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

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ClinicalTrials.gov Identifier: NCT04488081
Recruitment Status : Recruiting
First Posted : July 27, 2020
Last Update Posted : September 29, 2020
Sponsor:
Collaborators:
University of California, San Francisco
University of Pennsylvania
University of Minnesota
Emory University
University of Alabama at Birmingham
University of California, San Diego
University of Colorado, Denver
University of Southern California
Yale University
Columbia University
Wake Forest University Health Sciences
Sanford Health
Montefiore Medical Center
Information provided by (Responsible Party):
QuantumLeap Healthcare Collaborative

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.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Remdesivir Drug: Cenicriviroc Drug: Icatibant Drug: Razuprotafib Drug: Apremilast Phase 2

Detailed Description:

This platform trial will provide access to repurposed and investigational agents for critically ill patients infected with SARS-CoV-2 who have severe or life-threatening COVID-19. Any critically ill patient with known or presumed COVID-19 will be automatically entered into the screening phase of the trial until SARS-CoV-2 infection is confirmed. Basic data will be assembled for each patient (such as ventilatory status and survival). All patients who start high-flow oxygen (WHO COVID-19 level 5; > 6L oxygen by nasal prongs or mask) will be entered in an observational registry which will only require extraction of medical record data. Registry participants will be asked to sign a consent form for the backbone treatment and a specific investigational agent arm to which they are assigned. The primary endpoint will be time to recover to a durable level 4 (or less) on the WHO COVID-19 ordinal scale for clinical improvement. For this trial, a durable level 4 is defined as at least 48 hours at COVID level 4 or less (nasal prongs oxygen) without returning to high flow oxygen or intubation. Acute care facility resource utilization will be automatically calculated (total length of stay in a critical care setting, days intubated, and survival). Any change in status, including intubation, extubation, death or discharge, will be recorded and verified by the attending physician.

Patients will be evaluated based on their initial status (ventilation at entry vs. high flow oxygen). Exploratory biomarkers will be evaluated over time (ARDS phenotypes and other proposed markers) to facilitate clinical learning. The trial will begin enrollment with two investigational agents and quickly increase to four study arms as the pace of enrollment increases. The anticipated accrual will be 50 patients per week. The maximum number of participants assigned to an arm without graduation will be 125 patients. Agents can be dropped for futility after enrollment of 50 patients. It is anticipated that 10 investigational agents can be evaluated in the span of 4-6 months, depending on the time course of COVID-19 infections across the US. As the trial proceeds and a better understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded biomarker and data collection can be added as needed to further elucidate how agents are or are not working. The study design features comparison of investigational agent efficacy using a Bayesian design, which will allow the detection of strong efficacy signals with the fewest possible patients. Initially the control will be patients given current standard of care (supportive care for ARDS, including lung protective ventilation and remdesivir as backbone therapy). As other treatments (for example, anticoagulation) become part of standard supportive care across sites, these will be added to the backbone therapy. If an agent meets the threshold for graduation the company leadership will be informed as will the FDA. The arm with the graduated agent will cease to enroll, allowing a new arm with a different investigational agent to be added. Information about agents disposition will be as follows:

Every trial participant will have blood collected at trial enrollment, day 3, and day 7 for pre-specified biomarker and DNA and RNA analysis. Additional biomarkers can be added as the trial proceeds. Patient outcomes will also be evaluated on the basis of whether patients are ventilated initially or not.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Platform Trial, Bayesian Design
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: I-SPY COVID TRIAL: An Adaptive Platform Trial to Reduce Mortality and Ventilator Requirements for Critically Ill Patients
Actual Study Start Date : July 31, 2020
Estimated Primary Completion Date : July 24, 2022
Estimated Study Completion Date : November 1, 2022

Arm Intervention/treatment
Active Comparator: Remdesivir plus standard of care
  • See the Full EUA Prescribing Information for complete dosage, administration, and preparation instructions.
  • Remdesivir is available as a concentrated solution.
  • The recommended dose for adults weighing 40 kg and higher is a single loading dose of 200 mg on Day 1 followed by once- daily maintenance doses of 100 mg from Day 2.
  • The optimal duration of treatment for COVID-19 is unknown.
  • For patients requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO), the recommended total treatment duration is 10 days.
  • For patients not requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days for a total treatment duration of up to 10 days.
  • Administer remdesivir via IV infusion over 30 to 120 minutes.
Drug: Remdesivir
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.
Other Name: GS-5734

Experimental: Cenicriviroc (CVC) plus remdesivir

150 mg immediate release tablets Oral (subjects should take CVC twice daily at approximately 12-hour intervals with food orally or through a feeding tube).

