Initial Trial to Determine if Monoclonal Antibodies Can Shorten Severity of COVID-19 in Outpatients
August 4, 2020
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, 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.”
The initial stage of the trial is designed to enroll approximately 220 volunteers who report recently experiencing symptoms of COVID-19 and who test positive for the virus but are not hospitalized. Once enrolled, they will be randomly assigned to one of two groups: 110 volunteers will receive an intravenous (IV) infusion of LY-CoV555, and 110 volunteers will receive a placebo infusion of a saline solution. The infusion takes approximately an hour to deliver, and volunteers will be observed afterwards to note any reactions.
Over the next 28 days, participants will attend a series of clinic or at-home visits by clinicians to track their COVID-19 symptoms. Investigators also will check whether RNA from SARS-CoV-2, can still be detected in participants’ noses and saliva using a standard nasopharyngeal swab. Because people with COVID-19 often have unusually low blood oxygen levels, participants will receive pulse oximetry tests to help determine if the investigational therapeutic has a positive effect on blood oxygen levels. They also will give blood samples to help researchers understand how the experimental therapeutics are functioning in their bodies, as well as whether they are affecting the course of their SARS-CoV-2 infection. Participants will receive additional follow-up for up to 24 weeks.
The primary goals of the Phase 2 trial are to evaluate safety, to see if the investigational therapeutic can reduce the duration of symptoms through study day 28, and to see if the investigational therapeutic can increase the proportion of participants with undetectable virus in nasopharyngeal swabs at specific time points. If there are no serious safety concerns and if the investigational therapeutic appears to meet other specific other criteria (such as sufficiently reducing the duration of symptoms or the viral load in the volunteers’ bodies), the trial will transition to Phase 3 and enroll up to 1,780 additional outpatient volunteers, for a total of 2,000 trial participants. The primary goal of the Phase 3 study will be to determine if the investigational therapeutic can prevent either hospitalization or death through study day 28 while also continuing to evaluate its safety. Participants in the Phase 3 portion of the study will not be provided nasopharyngeal swabs, though they will still perform self-collected anterior nasal swabs, and they will attend fewer clinic visits.
The study team is led by Protocol Chair Davey Smith, M.D., of the University of California, San Diego, David Wohl, M.D., of the University of North Carolina at Chapel Hill (UNC), and Kara W. Chew, M.D., and Eric S. Daar, M.D., both of the University of California, Los Angeles (UCLA),serve as protocol vice-chairs. The ACTG network is led by chair Judith Currier, M.D. (UCLA) and co-chair Joseph Eron, M.D. (UNC).
To ensure that the trial is being conducted in a safe and effective manner, an independent data and safety monitoring board will oversee the trial and periodically review the accumulating data.
ACTIV-2 Clinical Trial to Evaluate Monoclonal Antibodies and Other Potential COVID-19 Treatments in People with Mild-to-Moderate Symptoms
This clinical trial, called ACTIV-2, will evaluate the safety and efficacy of investigational therapeutics as a treatment for participants currently infected with SARS-CoV-2 and experiencing mild-to-moderate COVID-19 that does not require hospitalization. The adaptive Phase 2 clinical trial will begin by evaluating LY-CoV555, an experimental monoclonal antibody treatment made by Lilly Research Laboratories, Eli Lilly and Company (based in Indianapolis), in partnership with AbCellera Biologics (Vancouver, British Columbia). AbCellera and scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, isolated the LY-CoV555 antibody from a blood sample from a patient who recovered from a confirmed case of COVID-19. The antibody was copied and then synthesized in a laboratory—the term “monoclonal” refers to these laboratory-manufactured versions of proteins naturally produced by the immune system in response to invading viruses or other pathogens.
The trial will begin by evaluating the LY-CoV555 monoclonal antibody but is designed to test other investigational therapeutics as they become available.
NIAID is the regulatory sponsor and holder of the investigational drug application to conduct the ACTIV-2 study. The trial is being funded by NIAID through “Operation Warp Speed,” a partnership led by the U.S. Department of Health and Human Services to invest in and coordinate the development, manufacturing and distribution of COVID-19 diagnostics, therapeutics, and vaccines.
The clinical trial is one of four ongoing or planned trials in NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, a public-private partnership or initiative to speed development of the most promising treatments and vaccine candidates.
