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 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
This study has closed.

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.
BRII-196 and BRII-198

Phase 2/3

Two monoclonal antibodies developed by Brii Biosciences. 
SNG001

Phase 2/3

Developed by Synairgen, an inhalable beta interferon that is delivered by a nebulizer.
AZD7442
This study has closed.

Phase 2/3

Combination of two monoclonal antibodies (AZD8895 and AZD1061) developed by AstraZeneca that will be studied as an infusion. 
AZD7442
This study has closed.

Phase 2/3

Combination of two monoclonal antibodies (AZD8895 and AZD1061) developed by AstraZeneca that will be studied as an intramuscular injection.
Camostat mesilate
This study has closed.

Phase 2/3

An orally administered serine protease inhibitor developed by Sagent Pharmaceuticals that may block SARS-CoV-2, the virus that causes COVID-19, from entering cells.
SAB-185 Phase 2/3 Fully-human polyclonal antibody therapeutic developed by SAB Biotherapeutics, Inc. administered intravenously, with the dose depending on the patient’s weight in kilograms (kg).
BMS-986414 and BMS-986413 (also known as C135-LS and C144-LS)

Phase 2/3

Combination monoclonal antibody treatment administered by subcutaneous injection, developed by The Rockefeller University and licensed to Bristol Myers Squibb.

ACTIV-3

Inpatient Monoclonal Antibodies and Other Therapies

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

ACTIV-3 protocols are Phase 3 randomized, placebo-controlled trials testing multiple therapies, beginning with monoclonal antibodies but including other types of therapeutics.

The ACTIV-3 inpatient protocol is designed 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. This protocol will enroll hospitalized patients with COVID-19 to evaluate investigational treatments for safety and efficacy in reducing time to recovery and effects on extrapulmonary complications and respiratory dysfunction.

Agent Trial Phase Description More Information

LY-CoV555
This 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 sub-study closed because the Data and Safety Monitoring Board determined low likelihood that the intervention would be of clinical value in this hospitalized patient population. 

VIR-7831
This study has closed.

Phase 3

A monoclonal antibody developed through a partnership between Glaxo-SmithKline plc and Vir Biotechnology, Inc. The Data and Safety Monitoring Board recommended that recruitment in the sub-study should cease, due to futility.
BRII-196 and BRII-198
This study has closed.

Phase 3

Two monoclonal antibodies developed by Brii Biosciences. The Data and Safety Monitoring Board determined that the therapeutics did not meet the inclusion for criteria for further enrollment in the trial, due to futility. 
AZD7442

Phase 3

An investigational long-acting antibody combination developed by AstraZeneca.
Ensovibep (MP0420)

Phase 3

A small-molecule therapeutic designed by Molecular Partners in partnership with Novartis. It consists of a single kind of small molecule, from a novel class of antimicrobials known as DARPins (designed ankyrin repeat proteins). Ensovibep has been designed to bind to three different locations on the spike protein on the surface of SARS-CoV-2. This may prevent the virus from infecting human cells. 

The ACTIV-3 critical care protocol will enroll hospitalized patients with life-threatening cases of COVID-19, including those with Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition in which the lungs are severely inflamed and may be unable to maintain sufficient oxygen in the blood. The trial will determine safety and efficacy of investigational agents for an outcome scale ranging from recovered and living at home without supplemental oxygen within two weeks of enrollment to death. The protocol allows for sub-studies of different therapeutics to run concurrently. Each sub-study will enroll approximately 620 participants.

Agent Trial Phase Description More Information

ZyesamiTM (aviptadil acetate) and Veklury® (remdesivir)

Phase 3

This sub-study will test ZyesamiTM and remdesivir (alone and in combination) in hospitalized patients who are experiencing ARDS. ZyesamiTM is a formulation of aviptadil acetate produced by NeuroRx. Remdesivir has been approved by the FDA for the treatment of hospitalized people 12 years and older with COVID-19.

ACTIV-4

Antithrombotics

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

ACTIV-4 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

Eliquis® (apixaban)
This study has closed.

