COVID-19 Therapeutics Prioritized for Testing in Clinical Trials

Overview

The ACTIV public-private partnership designed and harmonized adaptive master protocols to evaluate therapeutic agents with potential application against COVID-19. Master protocols allow coordinated and efficient evaluation of multiple investigational agents within the same clinical trial structure and across multiple study sites. 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.

After rigorously assessing data on more than 800 candidate therapeutic agents, the ACTIV partnership prioritized the most promising agents for inclusion in ACTIV master protocols. ACTIV rapidly deployed existing NIH networks of more than 620 trial sites across the U.S. and internationally to test these candidate therapeutics in randomized, placebo-controlled clinical trials.

This page provides descriptions of the ACTIV therapeutic adaptive master protocols; information about ACTIV clinical trials that are ongoing, completed, or ended; and information about ACTIV-associated COVID-19 clinical trials involving therapeutic agents prioritized by ACTIV and using master protocols informed or endorsed by the ACTIV public-private partnership.

Master Protocols

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

ACTIV-1: Immune Modulators

  • The ACTIV-1 protocol evaluated the safety and efficacy of immune modulators, a class of drugs that help minimize the deleterious effects of an overactive immune response to SARS-CoV-2 infection, when given as an add-on therapy to remdesivir, an antiviral approved for treatment of COVID-19, and the standard of care. The different treatments were assessed in hospitalized adults with moderate to severe COVID-19 disease with respect to illness severity, recovery speed, mortality and hospital resource utilization.

ACTIV-2: Outpatient Monoclonal Antibodies and Other Therapies

  • The ACTIV-2 protocol evaluated the safety of monoclonal antibodies and other therapies and their ability to reduce the duration of symptoms in in adults with COVID-19 who were not hospitalized and to test if the treatments could increase the proportion of participants with undetectable virus.
  • The ACTIV-2 SCORPIO-HR protocol is evaluating whether an antiviral can reduce the duration of symptoms in adults with COVID-19 who are not hospitalized.

ACTIV-3: Inpatient Monoclonal Antibodies and Other Therapies

  • The ACTIV-3 inpatient protocol evaluated monoclonal antibodies and other therapies for safety and efficacy in reducing time to recovery and effects on extrapulmonary complications and respiratory dysfunction in adults hospitalized with COVID-19.
  • The ACTIV-3 critical care protocol determined the safety and efficacy of monoclonal antibodies and other therapies in 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.

ACTIV-4: Antithrombotics

  • The ACTIV-4 outpatient protocol investigated whether anticoagulants or antithrombotic therapy could reduce life-threatening cardiovascular or pulmonary complications in newly diagnosed COVID-19 patients who did not require hospital admission.
  • The ACTIV-4 inpatient protocol evaluated the safety and effectiveness of using varying doses of heparin, a blood thinner, to prevent or reduce the formation of blood clots and improve outcomes in adults hospitalized COVID-19.
  • The ACTIV-4 convalescent protocol investigated the effectiveness and safety of anticoagulants and/or antiplatelets administered to patients who had 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.
  • The ACTIV-4 host tissue protocol evaluated the safety and effectiveness of a group of novel drugs at preventing host tissue damage, including potentially life-threatening complications such as blood vessel damage, lung damage, blood clots, and heart injury, in adults hospitalized with COVID-19.

ACTIV-5: Big Effect Trial

  • The ACTIV-5 protocol evaluated whether certain approved therapies or investigational drugs in late-stage clinical development show promise against COVID-19 in hospitalized patients.

ACTIV-6: Outpatient Repurposed Drugs

  • The ACTIV-6 protocol was 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; drugs that demonstrated efficacy were further evaluated for effects on clinical outcomes (hospitalization, mortality) and long-term COVID-19 symptoms.

Ongoing Clinical Trials

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Protocol Agent/Administration Description Status More Information
ACTIV-2

SCORPIO-HR

Xocova/Ensitrelvir fumaric acid/S-217622

(Oral)

A novel investigational 3CL protease inhibitor developed by Hokkaido University and Shionogi as an antiviral for COVID-19.

