Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics

Abstract

Working in an unprecedented time frame, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership developed and launched 9 master protocols between 14 April 2020 and 31 May 2021 to allow for the coordinated and efficient evaluation of multiple investigational therapeutic agents for COVID-19. The ACTIV master protocols were designed with a portfolio approach to serve the following patient populations with COVID-19: mild to moderately ill outpatients, moderately ill inpatients, and critically ill inpatients. To facilitate the execution of these studies and minimize start-up time, ACTIV selected several existing networks to launch the master protocols. The master protocols were also designed to test several agent classes prioritized by ACTIV that covered the spectrum of the disease pathophysiology. Each protocol, either adaptive or pragmatic, was designed to efficiently select those treatments that provide benefit to patients while rapidly eliminating those that were either ineffective or unsafe. The ACTIV Therapeutics-Clinical Working Group members describe the process by which these master protocols were designed, developed, and launched. Lessons learned that may be useful in meeting the challenges of a future pandemic are also described.

Figure 1.. Organization of the ACTIV partner leadership and working groups.

ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; FDA = Food and Drug Administration; NIH = National Institutes of Health. (Reproduced from Collins and Stoffels [1] with permission of the Journal of the American Medical Association.).

Appendix Figure 1.. Priority populations for ACTIV.

To appropriately prioritize agents for the master protocols, the desired target populations needed to be agreed on by the ACTIV Therapeutics-Clinical Working Group. After much deliberation, the group decided given the high hospitalization and death rate early in the pandemic that the COVID-19 patient population would be prioritized in the following order for agent review: 1) hospitalized/moderately ill (non-ICU) and critically ill/ventilated (ICU), 2) outpatient/ambulatory ill, and 3) prophylaxis. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; ICU = intensive care unit.

Figure 2.. Design decisions for ACTIV master protocols.

Each decision made for the master protocols was critical for tailoring them to the specific needs of the patients and the portfolio of studies that ACTIV was seeking to create to best address the therapeutic testing needs for the pandemic. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines.

Figure 3.. Summary of ACTIV master protocols along disease progression and their current status.

The top illustration outlines the disease progression and how each ACTIV master protocol targets the individual patient population. Our understanding of viral and immunomodulatory responses throughout the disease progression continues to evolve as we learn from available clinical data. ACTIV-1 is a phase 3 master protocol that tests promising immune modulators. ACTIV-2 is designed as a phase 2 trial that can expand seamlessly to phase 3 to evaluate the efficacy and safety of various investigational agents, including monoclonal antibodies and antiviral agents. ACTIV-3 primarily aims to assess safety and efficacy of investigational agents to reduce time to sustained recovery. The sister protocol, ACTIV-3B, aims to evaluate the safety and efficacy of investigational agents at improving outcomes for hospitalized patients with acute respiratory distress syndrome related to COVID-19. ACTIV-4 master protocols evaluate the safety and efficacy of various antithrombotic agents that aim to prevent, treat, and address COVID-19–associated coagulopathy (CAC), or clotting, as well as help understand the effects of CAC across 3 patient populations: inpatient, outpatient, and convalescent. ACTIV-5 is designed as a proof-of-concept phase 2 study to rapidly evaluate proposed treatments and advance them to phase 3 trials if efficacy is demonstrated. Finally, ACTIV-6 tests existing prescription and over-the-counter medications for people to self-administer (orally or with an inhaler), with the aim of providing evidence-based treatment options for most adult patients with COVID-19 and mild to moderate symptoms. ACTG = AIDS Clinical Trials Group; ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; ARDS = acute respiratory distress syndrome; CONNECTS = Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies; CRO = contract research organization; CTSN = Cardiothoracic Surgical Trials Network; DCRI = Duke Clinical Research Institute; ICU = intensive care unit; IFN = interferon; IV = intravenous; INSIGHT = International Network for Strategic Initiatives in Global HIV Trials; LMWH = low-molecular-weight heparin; NCATS = National Center for Advancing Translational Sciences; NEJM = New England Journal of Medicine; NHLBI = National Heart, Lung, and Blood Institute; NIAID = National Institute of Allergy and Infectious Diseases; nMAB = neutralizing monoclonal antibody; nPAB = neutralizing polyclonal antibody; PCORnet = National Patient-Centered Clinical Research Network; PETAL = Prevention and Early Treatment of Acute Lung Injury; TIN = Trial Innovation Network; TRI = Technical Resources International; UFH = unfractionated heparin; VA = Department of Veterans Affairs.

Figure 4.. Timeline for ACTIV-2 and ACTIV-3 master protocol development.

The time to design, obtain approval, and launch is shown here. Overall, trial initiation completed in about 2.5 mo. Having a dedicated network and principal investigator champion during the trial design and setup resulted in rapid trial activation. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; CRO = contract research organization; FDA = Food and Drug Administration; IND = investigational new drug.

Figure 5.. Strategic decisions and considerations for the ACTIV master protocols.

ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines; EUA = emergency use authorization; FDA = Food and Drug Administration; PI = principal investigator.

Appendix Figure 2.. Timelines for ACTIV master protocol development.

Each ACTIV master protocol undergoes 3 main development stages: 1) protocol development and approval, which consists of designing and drafting the protocol, onboarding participating companies for the refinement of the protocol, submitting for Food and Drug Administration (FDA) pre–investigational new drug (IND) review, revising the protocol, and submitting for FDA IND review; 2) operational planning/setup, which consists of assembling required resources (e.g., sponsors, networks, and contract research organizations) and initiating the study at the site level (e.g., site registration and activation); and 3) ongoing operations, which consists of trial execution, protocol amendments, and additional site identification, registration, and activation. ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines.

Appendix Figure 3.. Timelines for ACTIV-3B and ACTIV-6 master protocol development.

ACTIV = Accelerating COVID-19 Therapeutic Interventions and Vaccines.