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

• ClinicalTrials.gov Identifier: NCT04488081
• Recruitment Status: Recruiting
• First Posted: July 27, 2020
• Last Update Posted: July 21, 2021
• Sponsor: QuantumLeap Healthcare Collaborative
• Collaborators: University of California, San Francisco; University of Pennsylvania; Emory University; University of Alabama at Birmingham; University of Colorado, Denver; University of Southern California; Yale University; Columbia University; Wake Forest University Health Sciences; Sanford Health; Long Beach Memorial Medical Center; Georgetown University; Kalispell Regional Medical Center; Montefiore Medical Center; University of California, Davis; Hoag Memorial Hospital Presbyterian; University of Iowa; Main Line Health; Northwestern University
• Information provided by (Responsible Party): QuantumLeap Healthcare Collaborative

Tracking Information

• First Submitted Date: July 14, 2020
• First Posted Date: July 27, 2020
• Last Update Posted Date: July 21, 2021
• Actual Study Start Date: July 31, 2020
• Estimated Primary Completion Date: July 24, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 24, 2020)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 24, 2020)

• Improvement in disease severity [ Time Frame: Up to 60 days ]
  % of COVID-19 level 5 who never progress to COVID-19 level 6/7
• Health care utilization [ Time Frame: Up to 60 days ]
  Ventilator-free Days
• 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)
• Mortality [ Time Frame: Up to 28 days ]
  Mortality at 28 days after study enrollment

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: I-SPY COVID-19 TRIAL: An Adaptive Platform Trial for Critically Ill Patients
• Official Title: I-SPY COVID TRIAL: An Adaptive Platform Trial to Reduce Mortality and Ventilator Requirements for Critically Ill Patients
• 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.

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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Platform Trial, Bayesian Design, from 5 arms up to 8 arms

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: COVID-19

Intervention

• 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: Pulmozyme
  For high-flow nasal cannula (HFNC) 2.5 mg/2.5 mL nebulized BID; for mechanical ventilation (MV)5.0 mg/ 10 mL nebulized BID. Treatment course is 14 days total, return to room air or baseline oxygen use for 24 hours, or until hospital discharge, whichever comes first.
  Other Name: dornase alfa
• Drug: IC14
  4 mg/kg/day on Day 1, then 2 mg/kg/day on Days 2-4 as an IV infusion over 2 hours via peripheral or central vein
  Other Name: Atibuclimab
• Drug: Celecoxib Famotidine
  Clecoxib = 400 mg PO/ PNGT BID for 7 days. Famotidine = The course of treatment is a total of 21 days. High dose80 mg PO/PNGT four times daily (QID) for 7 days. Upon completion of the high dose, subjects should receive a lower 40 mg PO twice daily (BID) for a course of 14 days. For those with a serum Cr corresponding to an eGFR 30-59 mL/min/1.73m2, reduce the dose to 40 mg PO QID for 7 days, followed by 20 mg PO twice BID for 14 days. Stop at hospital discharge if a subject is discharged before day 21.
  Other Name: CELEBREX® PEPCID®
• Drug: Narsoplimab
  4 mg/kg, given as a 30-minute intravenous infusion (up to maximum of 370 mg/ infusion) twice weekly. If weekend narsoplimab administration is not feasible, administration day can be worked around aslong as the intervals do not exceed 2-3 days
  Other Name: OMS721
• Drug: Aviptadil Acetate
  100μg (microgram)in 1ml normal saline per dose. Drug solution is provided in a syringe for convenient filling of nebulizer and should be used neat (undiluted)
  Other Name: ZYESAMI™
• Drug: Cyclosporine
  5mg/kg/day given PO/NGT in two doses daily for 5 days while hospitalized as inpatients.
  Other Name: CsA

Study Arms

• 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.
  Intervention: Drug: Remdesivir
• Experimental: Pulmozyme plus remdesivir
  Nebulized aerosol medication that is inhaled recombinant DNAse. Dosing for high-flow nasal cannula (HFNC) 2.5 mg/2.5 mL nebulized BID; for mechanical ventilation (MV) 5.0 mg/10 mL nebulized BID. Treatment course is 14 days total (return to room air or baseline oxygen use for 24hours, or until hospital discharge, whichever comes first)
  Interventions:

  • Drug: Remdesivir
  • Drug: Pulmozyme
• Experimental: IC14 plus remdesivir
  Monoclonal antibody that blocks CD14, a cell surface and soluble protein that acts as a cofactor in triggering innate immune inflammation to pathogen- and damage-associated molecular patterns. Dosing: 4 mg/kg/day on Day 1, then 2 mg/kg/day on Days 2-4 as an IV infusion over 2 hours via peripheral or central vein. Additional Exclusions: Pre-existing thrombocytopenia (platelets <50,000/mm3); presence of serious coexisting infection, defined as HIV infection not virally suppressed and with pre-hospitalization CD4 counts ≤ 500 cell/mm3; or active tuberculosis or a history of inadequately treated tuberculosis; or active hepatitis B or hepatitis C viral infection (for questions, consult chaperones).
  Interventions:

  • Drug: Remdesivir
  • Drug: IC14
• Experimental: Celecoxib & Famotidine plus remdesivir
  Histamine-2 (H2) receptor antagonist and inverse agonist acts via a well-documented mechanism of action involving histamine H2 receptor blockade as well as interference with mast cell autocrine amplification of activation and degranulation which may reduce the proinflammatory response. The course of treatment is a total of 21 days. High dose 80 mg PO/PNGT four times daily (QID) for 7 days. Upon completion of the high dose, subjects should receive a lower 40 mg PO twice daily (BID) for a course of 14 days. Subjects will continue regimen upon discharge should it occur prior to 21 days from initiation of medication.
  Interventions:

  • Drug: Remdesivir
  • Drug: Celecoxib Famotidine
• Experimental: Narsoplimab plus remdesivir
  4 mg/kg, given as a 30-minute intravenous infusion (up to maximum of 370 mg/ infusion) twice weekly. If weekend narsoplimab administration is not feasible, administration day can be worked around as long as the intervals do not exceed 2-3 days
  Interventions:

  • Drug: Remdesivir
  • Drug: Narsoplimab
• Experimental: Aviptadil plus remdesivir
  100μg (microgram) in 1ml normal saline per dose. Drug solution is provided in a syringe for convenient filling of nebulizer and should be used neat (undiluted)1 ml total per dose for intubated and non-intubated subjects. Drug should be administered gradually, and it will take approximately 5 minutes to administer. Drug should be administered q8H, for a maximum of 14 days(maximum 42 doses)
  Interventions:

  • Drug: Remdesivir
  • Drug: Aviptadil Acetate
• Experimental: Cyclosporine plus remdesivir
  Dosing: 5mg/kg/ day given PO/NGT in two doses daily for 5 days while hospitalized as inpatients. Prior and after administration through an NGT/OGT, flush the NGT or OGT with 5-10ml of water. See instructions for dose adjustment based on CsA levels.
  Interventions:

  • Drug: Remdesivir
  • Drug: Cyclosporine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 24, 2020): 1500
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 1, 2022
• Estimated Primary Completion Date: July 24, 2022 (Final data collection date for primary outcome measure)

Eligibility 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 or Rapid antigen testing for SARS-CoV-2 infection 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 120 hours (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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Paul Henderson, PhD; 1-925-570-1615; p.henderson@quantumleaphealth.org

Contact: Karyn DiGiorgio, MS; 1-415-307-1539; karyn.digiorgio@quantumleaphealth.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04488081
• Other Study ID Numbers: I-SPY-COVID
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: 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.

• Responsible Party: QuantumLeap Healthcare Collaborative
• Study Sponsor: QuantumLeap Healthcare Collaborative

Collaborators

• University of California, San Francisco
• University of Pennsylvania
• Emory University
• University of Alabama at Birmingham
• University of Colorado, Denver
• University of Southern California
• Yale University
• Columbia University
• Wake Forest University Health Sciences
• Sanford Health
• Long Beach Memorial Medical Center
• Georgetown University
• Kalispell Regional Medical Center
• Montefiore Medical Center
• University of California, Davis
• Hoag Memorial Hospital Presbyterian
• University of Iowa
• Main Line Health
• Northwestern University

Investigators

• 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

• PRS Account: QuantumLeap Healthcare Collaborative
• Verification Date: July 2021