Continuing enrollment
ACTIV-4
Inpatient
SGLT-2 Inhibitors (Oral) Repurposed agents used for in-hospital anticoagulation. Continuing enrollment
ACTIV-4
Host Tissue
Fostamatinib (Oral) A tyrosine kinase inhibitor medication for the treatment of chronic immune thrombocytopenia (ITP) administered orally that blocks the activity of the enzyme spleen tyrosine kinase (SYK), an enzyme involved in stimulating parts of the immune system. Continuing enrollment
ACTIV-6 Fluvoxamine 100mg
(Oral)
Repurposed agent, donated by Apotex, 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. Continuing enrollment

Completed/Ended Clinical Trials

Happy senior woman listening as her doctor is explaining therapy details during house call visit
Protocol Agent/Administration Description Status More Information
ACTIV-1 Remicade®/ Infliximab (Intravenous) A repurposed 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. Completed enrollment. Efficacy shown to improve clinical status and reduce deaths. Awaiting published results in peer-reviewed journal.
ACTIV-1 Orencia®/Abatacept (Intravenous) A repurposed 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. Completed enrollment. Efficacy shown to improve clinical status and reduce deaths. Awaiting published results in peer-reviewed journal.
ACTIV-1 Cenicriviroc/CVC
(Oral)
Donated by AbbVie Inc., CVC blocks CCR2 and CCR5 chemokine receptors involved in the inflammatory and fibrogenic pathways of certain diseases potentially reduced with immunomodulation therapy. Ended due to lack of efficacy.
ACTIV-2 LY-CoV555 (Intravenous) 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. Completed enrollment. No differences in bamlanivimab vs. placebo were observed in the primary outcomes. Trial results published in Nature Communications.
ACTIV-2 BRII-196 and BRII-198 (Intravenous) Two monoclonal antibodies developed by Brii Biosciences. Completed enrollment. Efficacy shown and EUA filed.
ACTIV-2 SNG001 (Inhaled) Repurposed inhalable beta interferon developed by Synairgen. Enrollment closed due to operational futility.  No differences observed between treatment arm and placebo.
ACTIV-2 AZD7442 (Intravenous) Combination of two monoclonal antibodies (AZD8895 and AZD1061) developed by AstraZeneca that will be studied as an infusion. Enrollment completed. Potential benefit for reducing mortality.Trial closed at company’s request.
ACTIV-2 AZD7442 (Intramuscular) Combination of two monoclonal antibodies (AZD8895 and AZD1061) developed by AstraZeneca that will be studied as an intramuscular injection. Enrollment closed at company’s request.
ACTIV-2 Camostat Mesylate (Oral) Repurposed antiviral serine protease inhibitor developed by Sagent Pharmaceuticals that may block SARS-CoV-2 from entering cells. Ended due to lack of efficacy.
ACTIV-2 SAB-185 (Intravenous) Fully human polyclonal antibody therapeutic developed by SAB Biotherapeutics, Inc.  with the dose depending on the patient’s weight in kilograms. Enrollment closed due to operational futility. Data analysis underway.
ACTIV-2 BMS-986414 and BMS-986413/C135-LS and C144-LS (Subcutaneous Injection) Combination monoclonal antibody treatment developed by The Rockefeller University and licensed to Bristol Myers Squibb. Ended due to lack of efficacy.
ACTIV-3
Inpatient
LY-CoV555 (Intravenous) 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. Ended due to lack of efficacy. Trial results published in The New England Journal of Medicine.
ACTIV-3
Inpatient
VIR-7831 (Intravenous) Monoclonal antibody developed through a partnership between Glaxo-SmithKline plc and Vir Biotechnology, Inc. Ended following review of interim data. Trial results published in The Lancet.
ACTIV-3
Inpatient
BRII-196 and BRII-198
(Intravenous)
Two monoclonal antibodies developed by Brii Biosciences. Ended due to lack of efficacy. Trial results published in The Lancet.
ACTIV-3
Inpatient
AZD7442 (Intravenous) Investigational long-acting monoclonal antibody combination developed by AstraZeneca. Completed enrollment. Efficacy shown to improve clinical status and reduce deaths. Trial results published in The Lancet Respiratory Medicine.
ACTIV-3
Inpatient
Ensovibep/MP0420 (Intravenous) Designed by Molecular Partners in partnership with Novartis, a new therapeutic consisting 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. Ended due to lack of efficacy. Trial results published in Annals of Internal Medicine.
ACTIV-3
Inpatient
PF-07304814
(Intravenous)
New, selective inhibitor of the SARS-CoV-2 3CLpro (a viral protease) developed by Pfizer. Enrollment closed at company’s request.
ACTIV-3
Critical Care
ZyesamiTM/Aviptadil Acetate and Veklury®/Remdesivir
(Intravenous)
This trial is evaluating ZyesamiTM and remdesivir (alone and in combination) in hospitalized patients who are experiencing ARDS. ZyesamiTM is a formulation of aviptadil acetate produced by NeuroRx. Ended due to lack of efficacy.
