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

Purpose

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

  • COVID-19

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study: 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.

Exclusion Criteria

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.

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Platform Trial, Bayesian Design, from 2 arms up to 8 arms
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Control/Backbone - Remdesivir and Dexamethasone (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
Experimental
Imatinib + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Imatinib Mesylate
    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: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
Experimental
Cenicriviroc + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Drug: Cenicriviroc
    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.
Experimental
Icatibant + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Drug: Icatibant
    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.
    Other names:
    • Firazyr
Experimental
Apremilast + Standard of Care (CLOSED) 		Subjects administered standard of care + apremilast orally , 30 mg bid × 14 days.
  • 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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Drug: Apremilast
    oral, 30 mg bid × 14 days.
    Other names:
    • Otezla
Experimental
Dornase + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Biological: dornase alfa
    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.
    Other names:
    • Pulmozyme
Experimental
Celecoxib/famotidine + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Drug: Celecoxib
    Oral: 400 mg BID for 7 days.
    Other names:
    • celebrex
  • Drug: Famotidine
    Oral: High dose 80 mg QID for 7 days followed by 40 mg BID for a course of 14 days.
    Other names:
    • Pepcid
Experimental
IC14 + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Biological: IC14
    intravenous, 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4
Experimental
Narsoplimab + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Biological: 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.
    Other names:
    • OMS721
Experimental
Aviptadil + Standard of Care (CLOSED) 		Subjects administered standard of care + aviptadil (inhalation via nebulizer), 100 µg three times (TID) daily for a maximum of 14 days
  • 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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Drug: Aviptadil
    Inhalation via nebulizer, 100 µg three times (TID) daily for a maximum of 14 days
    Other names:
    • Zyesami
Experimental
Cyproheptadine + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Drug: Cyproheptadine
    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.
    Other names:
    • periactin
Experimental
Cyclosporine + Standard of Care (CLOSED) 		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
    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 names:
    • GS-5734
  • Drug: Dexamethasone
    6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
  • Drug: Cyclosporine
    Modified CsA at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.
    Other names:
    • CsA
Experimental
Imatinib (PENDING ACTIVATION) 		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
    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.

Recruiting Locations

University of Alabama at Birmingham
Birmingham, Alabama 35294
Contact:
Valerie Caterinicchia, RN, BSN
205-934-5367
val7@uab.edu

More Details

Status
Recruiting
Sponsor
QuantumLeap Healthcare Collaborative

Study Contact

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

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. The main focus of this trial is a platform study for identifying effective agents for the treatment of 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). If interested in the therapeutic portion of the trial, potential participants will be asked to sign a consent form describing the backbone treatment and the two specific investigational agent arms to which they may be randomized. The primary endpoints will be time to recover to a durable level 4 (or less) on the WHO COVID-19 ordinal scale for clinical improvement and time to mortality (death). 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. A maximum of two investigational arms may be open at a time. 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 40 patients. 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 and dexamethasone 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. 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. Observational Component: Initially, all COVID-19 confirmed patients who started high-flow oxygen (WHO COVID-19 level 5; ≥6L oxygen by nasal prongs or mask) were entered in an Observational Component which collected data via extraction of medical records. Patients in this Observational Component also had their daily COVID status and drug administration form CRFs completed. An expanded Observational Study will replace the original Observational Component. The expanded observational study (Supplement 1) will collect blood sample(s) and clinical data from ARDS and AHRF patients (including COVID ARDS patients) to test the feasibility of quantifying a set of biomarkers that will allow each patient to be classified into either a hyper-inflammatory or hypo-inflammatory subtype in real time. If treatment of these critically ill ICU patients is to be guided by subtype classification, it is essential that the operational time for classification is as quick as possible.