Treatment will be administered to subjects while hospitalized as in-patients and will continue whether or not the patient is discharged from the hospital for 28-days or until discharge from the hospital, whichever comes first but with a minimum course of 14 days. CVC should be administered twice daily at approximately 12-hour intervals in fed condition and at approximately the same time each day (±2 hours). Patients may receive a larger dose (450 mg total) for their first day of treatment as a loading dose administered as a morning dose of 300 mg and an evening dose of 150 mg. Remdesivir will be dosed as described for the active comparator arm.

Drug: Remdesivir
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.
Other Name: GS-5734

Drug: Cenicriviroc
Cenicriviroc given twice daily for 28 days: number of pills dependent on recommended modifications based on patients' other anti-retroviral medications and certain other medications anticipated to interact with cenicriviroc.
Other Name: CVC, TBR-652

Experimental: Icatibant plus remdesivir
A sterile, single-use, prefilled syringe solution for subcutaneous administration. Each syringe contains 3 mL of a sterile solution of icatibant 30 mg (as icatibant acetate). 30 mg in sterile, single-use syringe. Single-dose, single-use prefilled syringe with a hypodermic needle (25G) included in the package. Subcutaneous (SC) injection in the abdominal area over at least 30 seconds. 30 mg every 8 hours daily for 3 days. Treatment will be administered to subjects while hospitalized as inpatients. Remdesivir will be dosed as described for the active comparator arm.
Drug: Remdesivir
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.
Other Name: GS-5734

Drug: Icatibant
Participants will receive Icatibant 30mg SC injection in the abdominal area.
Other Name: Firazyr

Experimental: Razuprotafib plus remdesivir

Ready to dose sterile solution for subcutaneous injection. Razuprotafib (AKB-9778) Sterile Solution is supplied as a clear, colorless to slightly yellow isotonic, sterile, unpreserved solution. Strengths to be used in trial: 10 mg and 20 mg. Route: Subcutaneous (SC) injection in the 4 quadrants of the abdominal area is preferred.

Standard Regimen: 10 mg every 8 hours for 7 days, advancing to 20 mg q8h for 7 days once the safety run-in confirms tolerability. Agent Preparation: Aseptic filling of syringes to desired dose is required. Pre-medication: Specific pre-medication is not required for routine treatment. Administration: Treatment will be administered to subjects while hospitalized as inpatients. Remdesivir will be dosed as described for the active comparator arm.

Drug: Remdesivir
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.
Other Name: GS-5734

Drug: Razuprotafib
Subcutaneous (SC) injection in the 4 quadrants of the abdominal area is preferred. Standard Regimen: 10 mg every 8 hours for 7 days, advancing to 20 mg q8h for 7 days once the safety run-in confirms tolerability.
Other Name: AKB-9778

Experimental: Apremilast plus remdesivir

Single dose, film-coated tablet for oral administration. The Apremilast drug product used for clinical trials is supplied as a tablet for oral administration containing 30 mg of apremilast drug substance. The tablet formulation of apremilast will be provided in bottles.Route: Oral (subjects should take apremilast twice daily at approximately 12-hour intervals by swallowing or dissolved in water and administered through a feeding tube).

Standard Regimen: 30 mg twice daily (BID). Treatment will be administered to subjects while hospitalized as inpatients for a 14 day course. Subjects should be administered apremilast twice daily at approximately 12-hour intervals without restriction of food or drink, and at approximately the same time each day (±2 hours). Remdesivir will be dosed as described for the active comparator arm.

Drug: Remdesivir
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.
Other Name: GS-5734

Drug: Apremilast
Oral medication: subjects should take apremilast twice daily at approximately 12-hour intervals by swallowing or dissolved in water and administered through a feeding tube. Standard Regimen: 30 mg twice daily (BID).
Other Name: Otezla




Primary Outcome Measures :
  1. Identify agents that will result in substantial improvements to the clinical condition of participants with COVID-19 [ Time Frame: Up to 28 days ]
    Time to achieve durable change in COVID-19 to ordinal level 4 or less for at least 48 hours


Secondary Outcome Measures :
  1. Improvement in disease severity [ Time Frame: Up to 60 days ]
    % of COVID-19 level 5 who never progress to COVID-19 level 6/7

  2. Health care utilization [ Time Frame: Up to 60 days ]
    Ventilator-free Days

  3. Frequency of serious AEs [ Time Frame: Up to 60 days ]

    Total grade 3 or higher AEs by arm and total number of patients with grade 3 or higher AEs by arm.