ACTIV-4
Outpatient
Eliquis®/Apixaban (Oral) A repurposed anticoagulant donated by Bristol Myers Squibb/Pfizer. Closed due to operational futility.  Not a high enough event rate.
ACTIV-4
Outpatient
Aspirin (Oral) A repurposed anti-platelet agent donated by Bristol Myers Squibb/Pfizer. Closed due to operational futility.  Not a high enough event rate.
ACTIV-4
Inpatient
Unfractionated (UF) and Low Molecular Weight (LMW) Heparin (Intravenous and Injection) Repurposed agents used for in-hospital anticoagulation. Completed enrollment. Efficacy shown for moderately ill hospitalized patients. Trials results for moderately ill and critically ill hospitalized patients published separately in the New England Journal of Medicine.
ACTIV-4
Inpatient
Therapeutic Heparin and P2Y12 Inhibitors
(Intravenous and Oral)
IV infusion of a therapeutic dose of heparin, an anticoagulant, given according to local hospital guidelines. Administered with that an oral P2Y12 inhibitor, an antiplatelet agent. Ended due to lack of efficacy. Trial results published in JAMA.
ACTIV-4
Inpatient
Prophylactic Heparin and P2Y12 Inhibitors
(Intravenous and Oral)
IV infusion of a prophylactic dose of heparin, an anticoagulant, given according to local hospital guidelines. Administered with an oral P2Y12 inhibitor, an antiplatelet agent. Enrollment closed due to operational futility. Awaiting topline results.
ACTIV-4
Inpatient
Crizanlizumab (Intravenous) Repurposed monoclonal antibody that binds to P-selectin and blocks its interaction with P-selectin glycoprotein ligand 1 (PSGL-1). Enrollment closed due to lack of efficacy at interim analysis. Awaiting topline results.
ACTIV-4
Convalescent
Eliquis®/Apixaban
(Oral)
Repurposed anticoagulant donated by Bristol Myers Squibb/Pfizer. Enrollment closed due to operational futility. Awaiting topline results.
ACTIV-4
Host Tissue
TXA127
(Intravenous)
An investigational peptide agonist of Mas receptors. Ended due to lack of efficacy.
ACTIV-4
Host Tissue
TRV027
(Intravenous)
An investigational peptide biased agonist of the AT1 receptor. Ended due to lack of efficacy.
ACTIV-5 SkyrisiTM/Risankizumab
(Intravenous)
Monoclonal antibody developed by Boehringer Ingelheim and AbbVie and approved in the U.S. for the treatment of severe plaque psoriasis. Therapeutic given in conjunction with the antiviral drug remdesivir and compared with placebo and remdesivir. Completed enrollment. Awaiting topline results.
ACTIV-5 Lenzilumab
(Intravenous)
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. Completed enrollment. No statistically significant efficacy shown. Topline results announced by company.
ACTIV-5 Danicopan
(Oral)
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. Completed enrollment. Awaiting topline results.
ACTIV-6 Ivermectin 400 mcg
(Oral)
Repurposed agent, donated by Ingenus, that binds selectively to glutamate-gated chloride ion channels to increase cell membrane permeability to chloride ions. 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. Completed enrollment. No efficacy shown. Trial results published in JAMA.
ACTIV-6 Ivermectin 600mcg
(Oral)
Repurposed agent, donated by Ingenus, that binds selectively to glutamate-gated chloride ion channels to increase cell membrane permeability to chloride ions. 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. Completed enrollment. Awaiting topline results.
ACTIV-6 Fluvoxamine 50mg
(Oral)
Repurposed agent, donated by Apotex, 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. Completed enrollment. No efficacy shown. Awaiting topline results.
ACTIV-6 Fluticasone
(Inhaled)
Repurposed agent, donated by GlaxoSmithKline, 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. Completed enrollment. No efficacy shown.

ACTIV-Associated Trials

Old woman with Ventilator mask on Hospital bed - stock photo

These trials were other NIH-funded COVID-19 therapeutic trials of ACTIV-prioritized agents using protocols informed or endorsed by the ACTIV partnership. All of these trials have completed or ended. 

Adaptive COVID-19 Treatment Trial (ACTT)
These clinical trials evaluated the safety and efficacy of the antiviral Veklury® (remdesivir), developed by Gilead Sciences Inc., alone and in combination with other therapeutics.

Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) clinical trial evaluated the 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.

Convalescent Plasma in Outpatients with COVID-19 (C3PO) clinical trial evaluated 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.

Convalescent Plasma to Limit COVID-19 Complications in Hospitalized Patients (CONTAIN COVID-19) clinical trial evaluated 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.

Passive Immunity Trial of Our Nation (PassItOn) clinical trial evaluated 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.

This page last reviewed on January 26, 2023