I-SPY COVID-19 TRIAL: An Adaptive Platform Trial for Critically Ill Patients

NCT04488081 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: I-SPY-COVID
• Study Type: interventional
• Target: 1,500
• Locations: 1 country
• Sites: 36

Brief Summary

The goal of this project is to rapidly screen promising agents, in the setting of an adaptive platform trial, for treatment of critically ill COVID-19 patients. In this phase 2 platform design, agents will be identified with a signal suggesting a big impact on reducing mortality and the need for, as well as duration, of mechanical ventilation.

Conditions

COVID-19

Keywords

COVID-19; severe disease; Platform Trial; Acute Respiratory Distress Syndrome; ARDS; SARS-COV-2; AHRF; Acute Hypoxemic Respiratory Failure

Outcome Measures

Primary Outcomes (1)

• Identify agents that will result in substantial improvements to the clinical condition of participants with COVID-19.

  Time to reach a durable COVID-19 level 4 or less or discharge at COVID-level 4 or lower (except for discharge to another hospital), and time to death (mortality). Data will be analyzed for 3 groups: * All * COVID-19 level 6/7 (those intubated immediately) * COVID-19 level 5 (high flow oxygen to start) World Health Organization 9-point ordinal scale: 0\. No clinical or virologic evidence of infection 1. Not hospitalized, no limitations on activities; 2. Not hospitalized, limitation on activities; 3. Hospitalized, not requiring supplemental oxygen; 4. Hospitalized, requiring supplemental oxygen (\< 6L by nasal cannula or mask delivery system); 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices (≥6L per minute, mask or intranasal cannula); 6. Hospitalized, on invasive mechanical ventilation; 7. Hospitalized, ventilation plus additional organ support-pressors, RRT, ECMO 8. Death.

  Up to 28 days

Secondary Outcomes (4)

• Mortality

  Up to 28 days

• Improvement in disease severity

  Up to 60 days

• Health care utilization

  Up to 28 days

• Safety: Frequency of serious AEs

  Up to 60 days

Study Arms (13)

Control/Backbone - Remdesivir and Dexamethasone (CLOSED)

ACTIVE COMPARATOR

Participants randomized to the backbone control will be given standard of care (supportive care for ARDS, including remdesivir and, if needed, lung protective ventilation). Because dexamethasone was shown to have benefit in at least one large randomized clinical trial, patients in the backbone control arm should receive dexamethasone for a total of 10 days during the hospitalization or until or hospital discharge. Remdesivir (intravenous): 200-mg loading dose on day 1, followed by a daily maintenance dose of 100-mg on days 2 through 10. Dexamethasone (intravenous): 6 mg intravenous or oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.

Drug: Remdesivir; Drug: Dexamethasone

Imatinib + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects will be administered standard of care + 800 mg imatinib on Day 1 orally, in divided doses of 400 mg administered twice per day. 400 mg daily will be administered orally for the following 9 days or until discharge, whichever is sooner.

Drug: Remdesivir; Drug: Imatinib Mesylate; Drug: Dexamethasone

Cenicriviroc + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + cenicriviroc orally , loading 300 mg qAM followed by 150 mg qPM, 12 hours apart on day 1, then 150 mg BID for total of 14 to 28 days depending on date of hospital discharge.

Drug: Remdesivir; Drug: Dexamethasone; Drug: Cenicriviroc

Icatibant + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + icatibant subcutaneously, a safety run-in for the first 10 subjects was conducted using a regimen of 30 mg q8h × 3 days. All subsequent subjects received drug at 30 mg q8h x 6 days.

Drug: Remdesivir; Drug: Dexamethasone; Drug: Icatibant

Apremilast + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + apremilast orally , 30 mg bid × 14 days.

Drug: Remdesivir; Drug: Dexamethasone; Drug: Apremilast

Dornase + Standard of Care (CLOSED)

EXPERIMENTAL

For Non-intubated subjects: Subjects administered standard of care + dornase, 2.5 mg BID until hospital discharge, improvement to room air (or baseline oxygen use prior to illness) for 24 hours, or total of 14 days of study drug, whichever comes first. For intubated subjects: Subjects administered standard of care + dornase, 5.0 mg BID in 10 mL normal saline until extubation or 14 days, whichever comes first. If intubated for less than 14 days, extubated subjects received 2.5 mg BID for a total Dornase treatment of 14 days, or until hospital discharge, whichever comes first.

Drug: Remdesivir; Drug: Dexamethasone; Biological: dornase alfa

Celecoxib/famotidine + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + celecoxib/famotidine orally . Celecoxib, oral: 400 mg BID for 7 days. Famotidine, oral: High dose 80 mg QID for 7 days followed by 40 mg BID for a course of 14 days.