    ● Total grade 3 or higher AEs of special interest by arm and total number of patients with grade 3 or higher AEs of special interest by arms (based upon lab assessments)


  4. Mortality [ Time Frame: Up to 28 days ]
    Mortality at 28 days after study enrollment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A. Male or Female, at least 18 years old.

B. Admitted to the hospital and placed on high flow oxygen (greater than 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 or health care proxy.

D. Confirmation of SARS-CoV-2 infection by PCR prior to randomization.

Exclusion Criteria:

A. Pregnant or breastfeeding women.

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 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 72 hours.

H. Anticipated transfer to another hospital which is not a study site within 72 hours.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04488081


Contacts
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Contact: Paul Henderson, PhD 1-925-570-1615 p.henderson@quantumleaphealth.org
Contact: Karyn DiGiorgio, MS 1-415-307-1539 karyn.digiorgio@quantumleaphealth.org

Locations
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United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Valerie Caterinicchia, RN, BSN    205-934-5367    val7@uab.edu   
Principal Investigator: Derek Russell, MD         
Sub-Investigator: Sheetal Gandotra, MD         
United States, California
University of Southern California Not yet recruiting
Los Angeles, California, United States, 90033
Contact: Kristy Watkins, RN    323-865-0452    Watkins_K@ccnt.usc.edu   
Principal Investigator: Julie Lang, MD         
University of California San Francisco (UCSF) Recruiting
San Francisco, California, United States, 94115
Contact    877-827-3222      
Principal Investigator: Kathleen Liu, MD         
Principal Investigator: Carolyn Calfee, MD         
Principal Investigator: Laura Esserman, MD         
United States, Colorado
University of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Tessa Mcspadden    720-848-0609    tessa.mcspadden@ucdenver.edu   
Principal Investigator: Ellen Burnham, MD         
United States, Connecticut
Yale Cancer Center Recruiting
New Haven, Connecticut, United States, 06510
Contact: Trisha Burello, MS    203-737-2848    trisha.burrello@yale.edu   
Principal Investigator: Jonathan Koff, MD         
United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10461
Principal Investigator: Michelle Gong, MD         
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Leslie Segal, MPH    212-304-6346    ls3429@cumc.columbia.edu   
Principal Investigator: Jeremy Beitler, MD         
United States, North Carolina
Wake Forest Baptist Comprehensive Cancer Center Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Angela Howell, MD    336-716-5440    anhowell@wakehealth.edu   
Principal Investigator: D. Clark Files, MD         
Principal Investigator: Karl Thomas, MD         
United States, Pennsylvania
University of Pennsylvania (U Penn) Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Lauren Bayne    215-349-5398    Lauren.Bayne@uphs.upenn.edu   
Principal Investigator: Amy Clark, MD         
United States, South Dakota
Sanford Health Recruiting
Sioux Falls, South Dakota, United States, 57109
Principal Investigator: Paul Berger, MD         
Sponsors and Collaborators
QuantumLeap Healthcare Collaborative
University of California, San Francisco
University of Pennsylvania
University of Minnesota
Emory University
University of Alabama at Birmingham
University of California, San Diego
University of Colorado, Denver
University of Southern California
Yale University
Columbia University
Wake Forest University Health Sciences
Sanford Health
Montefiore Medical Center
Investigators
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Principal Investigator: Carolyn Carolyn, MD University of California, San Francisco
Principal Investigator: Kathleen D Liu, MD University of California, San Francisco
Principal Investigator: Laura Esserman, MD University of California, San Francisco
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Responsible Party: QuantumLeap Healthcare Collaborative
ClinicalTrials.gov Identifier: NCT04488081    
Other Study ID Numbers: I-SPY-COVID
First Posted: July 27, 2020    Key Record Dates
Last Update Posted: September 29, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: We will share data on a case by case basis with appropriate IRB review and review by our Data Safety Monitoring Comittee.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by QuantumLeap Healthcare Collaborative:
COVID-19
severe disease
Platform Trial
Additional relevant MeSH terms:
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Bradykinin B2 Receptor Antagonists
Bradykinin Receptor Antagonists
Critical Illness
Disease Attributes
Pathologic Processes
TAK-652
Apremilast
Icatibant
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
CCR5 Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors