The National Institutes of Health (NIH) sponsored Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partners involved with determining where federal research dollars are allocated for COVID-19 research recently announced its “ACTIV-3” clinical trial program focusing on monoclonal antibody therapy for patients hospitalized with COVID-19 closed enrollment in two of the sub-studies including one examining the investigational monoclonal antibody therapy VIR-7831 (Vir Biotechnology and GSK partnership) and another involving the investigational combination monoclonal antibody therapy containing BRII-196 and BRII-198 (China’s Brii Biosciences). The latter study just recently launched and was reported on in TrialSite. These sub-studies were halted by the trial sponsor, the national Institute of Allergy and Infectious Diseases (NIAID), part of the NIH on March 1, 2021 following an interim review and recommendation from the independent Data and Safety Monitoring Board (DSMB).
What is ACTIV-3
ACTIV-3, part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership, is a master protocol designed to allow for the study of multiple investigational agents compared to placebo in adults hospitalized with COVID-19. All trial participants receive Veklury (remdesivir), a drug approved by the Food and Drug Administration for the treatment of COVID-19 in hospitalized patients. The trial is divided into sub-studies, each of which evaluates a different candidate therapeutic. After five days, the clinical status of the participants is assessed using two seven-point ordinal scales. Each scale ranges from being able to undertake usual activities with minimal or no symptoms, to death. After approximately 150 participants are enrolled in each sub-study and 150 enrolled in the corresponding placebo group, the DSMB conducts a pre-planned interim safety and efficacy review to determine if the sub-study should be expanded to enroll additional participants or if it should be closed.
Why did the DSMB shut the studies down?
As reported on in a recent NIH press release, the DSMB analysis determined that the Brii therapeutic did not meet the inclusion criteria for further enrollment in the trial, due to futility. The initial analysis of data from the VIR-7831 sub-study indicated that the investigational treatment met the pre-specified criteria for study continuation. However, participants entering the control group had more advanced illness overall than those enrolling in the group receiving the therapeutic, so the data were adjusted to account for this imbalance. Once this difference was taken into account, the DSMB recommended that recruitment in the VIR-7831 sub-study should cease, due to futility.
No Safety Issues
The studies were not ceased due any safety issues and there was no indication of harm in the therapeutic arms compared to the placebo arm.
The Investigational Products
Developed by Vir Biotechnology, Inc. (San Francisco), the company came together with GlaxoSmithKline (GSK) to develop investigational products while BRII-196 and BRII-198 are produced by a biotech headquartered in China called Brii Biosciences. The company’s American base is in Durham, NC.
As far as those participants that have been treated The DSMB reviewed data on 344 people in the VIR-7831 sub-study and 343 people in the Brii-196 and Brii-198 combination sub-study. Volunteers in both sub-studies will continue to be followed for 18 months. Currently, NIAID and trial coordinating investigators are analyzing the data, and they will provide more information in a forthcoming report.
ACTIV-3 Ongoing: AstraZeneca’s Long-Acting mAbs
Participants continue to be enrolled in the ACTIV-3 sub-study evaluating AZD7442, an investigational long-acting antibody combination developed by biopharmaceutical company AstraZeneca (Cambridge, United Kingdom). The DSMB will review the safety and efficacy of this sub-study once approximately 300 participants have been enrolled.
ACTIV-2 Trial Continues with BRII-196 & BRII-198
The NIAID-supported ACTIV-2 trial will continue to test the BRII-196 and BRII-198 combination monoclonal antibody therapeutic regimen in people with mild-to-moderate COVID-19 who have not required hospitalization. It is being overseen by the same DSMB that oversees ACTIV-3, and the DSMB does not recommend any changes to ACTIV-2 at this time, reports the NIH.