Drug: Remdesivir; Drug: Dexamethasone; Drug: Celecoxib; Drug: Famotidine

IC14 + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + IC14 intravenously , 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4

Drug: Remdesivir; Drug: Dexamethasone; Biological: IC14

Narsoplimab + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + narsoplimab dosed at 4 mg/kg, given as a 30-minute intravenous infusion (up to a maximum of 370 mg per infusion) twice weekly for a total of four weeks (i.e. 9 doses) or until hospital discharge whichever comes first.

Drug: Remdesivir; Drug: Dexamethasone; Biological: narsoplimab

Aviptadil + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + aviptadil (inhalation via nebulizer), 100 µg three times (TID) daily for a maximum of 14 days

Drug: Remdesivir; Drug: Dexamethasone; Drug: Aviptadil

Cyproheptadine + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + cyproheptadine via 4 mg tablet, with dosing regimen of 8 mg every 8 hours daily for ten (10) days.

Drug: Remdesivir; Drug: Dexamethasone; Drug: Cyproheptadine

Cyclosporine + Standard of Care (CLOSED)

EXPERIMENTAL

Subjects administered standard of care + modified cyclosporine at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.

Drug: Remdesivir; Drug: Dexamethasone; Drug: Cyclosporine

Imatinib (PENDING ACTIVATION)

EXPERIMENTAL

Subjects will be administered 800 mg on Day 1 orally, in divided doses of 400 mg administered twice per day. 400 mg daily will be administered orally for the following 9 days or until discharge, whichever is sooner.

Drug: Imatinib Mesylate

Interventions

Cenicriviroc DRUG

Oral, loading 300 mg qAM followed by 150 mg qPM, 12 hours apart on day 1, then 150 mg BID for total of 14 to 28 days depending on date of hospital discharge.

Cenicriviroc + Standard of Care (CLOSED)

Icatibant DRUG

Subcutaneous, a safety run-in for the first 10 subjects was conducted using a regimen of 30 mg q8h × 3 days. All subsequent subjects received drug at 30 mg q8h x 6 days.

Also known as: Firazyr

Icatibant + Standard of Care (CLOSED)

Apremilast DRUG

oral, 30 mg bid × 14 days.

Also known as: Otezla

Apremilast + Standard of Care (CLOSED)

dornase alfa BIOLOGICAL

For Non-intubated subjects: 2.5 mg BID until hospital discharge, improvement to room air (or baseline oxygen use prior to illness) for 24 hours, or total of 14 days of study drug, whichever comes first. For intubated subjects: 5.0 mg BID in 10 mL normal saline until extubation or 14 days, whichever comes first. If intubated for less than 14 days, extubated subjects received 2.5 mg BID for a total Dornase treatment of 14 days, or until hospital discharge, whichever comes first.

Also known as: Pulmozyme

Dornase + Standard of Care (CLOSED)

Celecoxib DRUG

Oral: 400 mg BID for 7 days.

Also known as: celebrex

Celecoxib/famotidine + Standard of Care (CLOSED)

Famotidine DRUG

Oral: High dose 80 mg QID for 7 days followed by 40 mg BID for a course of 14 days.

Also known as: Pepcid

Celecoxib/famotidine + Standard of Care (CLOSED)

IC14 BIOLOGICAL

intravenous, 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4

IC14 + Standard of Care (CLOSED)

Aviptadil DRUG

Inhalation via nebulizer, 100 µg three times (TID) daily for a maximum of 14 days

Also known as: Zyesami

Aviptadil + Standard of Care (CLOSED)

narsoplimab BIOLOGICAL

Dosed at 4 mg/kg, given as a 30-minute intravenous infusion (up to a maximum of 370 mg per infusion) twice weekly for a total of four weeks (i.e. 9 doses) or until hospital discharge whichever comes first.

Also known as: OMS721

Narsoplimab + Standard of Care (CLOSED)

Cyproheptadine DRUG

4 mg tablet, with dosing regimen of 8 mg every 8 hours daily for ten (10) days. If the patient weighs less than 48 kg, the regimen is 6 mg every 8 hours daily for ten (10) days. If the participant was discharged before completion of this dosing regimen the drug was not continued.

Also known as: periactin

Cyproheptadine + Standard of Care (CLOSED)

Cyclosporine DRUG

Modified CsA at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.

