COVID-19 Therapeutics Prioritized for Testing in Clinical Trials

Working in an unprecedented timeframe, the ACTIV public-private partnership has evaluated hundreds of available therapeutic agents with potential application for COVID-19, prioritized the most promising candidates, designed and harmonized five adaptive master protocols for ACTIV clinical trials, and selected numerous NIH-supported networks to launch these clinical trials to test prioritized therapeutic candidates.

Master protocols allow coordinated and efficient evaluation of multiple investigational agents as they become available, but within the same clinical trial structure, across multiple study sites. Adaptive protocols swiftly weed out experimental drugs that do not demonstrate effectiveness and identify those that do. Adaptive master protocols reduce administrative burden and cost, provide a flexible framework to rapidly identify drugs that work, and rapidly move additional experimental agents into the trial.

The ACTIV master protocols are listed below. As studies of specific compounds are launched, NIH will list those studies under each protocol.

ACTIV-1

Immune Modulators

Young male nurse in white scrubs standing at bedside with hand on shoulder of recovering mature male COVID-19 patient, both wearing protective masks.

The ACTIV-1 master protocol will test promising immune modulator compounds, a class of drugs that help minimize the deleterious effects of an overactive immune response to SARS-CoV-2 infection. This Phase 3 trial will enroll hospitalized adults with moderate to severe COVID-19 disease. It will evaluate the safety and efficacy of at least three immune modulators when given as an add-on therapy to remdesivir, an antiviral approved for treatment of COVID-19, and the standard of care in use at local clinics. The different treatments will be assessed with respect to illness severity, recovery speed, mortality and hospital resource utilization.

Agent Trial Phase Description More Information

Remicade® (infliximab)

Phase 3

A monoclonal antibody donated by Janssen Biotech, Inc., that inhibits tumor necrosis factor, a pro-inflammatory cytokine hypothesized to drive the excess inflammatory response some experience during advanced stages of COVID-19. Remicade received FDA approval in 1998 to treat several chronic auto-immune inflammatory diseases.

Orencia® (abatacept)

Phase 3

Orencia, a selective T-cell co-stimulation immunomodulator donated by Bristol Myers Squibb, consists of the extracellular domain of human cytotoxic T cell-associated antigen 4 fused to a modified immunoglobulin tail and works by preventing the full activation of T cells, which also helps inhibit the downstream inflammatory cascade.

Cenicriviroc (CVC)

Phase 3

CVC, donated by AbbVie Inc., blocks CCR2 and CCR5 chemokine receptors involved in the inflammatory and fibrogenic pathways of certain diseases potentially reduced with immunomodulation therapy.

ACTIV-2

Outpatient Monoclonal Antibodies and Other Therapies

Doctor talking to senior female patient while being in a home visit

The ACTIV-2 master protocol is designed as a Phase 2 trial that can expand seamlessly to Phase 3. The trial will enroll adults with COVID-19 who are not hospitalized and aims to evaluate safety, to understand if the investigational treatment can reduce the duration of symptoms, and to test if the treatment can increase the proportion of participants with undetectable virus. It will perform testing using nasopharyngeal swabs at specific time points. Multiple therapies, beginning with a monoclonal antibody but including other types of therapeutics, will be tested in ACTIV-2.

Agent Trial Phase Description More Information

LY-CoV555

Phase 2/3

An investigational antibody developed by Eli Lilly and Co. in partnership with AbCellera Biologics. AbCellera collaborated with NIAID’s Vaccine Research Center to identify and isolate the antibody from a blood sample from a person who recovered from COVID-19.

ACTIV-3

Inpatient Monoclonal Antibodies and Other Therapies

Health visitor using digital tablet and talking to a senior man during home visit

The ACTIV-3 master protocol is designed as a Phase 3 trial with two stages of testing, allowing for quick analysis of compounds for effectiveness in Stage 1 and then a seamless progression to Stage 2 to validate the compound for broader use in patients. The trial will enroll hospitalized adults with COVID-19 and primarily aims to evaluate safety and to understand if the investigational treatment can reduce time to recovery and to understand a treatment’s effect on extrapulmonary complications and respiratory dysfunction. Multiple therapies, beginning with a monoclonal antibody but including other types of therapeutics, will be tested in ACTIV-3.

