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. 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.

Recruiting
COVID-19

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: 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.

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.

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 Name: Firazyr

Drug: Apremilast

oral, 30 mg bid × 14 days.
Other Name: Otezla

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 Name: Pulmozyme

Drug: Celecoxib

Oral: 400 mg BID for 7 days.
Other Name: celebrex

Drug: Famotidine

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

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
Other Name: Zyesami

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 Name: OMS721

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 Name: periactin

Drug: Cyclosporine

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

Eligibility Criteria

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.

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years ~ Maximum: N/A
Countries
United States
Locations

University of Alabama at Birmingham
Birmingham, Alabama, United States

UC Davis Medical Center
Davis, California, United States

UC Irvine Medical Center
Irvine, California, 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

Hoag Memorial Hospital Presbyterian
Newport Beach, California, United States

University of California San Francisco (UCSF)
San Francisco, California, United States

University of Colorado
Aurora, Colorado, United States

Yale Cancer Center
New Haven, Connecticut, United States

Stamford Health
Stamford, Connecticut, United States

Georgetown University
Washington, District of Columbia, United States

University of Miami
Coral Gables, Florida, United States

University of Florida
Gainesville, Florida, United States

Emory University
Atlanta, Georgia, United States

Northwestern University
Chicago, Illinois, United States

University of Iowa
Iowa City, Iowa, United States

University of Michigan
Ann Arbor, Michigan, United States

Corewell Health
Grand Rapids, Michigan, United States

Mercy Hospital Springfield
Springfield, Missouri, United States

Kalispell Regional Medical Center
Kalispell, Montana, United States

Logan Health Medical Center
Kalispell, Montana, United States

Virtua Mount Holly Hospital
Mount Holly, New Jersey, United States

Virtua Voorhees Hospital
Voorhees, New Jersey, United States

Montefiore Medical Center
Bronx, New York, United States

Columbia University Medical Center
New York, New York, United States

University of Rochester Medical Center
Rochester, New York, United States

Wake Forest Baptist Comprehensive Cancer Center
Winston-Salem, North Carolina, United States

University Hospital Cleveland Medical Center
Cleveland, Ohio, United States

University of Pennsylvania (U Penn)
Philadelphia, Pennsylvania, United States

Lankenau Medical Center (Mainline Health)
Wynnewood, Pennsylvania, United States

Main Line Health - Lankenau Medical Center
Wynnewood, Pennsylvania, United States

Sanford Health
Sioux Falls, South Dakota, United States

DHR Health
Edinburg, Texas, United States

University of Texas MD Anderson Cancer Center
Houston, Texas, United States

WVU Medicine
Morgantown, West Virginia, United States

Contacts

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

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

QuantumLeap Healthcare Collaborative
NCT Number
Keywords
Covid-19
severe disease
Platform Trial
Acute Respiratory Distress Syndrome
ARDS
SARS-CoV-2
AHRF
acute hypoxemic respiratory failure
MeSH Terms
COVID-19
Cyproheptadine
Cyclosporine
Remdesivir
Cenicriviroc
Dexamethasone
Celecoxib
Apremilast
Icatibant
Imatinib Mesylate
Famotidine
Cyclosporins