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

COVID-19 Clinical Trial

— I-SPY_COVID  

Official title:

I-SPY COVID TRIAL: An Adaptive Platform Trial to Reduce Mortality and Ventilator Requirements for Critically Ill Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04488081
• Other study ID #: I-SPY-COVID
• Status: Recruiting
• Phase: Phase 2
• Start date: July 31, 2020
• Est. completion date: July 31, 2030

Study information

• Verified date: March 2024
• Source: QuantumLeap Healthcare Collaborative
• Contact: Paul Henderson, PhD
• Phone: 1-925-570-1615
• Email: p.henderson[@]quantumleaphealth.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1500
• Est. completion date: July 31, 2030
• Est. primary completion date: July 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• 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.
• 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.
• Dexamethasone
6 mg intravenous of oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.
• 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.
• 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.
• Apremilast
oral, 30 mg bid × 14 days.

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.

Drug:
• 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.

Biological:
• IC14
intravenous, 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4

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

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.

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

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Montefiore Medical Center	Bronx	New York
United States	Northwestern University	Chicago	Illinois
United States	University Hospital Cleveland Medical Center	Cleveland	Ohio
United States	University of Miami	Coral Gables	Florida
United States	UC Davis Medical Center	Davis	California
United States	DHR Health	Edinburg	Texas
United States	University of Florida	Gainesville	Florida
United States	Corewell Health	Grand Rapids	Michigan
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	UC Irvine Medical Center	Irvine	California
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Logan Health Medical Center	Kalispell	Montana
United States	Long Beach Memorial Medical Center	Long Beach	California
United States	Kaiser LAMC	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	WVU Medicine	Morgantown	West Virginia
United States	Virtua Mount Holly Hospital	Mount Holly	New Jersey
United States	Yale Cancer Center	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	University of Pennsylvania (U Penn)	Philadelphia	Pennsylvania
United States	University of Rochester Medical Center	Rochester	New York
United States	University of California San Francisco (UCSF)	San Francisco	California
United States	Sanford Health	Sioux Falls	South Dakota
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Stamford Health	Stamford	Connecticut
United States	Virtua Voorhees Hospital	Voorhees	New Jersey
United States	Georgetown University	Washington	District of Columbia
United States	Wake Forest Baptist Comprehensive Cancer Center	Winston-Salem	North Carolina
United States	Lankenau Medical Center (Mainline Health)	Wynnewood	Pennsylvania
United States	Main Line Health - Lankenau Medical Center	Wynnewood	Pennsylvania

Sponsors (25)

Lead Sponsor

Collaborator

QuantumLeap Healthcare Collaborative

Corewell Health, DHR Health Institute for Research and Development, Emory University, Georgetown University, Hoag Memorial Hospital Presbyterian, Kaiser Permanente, Long Beach Memorial Medical Center, M.D. Anderson Cancer Center, Main Line Health, Sanford Health, University Hospitals Cleveland Medical Center, University of Alabama at Birmingham, University of California, Davis, University of California, Irvine, University of California, San Francisco, University of Colorado, Denver, University of Miami, University of Michigan, University of Pennsylvania, University of Southern California, Virtua Health, Wake Forest University Health Sciences, West Virginia University, Yale University

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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; Not hospitalized, no limitations on activities; Not hospitalized, limitation on activities; Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen (< 6L by nasal cannula or mask delivery system); Hospitalized, on non-invasive ventilation or high flow oxygen devices (=6L per minute, mask or intranasal cannula); Hospitalized, on invasive mechanical ventilation; Hospitalized, ventilation plus additional organ support-pressors, RRT, ECMO; Death.	Up to 28 days
Secondary	Mortality	Proportion of patients alive in the treatment and control arm at day 7, 14, 21, and 28 (The proportion of patients alive, i.e., alive and still at risk of both reaching level 4 and death is given by the survival function).; The cumulative incidence function for mortality.	Up to 28 days
Secondary	Improvement in disease severity	Sustained recovery which is defined as time to discharge at COVID-level 4 or lower and not subsequently re-admitted to the hospital or die at Day 28 follow-up if discharged before 28 days, and Day 60 follow-up if discharged between 28 to 60 days.; % of COVID-19 level 5 who never progress to COVID-19 level 6/7; The measure for recovery is defined as time to reach level 4 or less in the World Health Organization COVID-19 scale for at least 48 hours - without returning to high flow oxygen or intubation, or discharge at COVID level 4 or less except for discharge to another hospital. (0 being minimum and 8 being maximum)	Up to 60 days
Secondary	Health care utilization	Ventilator-free days	Up to 28 days
Secondary	Safety: Frequency of serious AEs	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); All AEs will be identified and assessed for severity using the National Cancer Institute - Common Terminology Criteria for Adverse Events v5.0 which provides a grading scale for each AE listed.; Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.; Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL*.; Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**.; Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.	Up to 60 days

External Links

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