The study team will be led by Protocol Chair Davey Smith, M.D., M.A.S., of the University of California, San Diego. David Wohl, M.D., of the University of North Carolina at Chapel Hill (UNC), and Kara W. Chew, M.D., and Eric S. Daar, M.D., both of the University of California, Los Angeles (UCLA), will serve as protocol co-chairs.
The NIAID-funded AIDS Clinical Trials Group, which is led by chair Judith Currier, M.D. (UCLA), and co-chair Joseph Eron, M.D. (UNC), will conduct the ACTIV-2 clinical trial.
The study will have approximately 40 sites.
The study is a randomized, blinded, placebo-controlled clinical trial that will begin as a Phase 2 clinical trial to evaluate the safety and efficacy of investigational agents for the treatment of symptomatic non-hospitalized adults with COVID-19. The trial is designed to allow investigational treatments to be added and dropped during the study to efficiently test new agents against placebo within the same trial infrastructure. Although the trial is starting as a Phase 2, it is designed to seamlessly transition into a larger Phase 3 clinical trial.
At this initial stage of the Phase 2 clinical trial, researchers plan to enroll approximately 220 adults with a documented positive SARS-CoV-2 test within 7 days of study entry and within 10 days of experiencing the first symptoms of infection at time of study entry. Approximately 220 study participants will be randomized to receive either an intravenous infusion of the investigational monoclonal antibody LY-CoV555 or an IV infusion of placebo (saline solution). The randomization of the volunteers to the study arms will be stratified based on time of symptom onset (less than or equal to 5 days versus greater than 5 days) and “high” versus “low” risk of progression to severe COVID-19, so that proportions of these individuals will be balanced between the study arms. “High risk” is defined as volunteers who are: 55 years and older or have at least one of the following conditions: chronic lung disease or moderate-to-severe asthma; severe obesity (body mass index greater than 35); hypertension; cardiovascular disease (including history of stroke); diabetes; chronic kidney disease; or chronic liver disease.
Once study volunteers have finished the hour-long infusion process, they will be monitored immediately afterward for any adverse reaction. For 28 days following the infusion, participants will receive intensive follow-up to include a series of clinic or at-home visits by study clinicians to track the volunteers’ COVID-19 symptoms. Participants will also be monitored over time to determine if SARS-CoV-2 viral genetic material can still be detected in their noses and saliva. Oxygen levels will be monitored at study visits using pulse oximetry performed by study staff to determine if the experimental treatment is having a positive effect on blood oxygen levels. Additionally, volunteers will be asked to provide blood samples to evaluate safety parameters and markers of inflammation. Participants will receive additional, periodic follow-up for up to 24 weeks.
An independent data and safety monitoring board (DSMB) will regularly review the clinical trial’s safety and efficacy data. The DSMB can recommend that NIH terminate the study at any time if deemed necessary for safety reasons. The DSMB for this trial is a multi-disciplinary team.
The primary goals of the Phase 2 trial are to evaluate whether the investigational treatment is safe; reduces the duration of COVID-19 symptoms through 28 days; and can increase the proportion of volunteers with undetectable virus in nasopharyngeal swabs at days 3, 7, 14, 21 and 28 following infusion. If there are no serious safety concerns and the experimental treatment demonstrates benefits related to duration of symptoms, virus levels or level of oxygenation, the study may transition to a Phase 3 clinical trial enrolling a larger number of study volunteers to see if it reduces the risk of hospitalization and/or death.
The trial sites that are being used for the ACTIV-2 study have experience enrolling diverse populations into clinical trials. In Phase 2, the sites will primarily be in the United States; however, when investigational therapeutics progress to Phase 3, sites outside the U.S. will be added. In addition, the study team is working with NIAID and others within the NIH, as well as representatives from professional and community-based organizations, to develop effective outreach into communities most impacted by COVID-19, including African-American, Latinx, and Native American communities. A COVID-19 community advisory board has also been assembled and will assist in guiding these efforts, reviewing study-related materials to ensure that they are culturally appropriate and that information about the study is clear, understandable, and relevant to these diverse communities. The ACTG’s Under-represented Populations Sub-Committee will also provide assistance as study leadership and staff develop and implement approaches for engaging and recruiting racially and ethnically diverse participants.
Approximately 8 weeks.
The study is designed to add other investigational treatments as they become available. Each new investigational therapeutic will be compared to a shared placebo group.