Agent Trial Phase Description More Information

LY-CoV555
This sub-study has closed.

Phase 3

An investigational antibody developed by Eli Lilly and Co. in partnership with AbCellera Biologics. AbCellera collaborated with NIAID’s Vaccine Research Center to identify and isolate the antibody from a blood sample from a person who recovered from COVID-19. This study closed because the Data Safety Monitoring Board determined low likelihood that the intervention would be of clinical value in this hospitalized patient population. 

ACTIV-4

Antithrombotics

Happy senior woman listening as her doctor is explaining therapy details during house call visit

The ACTIV-4 master protocol will evaluate the safety and effectiveness of varying types of blood thinners to treat adults diagnosed with COVID-19. Currently there are three adaptive platform clinical trials within ACTIV-4 that aim to prevent, treat, and address COVID-19-associated coagulopathy (CAC), or clotting, as well as help understand the effects of CAC across three patient populations: inpatient, outpatient, and convalescent. The trial infrastructure will also be poised to rapidly test promising new agents. The adaptive nature of the platform will allow a seamless transition to studies that will test multi-regimen anticoagulation approaches.

 The ACTIV-4 outpatient protocol investigates whether anticoagulants or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonary complications in newly diagnosed COVID-19 patients who do not require hospital admission. Participants will be assigned to take either a placebo, aspirin, or a low or therapeutic dose the blood thinner apixaban.

Agent Trial Phase Description More Information

Apixaban

Phase 3

Direct oral anticoagulant donated by Bristol Myers Squibb/Pfizer

Aspirin

Phase 3

Anti-platelet agent donated by Bristol Myers Squibb/Pfizer

The ACTIV-4 inpatient protocol investigates an approach aimed at preventing clotting events and improving outcomes in hospitalized COVID-19 patients. It will evaluate the safety and effectiveness of using varying doses of heparin, a blood thinner, to prevent or reduce the formation of blood clots.

Agent Trial Phase Description More Information

Unfractionated (UF) and  Low Molecular Weight (LMW) heparin

Phase 3

Agents used for in-hospital anticoagulation

The ACTIV-4 convalescent protocol will investigate the effectiveness and safety of anticoagulants and/or antiplatelets administered to patients who have been discharged from the hospital or are convalescing in reducing thrombotic complications such as heart attack, stroke, blood clots in major veins and arteries, deep vein and pulmonary thrombosis, and death. Researchers will assess if patients develop these complications within 45 days of being hospitalized for moderate and severe COVID-19.

ACTIV-5

Big Effect Trial

Nurse Listening to Senior Male Patient with Stethoscope.

The ACTIV-5 master protocol is designed to conduct a series of randomized, double-blind, placebo-controlled Phase 2 trials using common assessments and endpoints. Trials using this protocol will enroll hospitalized adults with COVID-19 to evaluate whether certain approved therapies or investigational drugs in late-stage clinical development show promise against COVID-19. Compounds that do not demonstrate efficacy based in interim evaluations will be dropped, while those that demonstrate efficacy will move forward to Phase 3 trials.

Agent Trial Phase Description More Information

Risankizumab

Phase 2

A monoclonal antibody developed by Boehringer Ingelheim and AbbVie and approved in the U.S. for the treatment of severe plaque psoriasis. The therapeutic will be given in conjunction with the antiviral drug remdesivir and will be compared with placebo and remdesivir. 

Lenzilumab

Phase 2

An investigational monoclonal antibody developed by Humanigen. The therapeutic will be given in conjunction with the antiviral drug remdesivir and will be compared with placebo and remdesivir.

This page last reviewed on November 9, 2020