and Rigshospitalet. Leads of the participating networks include James Neaton, Ph.D., of the INSIGHT network, Taylor Thompson, M.D., of the PETAL network, Annetine Gelijns, Ph.D., and Alan Moskowitz, M.D., of the CTSN, and Rachel Ramoni, D.M.D., Sc.D., of the U.S. Department of Veterans Affairs. To ensure that the trial is being conducted in a safe and effective manner, an independent DSMB will oversee the trial and conduct periodic reviews of the accumulating data...

Initial trial to determine if monoclonal antibodies can shorten severity of COVID-19 in outpatients. Study aims to determine safety and efficacy of experimental monoclonal antibodies. A Phase 2 clinical trial will evaluate the safety and efficacy of potential new therapeutics for COVID-19, including an investigational therapeutic based on synthetic monoclonal antibodies (mAbs) to treat the disease. Researchers sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, are working with clinical sites to identify potential patient volunteers currently infected with SARS-CoV-2, the virus which causes COVID-19, who have mild to moderate disease not requiring hospitalization. They will be invited to take an experimental therapy or a placebo as part of a rigorously designed randomized clinical trial. The trial, which is known as ACTIV-2, also may investigate other experimental therapeutics later under the same trial protocol. If the investigational mAbs show promise, the study would expand from a Phase 2 to a Phase 3 trial to gather additional critical data from a larger pool of volunteers without delay. The trial will be led by the NIAID-funded AIDS Clinical Trials Group (ACTG) and will enroll participants at sites around the world.

ACTIV-2 was established as part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program instituted to speed development of the most promising treatments and vaccines. This study is also receiving support through Operation Warp Speed(link is external), the U.S. government’s multi-agency effort to develop, manufacture and distribute medical countermeasures to fight COVID-19. The design of the study is adaptive to enable maximum flexibility in the shortest time frame. If the experimental treatment appears effective in the first stage, the treatment can be advanced rapidly to testing in larger groups of volunteers. The study also can be adapted to test additional therapeutics. “We have seen encouraging, rapid results from other adaptive treatment trials for COVID-19,” said NIH Director Francis S. Collins, M.D., Ph.D. “Under ACTIV, specific therapeutics are being prioritized based on their likelihood for success. Prioritized therapeutics under ACTIV will use a master protocol that emphasizes flexibility, which enables these critical trials to be conducted without incurring delays when a treatment shows promise.”

The first therapeutic to be tested in this trial will be LY-CoV555, an investigational monoclonal antibody made by Eli Lilly and Company (Indianapolis, Indiana). LY-CoV555 emerged from Lilly’s collaboration with AbCellera Biologics (Vancouver, British Columbia). Antibodies are infection-fighting proteins produced by immune cells. So-called neutralizing antibodies target specific viruses or other pathogens. This antibody, which was discovered by AbCellera in collaboration with NIAID’s Vaccine Research Center, was isolated from a blood sample from a recovered COVID-19 patient. Copies of this antibody were then synthesized in a lab—the term “monoclonal” refers to these laboratory-manufactured antibodies. “Using an antibody generated by the immune system of a recovered COVID-19 patient gives us a jump start on finding a safe and effective therapeutic,” said NIAID Director Anthony S. Fauci, M.D. “Investigating a variety of different therapeutics, including monoclonal antibodies, will help ensure that we advance towards an effective treatment for people suffering from COVID-19 disease as quickly as possible.”...