Also known as: CsA

Cyclosporine + Standard of Care (CLOSED)

Remdesivir DRUG

Participants who receive remdesivir as part of their standard of care will be administered remdesivir by IV for up to ten days. Remdesivir 200mg loading dose on day 1, followed by 100mg IV once daily maintenance doses for 4 or 9 days.

Also known as: GS-5734

Apremilast + Standard of Care (CLOSED); Aviptadil + Standard of Care (CLOSED); Celecoxib/famotidine + Standard of Care (CLOSED); Cenicriviroc + Standard of Care (CLOSED); Control/Backbone - Remdesivir and Dexamethasone (CLOSED); Cyclosporine + Standard of Care (CLOSED); Cyproheptadine + Standard of Care (CLOSED); Dornase + Standard of Care (CLOSED); IC14 + Standard of Care (CLOSED); Icatibant + Standard of Care (CLOSED); Imatinib + Standard of Care (CLOSED); Narsoplimab + Standard of Care (CLOSED)

Imatinib Mesylate DRUG

Subjects will be administered 800 mg on Day 1 orally, in divided doses of 400 mg administered twice per day. 400 mg daily will be administered orally for the following 9 days or until discharge, whichever is sooner.

Imatinib (PENDING ACTIVATION); Imatinib + Standard of Care (CLOSED)

Dexamethasone DRUG

6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.

Apremilast + Standard of Care (CLOSED); Aviptadil + Standard of Care (CLOSED); Celecoxib/famotidine + Standard of Care (CLOSED); Cenicriviroc + Standard of Care (CLOSED); Control/Backbone - Remdesivir and Dexamethasone (CLOSED); Cyclosporine + Standard of Care (CLOSED); Cyproheptadine + Standard of Care (CLOSED); Dornase + Standard of Care (CLOSED); IC14 + Standard of Care (CLOSED); Icatibant + Standard of Care (CLOSED); Imatinib + Standard of Care (CLOSED); Narsoplimab + Standard of Care (CLOSED)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A. Male or Female, at least 18 years old
• B. Admitted to the hospital and placed on high flow oxygen (≥6L by nasal cannula or mask delivery system) or intubated for the treatment of (established or presumed) COVID-19.
• C. Informed consent provided by the patient, LAR or health care proxy.
• D. Confirmation of SARS-CoV-2 infection by PCR or Rapid antigen testing for SARS- CoV-2 infection prior to randomization.

You may not qualify if:

• A. Pregnant or breastfeeding women (must be documented by a pregnancy test during hospitalization)
• B. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent based on review of the medical record and patient history.
• C. Comfort measures only.
• D. Acute liver disease, or chronic liver disease with a Child-Pugh score greater than 11.
• E. Resident for more than six months at a skilled nursing facility.
• F. Estimated mortality greater than 50% over the next six months from underlying chronic conditions.
• G. Time since requirement for high flow oxygen or ventilation greater than 5 days.
• H. Anticipated transfer to another hospital which is not a study site within 72 hours.
• I. Patients with either end-stage kidney disease or acute kidney injury who are on dialysis.
• J. Co-enrollment in clinical trials of pharmacologic agents requiring an IND.
• K. On 3 or more vasopressors.
• L. Pre-existing heart failure with a known left ventricular ejection fraction \<25% or unstable angina pectoris.

Sponsors & Collaborators

• QuantumLeap Healthcare Collaborative: lead
• University of California, San Francisco: collaborator
• Emory University: collaborator
• Long Beach Memorial Medical Center: collaborator
• Georgetown University: collaborator
• University of California, Davis: collaborator
• Main Line Health: collaborator
• University of Alabama at Birmingham: collaborator
• University of Colorado, Denver: collaborator
• University of Southern California: collaborator
• Yale University: collaborator
• Wake Forest University Health Sciences: collaborator
• DHR Health Institute for Research and Development: collaborator
• University of California, Irvine: collaborator
• University of Michigan: collaborator
• West Virginia University: collaborator
• University of Miami: collaborator
• University Hospitals Cleveland Medical Center: collaborator
• M.D. Anderson Cancer Center: collaborator

Study Sites (36)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

UC Davis Medical Center

Davis, California, 95817, United States

Location

UC Irvine Medical Center

Irvine, California, 92868, United States

Location

Long Beach Memorial Medical Center

Long Beach, California, 90806, United States

Location

Kaiser LAMC

Los Angeles, California, 90027, United States

Location

University of Southern California

Los Angeles, California, 90033, United States

Location

Hoag Memorial Hospital Presbyterian

Newport Beach, California, 92663, United States

Location

University of California San Francisco (UCSF)

San Francisco, California, 94115, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Yale Cancer Center