Phase 3

Direct oral anticoagulant donated by Bristol Myers Squibb/Pfizer. The Data and Safety Monitoring Board recommended stopping enrollment due to futility.

Aspirin
This study has closed.

Phase 3

Anti-platelet agent donated by Bristol Myers Squibb/Pfizer. The Data and Safety Monitoring Board recommended stopping enrollment due to futility.

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

Unfractionated Heparin and P2Y12 Inhibitors

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.

Agent Trial Phase Description More Information

Eliquis® (apixaban)

Phase 3

Direct oral anticoagulant donated by Bristol Myers Squibb/Pfizer

The ACTIV-4 host tissue protocol is a randomized, placebo-controlled clinical trial designed to explore the safety and effectiveness of a group of novel drugs designed to protect patients hospitalized with COVID-19 and at risk of poor outcomes. The large study will evaluate the effectiveness of these drugs at preventing host tissue damage, including a cascade of potentially life-threatening complications such as blood vessel damage, lung damage, blood clots, and heart injury. The study design allows different agents to be started, stopped, or combined during the study in response to emerging trial data.  

Agent Trial Phase Description More Information
TXA127 Phase 2 An investigational peptide agonist of Mas receptors.
TRV027 Phase 3 An investigational peptide biased agonist of the AT1 receptor.

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
SkyrisiTM (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. Enrollment in this portion of the trial has been completed.

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.
Danicopan Phase 2 A small molecule inhibitor of factor D (alternate complement pathway), initially developed by Alexion to treat symptoms of paroxysmal nocturnal hemoglobinuria. The therapeutic will be given in oral form, in conjunction with the antiviral drug remdesivir. This combination will be compared with placebo and remdesivir.

ACTIV-6

Outpatient Repurposed Drugs

Shot of an unrecognisable senior man taking medication at home

The ACTIV-6 master protocol is designed to test the effectiveness of repurposed drugs (drugs that are FDA-approved for non-COVID-19 indications and have known safety profiles) in reducing the duration and severity of symptoms associated with mild-to-moderate COVID-19. The large, randomized, placebo‑controlled Phase 3 trial will enroll participants who are at least 30 years old, have tested positive for SARS-CoV-2 infection and show two or more mild-to-moderate symptoms of COVID-19 for no more than seven days.  Drugs that demonstrate efficacy in reducing symptoms of mild-to-moderate COVID-19 will be further evaluated for effects on clinical outcomes (hospitalization, mortality) and long-term COVID-19 symptoms.

Agent Trial Phase Description More Information
 Ivermectin Phase 3

Ivermectin, donated by Ingenus, is an oral agent that binds selectively to glutamate-gated chloride ion channels to increase cell membrane permeability to chloride ions.  Ivermectin is primarily used to treat parasitic diseases and is FDA-approved for the following indications: strongyloidiasis of the intestinal tract due to the nematode parasite Strongyloides stercoralis and onchocerciasis due to the nematode parasite Onchocerca volvulus

 Fluvoxamine Phase 3

Fluvoxamine, donated by Apotex, is an oral agent that binds selectively and with high affinity to the serotonin transporter to limit the reuptake of serotonin by presynaptic cells.  Fluvoxamine belongs to a class of drugs known as selective serotonin reuptake inhibitors (SSRIs) and is primarily used to treat depression, anxiety and obsessive-compulsive disorders.  

Fluticasone Phase 3

Fluticasone, donated by GlaxoSmithKline, is an inhaled agent that binds selectively to the glucocorticoid receptor to induce a wide variety of anti-inflammatory effects.  Fluticasone belongs to a class of drugs known as steroids.  Inhaled fluticasone is primarily used to treat asthma and COPD.

ACTIV-Associated

Old woman with Ventilator mask on Hospital bed - stock photo

These trials are other NIH-funded flagship COVID-19 therapeutic trials of ACTIV-prioritized agents using protocols informed or endorsed by the ACTIV partnership.

