Preparing better: Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) therapeutics trials lessons learned: A call to the future

Abstract

The Accelerating COVID-19 Therapeutic Interventions and Vaccines Therapeutic-Clinical Working Group members gathered critical recommendations in follow-up to lessons learned manuscripts released earlier in the COVID-19 pandemic. Lessons around agent prioritization, preclinical therapeutics testing, master protocol design and implementation, drug manufacturing and supply, data sharing, and public-private partnership value are shared to inform responses to future pandemics.

Keywords: Covid-19; lessons learned; master protocol; therapeutics; trials.

Figure 1.

ACTIV therapeutics testing achievements. The ACTIV Therapeutics-Clinical Working Group and master protocols achieved a number of successes that furthered the global understanding of which therapies were and were not beneficial for treating COVID-19. Provided here is a snapshot of the high-level achievements to date of the ACTIV master protocols and their impact on the pandemic, patients, the scientific community, and knowledge of the disease. The figure summarizes the number of participants enrolled, global sites participating in the trials, the number of agents reviewed and tested in the trials, and the current number of journal articles and citations from this work. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines, ACTIV tx-clinical WG = ACTIV Therapeutic-Clinical Working Group, EUA = emergency use authorization, Lilly = eli Lilly and Company.

Figure 2.

ACTIV therapeutics-clinical working group overarching recommendations for future pandemic responses. The high-level takeaway lessons learned from the ACTIV master protocols can be organized topically in order of the overarching steps of establishing the platform, including prioritizing potential agents, utilizing preclinical data, creating the master protocols, implementing the master protocols, gathering, analyzing, and sharing data, handling logistics of manufacturing and drug scaling, and utilizing the PPP network. These lessons build on those from publications released earlier in the pandemic by the ACTIV Therapeutics-Clinical Working Group. MOAs = mechanisms of action, PPP = publicprivate partnership, RWD = real-word data, US = United States.

Figure 3.

Results of compounds tested in the ACTIV master protocols. Status at the time of report submission of the 37 agents and compounds tested in the ACTIV trials. Determination of an agent as either successful or unsuccessful in one of the master protocols is determined by the completion of the predetermined primary or significant secondary endpoints of trials. The dark blue box on the left reflects the agents tested in any of the 11 ACTIV master protocols that were determined at any interim review to have met the criteria to stop the trial early due to preset futility boundaries; agents that were stopped due to a company decision to no longer pursue the agent; or agents that were ceased due to operational futility causing an in ability to complete enrollment in the given patient population as the pandemic progressed. The light blue box in the middle reflects those agents that completed full enrollment of the prespecified number of patients for their sub-study within the master protocol, but upon final statistical analysis did not achieve significance according to prespecified primary endpoints. The green box in the right reflects the agents that upon testing proved efficacious either by prespecified primary endpoints or significant secondary endpoints within the master protocols. Finally, the yellow box at the bottom reflects those agents that are still undergoing testing within one of the 11 master protocols or statistical analysis by the trial teams and therefore their outcomes are unknown at the time of this report. ACTIV = accelerating COVID-19 Therapeutic Interventions and Vaccines, EUA = emergency use authorization, IM = intramuscular injection, IV = intravenous.

Figure 4.

Summary of ACTIV therapeutics master protocols. The 11 ACTIV master protocols tested 37 single agents or combinations. This table summarizes the important design aspects for each protocol, including the patient population studied, phase of the trial, drug class researched, networks leading the conduct of the trial, target sample size for each trial arm, and finally the agents tested. ACTG = AIDS Clinical Trials Group, ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines, ARDS = acute respiratory distress syndrome, ARI = acute respiratory infection, AZ = astraZeneca, BMS = bristol myers squibb, CONNECTS = Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies, CTSN = Cardiothoracic Surgical Trials Network, CRO = Contract Research Organization, DCRI = Department of Clinical Research Informatics, INSIGHT = International Network for Strategic Initiatives in Global HIV Trials, lilly = eli Lilly and Company, mAbs = monoclonal antibodies, NCATS = National Center for Advancing Translational Sciences, NHLBI = National Heart, Lung, and Blood Institute, NIAID = National Institute of Allergy and Infectious Diseases, OTC = over-the-counter, PETAL = prevention and early treatment of lung injury, PCORnet = National Patient-Centered Clinical Research Network, SGLT2 = sodium-glucose cotransporter-2, TIN = Trial Innovation Network, TRI = Technical Resources International, inc, VA = veterans affairs.