New Haven, Connecticut, 06510, United States

Location

Stamford Health

Stamford, Connecticut, 06904, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007, United States

Location

University of Miami

Coral Gables, Florida, 33124, United States

Location

University of Florida

Gainesville, Florida, 32608, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Corewell Health

Grand Rapids, Michigan, 49503, United States

Location

Mercy Hospital Springfield

Springfield, Missouri, 65804, United States

Location

Kalispell Regional Medical Center

Kalispell, Montana, 59901, United States

Location

Logan Health Medical Center

Kalispell, Montana, 59901, United States

Location

Virtua Mount Holly Hospital

Mount Holly, New Jersey, 08060, United States

Location

Virtua Voorhees Hospital

Voorhees Township, New Jersey, 08043, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Wake Forest Baptist Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157, United States

Location

University Hospital Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

University of Pennsylvania (U Penn)

Philadelphia, Pennsylvania, 19104, United States

Location

Lankenau Medical Center (Mainline Health)

Wynnewood, Pennsylvania, 19096, United States

Location

Main Line Health - Lankenau Medical Center

Wynnewood, Pennsylvania, 19096, United States

Location

Sanford Health

Souix Falls, South Dakota, 57109, United States

Location

DHR Health

Edinburg, Texas, 78539, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

WVU Medicine

Morgantown, West Virginia, 26506, United States

Location

Related Publications (5)

• Files DC, Matthay MA, Calfee CS, Aggarwal NR, Asare AL, Beitler JR, Berger PA, Burnham EL, Cimino G, Coleman MH, Crippa A, Discacciati A, Gandotra S, Gibbs KW, Henderson PT, Ittner CAG, Jauregui A, Khan KT, Koff JL, Lang J, LaRose M, Levitt J, Lu R, McKeehan JD, Meyer NJ, Russell DW, Thomas KW, Eklund M, Esserman LJ, Liu KD; ISPY COVID Adaptive Platform Trial Network; undefined. I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations. BMJ Open. 2022 Jun 6;12(6):e060664. doi: 10.1136/bmjopen-2021-060664.

  PMID: 35667714 BACKGROUND

• Mabrey FL, Martin TR, Calfee CS, Liu KD, LaCombe B, Brown-Swigart L, Discacciati A, Eklund M, Heckbert SR, Matthay MA, Esserman L, Wurfel MM. Anti-CD14 treatment in patients with severe COVID-19: Clinical and biological effects in a Phase 2 randomized open-label adaptive platform clinical trial. CHEST Crit Care. 2025 Mar;3(1):100117. doi: 10.1016/j.chstcc.2024.100117. Epub 2024 Dec 9.

  PMID: 40462830 DERIVED

• Pomponio R, Peterson RA, Owusu M, Slaughter S, Melgar S, Jolley SE, Burnham EL. Phosphatidylethanol measures in patients with severe COVID-19-associated respiratory failure identify a subset with alcohol misuse. Alcohol Clin Exp Res (Hoboken). 2025 Jan;49(1):165-174. doi: 10.1111/acer.15495. Epub 2024 Nov 26.

  PMID: 39592213 DERIVED

• I-SPY COVID Consortium. Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial. EClinicalMedicine. 2023 Apr;58:101889. doi: 10.1016/j.eclinm.2023.101889. Epub 2023 Mar 3.

  PMID: 36883141 DERIVED

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

  PMID: 34473343 DERIVED

Related Links

• Clinical trial design during and beyond the pandemic: the I-SPY COVID trial, 20Jan2022

MeSH Terms

Conditions

COVID-19; Disease; Respiratory Distress Syndrome; Respiratory Insufficiency

Interventions

remdesivir; Imatinib Mesylate; Dexamethasone; cenicriviroc; icatibant; apremilast; dornase alfa; Celecoxib; Famotidine; aviptadil; narsoplimab; Cyproheptadine; Cyclosporine

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonamides; Sulfonamides; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Thiazoles; Dibenzocycloheptenes; Benzocycloheptenes; Polycyclic Aromatic Hydrocarbons; Piperidines; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Derek W Russell, MD

  University of Alabama at Birmingham Heersink School of Medicine

  PRINCIPAL INVESTIGATOR

• Kathleen D Liu, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Laura Esserman, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Platform Trial, Bayesian Design, from 2 arms up to 8 arms

Study Record Dates

• First Submitted: July 14, 2020
• First Posted: July 27, 2020
• Study Start: July 31, 2020
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2030
• Last Updated: March 16, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Post publication or earlier if warranted.
• Access Criteria: Sharing criteria are based on the circumstances of the request and whether the data have been published.

Locations

US (36)