The Adaptive COVID-19 Treatment Trial (ACTT) is evaluating the safety and efficacy of the investigational antiviral Veklury® (remdesivir), developed by Gilead Sciences Inc., alone and in combination with other therapeutics. The patient population is hospitalized adults with COVID-19 and evidence of lung involvement, including rattling sounds when breathing (rales) with a need for supplemental oxygen or abnormal chest X-rays, or illness requiring mechanical ventilation.

Agent Trial Phase Description More Information
Veklury® (remdesivir)
This study has closed.
Phase
ACTT-1 evaluated remdesivir alone against placebo. Remdesivir has been approved by the FDA for the treatment of hospitalized people 12 years and older with COVID-19.

Veklury® (remdesivir) and Olumiant® (baricitinib)
This study has closed.

Phase 3

ACTT-2 evaluated remdesivir plus baricitinib, an anti-inflammatory drug licensed to Eli Lilly and Company by Incyte, against remdesivir and placebo. Baricitinib is approved in the U.S. and ~65 other countries as a treatment for adults with moderate to severe rheumatoid arthritis. Baricitinib received emergency use authorization for the treatment of hospitalized people with COVID-19.

Veklury® (remdesivir) and Rebif® (Interferon Beta-1a)
This study has closed.
Phase 3

ACTT-3 is evaluating remdesivir plus interferon beta-1a, approved in the U.S. and ~90 other countries for the treatment of multiple sclerosis, against remdesivir and placebo. Interferons have both antiviral and anti-inflammatory properties.

Veklury® (remdesivir) and Dexamethasone compared to Veklury® (remdisivir) and Olumiant® (baricitinib) 
This study has closed.
Phase 3 ACTT-4 is evaluating one arm of remdesivir and dexamethasone, a corticosteroid, (or placebo) against a second arm of remdesivir and baricitinib (or placebo). This study closed because the Data Safety Monitoring Board determined that neither treatment regimen was significantly better than the other.

The Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) clinical trial is evaluating the investigational antiviral Veklury® (remdesivir), developed by Gilead Sciences Inc., in combination with hyperimmune intravenous immunoglobulin (hIVIG) for adult patients hospitalized for medical management of COVID-19 without related serious end-organ failure.

Agent Trial Phase Description More Information

Veklury® (remdesivir) and Hyperimmune Intravenous Immunoglobulin (hIVIG)
This study has closed.

Phase 3 ITAC is evaluating Veklury® (remdesivir) and hIVIG against remdesivir and placebo. hIVIG are antibodies that come from the liquid portion of blood called plasma donated by healthy people who have recovered from COVID-19. The antibodies are highly purified and concentrated so they contain several times more SARS-CoV-2 antibodies than typically found in plasma.

The Convalescent Plasma in Outpatients with COVID-19 (C3PO) is evaluating the safety and effectiveness of a single dose of convalescent plasma for preventing the progression from mild to severe COVID-19 illness in patients coming to the emergency department who have developed mild to moderate symptoms of COVID-19 within past week.

Agent Trial Phase Description More Information

Convalescent Plasma
This study has closed.

Phase 3 Single dose of convalescent plasma. This study closed because the Data Safety Monitoring Board determined that the intervention is unlikely to benefit this group of patients.

The Convalescent Plasma to Limit COVID-19 Complications in Hospitalized Patients (CONTAIN COVID-19) trial is evaluating clinical improvement at 14 and 28 days and survival from a single dose of convalescent plasma in adults with acute respiratory symptoms of COVID-19 within 3-7 days from onset of illness or within 3 days of hospitalization.

Agent Trial Phase Description More Information
Convalescent Plasma
This study has closed.
Phase 2 Single dose of convalescent plasma.

The Passive Immunity Trial of Our Nation (PassItOn) is evaluating a single dose of convalescent plasma in adults with acute respiratory infection symptoms and laboratory-confirmed SARS-CoV-2 infection who are hospitalized or in an emergency department and likely to be admitted. The trial will assess clinical improvement at 15 days and use of ventilation, supplemental oxygen, and acute kidney injury and cardiovascular events.

Agent Trial Phase Description More Information
Convalescent Plasma
This study has closed.
Phase 3 Single dose of convalescent plasma.

This page last reviewed on August 13, 2021