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COVID-19 Therapeutics Prioritized for Testing in Clinical Trials
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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
ACTIV-1: Immune Modulators
- The 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 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 isÌýevaluating 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 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 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 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 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 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 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 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 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.
ACTIV STRIVE: Inpatients with Acute Severe Respiratory Infection
- The is designed to identify improved treatments for severe respiratory infections and can be adapted to accommodate various types of interventions, including antivirals, passive immunity agents, immunomodulators, host pathways, combination therapies, repurposed drugs, novel drugs and supportive care approaches. Interventions are typically randomized and placebo-controlled with all participants receiving the current standard of care. Studies will focus on determining if the proposed intervention can improve clinical outcomes. STRIVE aims to maintain a global clinical trials infrastructure for pandemic preparedness. It will initially focus on COVID-19 but has the potential to study additional pathogens in the future.
Ongoing Clinical Trials
| Protocol | Agent/Administration | Description | Status | More Information |
|---|---|---|---|---|
| ACTIV STRIVE |
Orencia®/Abatacept (Intravenous) |
A repurposed selective T-cell co-stimulation immunomodulator donated by Bristol Myers Squibb that consists of the extracellular domain of human cytotoxic T cell-associated antigen 4 fused to a modified immunoglobulin tail. It works by preventing the full activation of T cells, which also helps inhibit the downstream inflammatory cascade. |
Continuing enrollment | |
| ACTIV STRIVE |
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-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-6 | Montelukast 10mg (Oral) |
Repurposed agent,Ìýdonated by Accord Healthcare, that binds selectively and with high affinity to the cysteinyl leukotriene type 1 receptor to block the action of leukotriene D4. Montelukast belongs to a class of drugs known as leukotriene receptor antagonists and is primarily used as a maintenance treatment for chronic asthma. | Continuing enrollment |
|
Completed/Ended Clinical Trials
| 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; did not significantly shorten time to recovery. Trial results published inÌýJAMA. | |
| 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; did not significantly shorten time to recovery. Trial results published inÌýJAMA. | |
| 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.ÌýTrial results published inÌýJAMA. | |
| 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. ÌýNo 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.Ìý with the dose depending on the patient’s weight in kilograms. | Enrollment closed due to operational futility. Trial results published inÌýThe Journal of Infectious Diseases. | |
| 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 |
·¡±ô¾±±ç³Ü¾±²õ®/´¡±è¾±³æ²¹²ú²¹²Ô (Oral) | A repurposed anticoagulant donated by Bristol Myers Squibb/Pfizer. | Closed due to operational futility.Ìý 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.ÌýTrial results published inÌýJAMA. | |
| ACTIV-4 Inpatient |
SGLT-2 Inhibitors (Oral) | Repurposed agents used for in-hospital anticoagulation. | Enrollment closed due to declining hospitalization rates and lack of efficacy at interim analysis. Awaiting topline results. |
Ìý |
| 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. Trial results published inÌýJAMA. |
|
| 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 |
·¡±ô¾±±ç³Ü¾±²õ®/´¡±è¾±³æ²¹²ú²¹²Ô (Oral) |
Repurposed anticoagulant donated by Bristol Myers Squibb/Pfizer. | Enrollment closed due to lower than anticipated event rate and declining rate of COVID-19 hospitalizations.ÌýTrial results published inÌýAnnals of Internal Medicine. | |
| 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-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. | 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. No efficacy shown. Trial results published inÌýJAMA. |
Ìý |
| 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. Trial results published in JAMA. |
|
| 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. | Completed enrollment. Awaiting topline results.Ìý |
|
| 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
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.Ìý
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.
- : Remdesivir alone against placebo
- : Remdesivir plus baricitinib, an anti-inflammatory drug licensed to Eli Lilly and Company by Incyte, against remdesivir and placebo
- : Remdesivir plus interferon beta-1a, an approved treatment for multiple sclerosis, against remdesivir and placebo
- : Remdesivir and dexamethasone, a corticosteroid, (or placebo) against remdesivir and baricitinib (or placebo)
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.
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.
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.
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.
Biospecimen Resource for Researchers
ACTIV clinical trials have generated biospecimens that could be a critical resource for researchers studying the pathobiology of COVID-19 and investigating potential therapeutic targets. The provides a central, searchable inventory of the residual, de-identified biospecimen samples. Consent from participants for future use these samples has been obtained from the ACTIV therapeutic clinical trials following completion of the ACTIV study analysis. All interested researchers can apply for access to the samples and associated metadata, including participant-level demographic data and sample timepoints, through theÌý. Requests for samples will be reviewed on a rolling basis by an internal NIH committee. ÌýIt is expected that biospecimens will be used in a timely manner and that results will be shared per the . Applicants are responsible for providing funding for the proposed research. There is no cost associated with requesting individual biospecimens.
This page last reviewed on May 21, 2024