Clinical trial NCT04488081: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
severe disease
Platform Trial
Acute Respiratory Distress Syndrome
ARDS
SARS-COV-2
AHRF
Acute Hypoxemic Respiratory Failure
Lead sponsor: QuantumLeap Healthcare Collaborative
Sponsor class: OTHER
Collaborators: name: University of California, San Francisco
name: University of Pennsylvania
name: Emory University
name: University of Alabama at Birmingham
name: University of Colorado, Denver
name: University of Southern California
name: Yale University
name: Wake Forest University Health Sciences
name: Sanford Health
name: Long Beach Memorial Medical Center
name: Georgetown University
name: University of California, Davis
name: Hoag Memorial Hospital Presbyterian
name: Main Line Health
name: DHR Health Institute for Research and Development
name: University of California, Irvine
name: Corewell Health
name: Kaiser Permanente
name: University of Michigan
name: West Virginia University
name: University of Miami
name: University Hospitals Cleveland Medical Center
name: Virtua Health
name: M.D. Anderson Cancer Center
First posted: 2020-07-27
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Platform Trial, Bayesian Design, from 2 arms up to 8 arms
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Identify agents that will result in substantial improvements to the clinical condition of participants with COVID-19.
timeFrame: Up to 28 days
Secondary outcomes:
measure: Mortality
timeFrame: Up to 28 days
measure: Improvement in disease severity
timeFrame: Up to 60 days
measure: Health care utilization
timeFrame: Up to 28 days
measure: Safety: Frequency of serious AEs
timeFrame: Up to 60 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Davis
country: United States
facility: UC Davis Medical Center
state: California
city: Irvine
country: United States
facility: UC Irvine Medical Center
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Los Angeles
country: United States
facility: Kaiser LAMC
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: San Francisco
country: United States
facility: University of California San Francisco (UCSF)
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Stamford
country: United States
facility: Stamford Health
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Coral Gables
country: United States
facility: University of Miami
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Corewell Health
state: Michigan
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Kalispell
country: United States
facility: Kalispell Regional Medical Center
state: Montana
city: Kalispell
country: United States
facility: Logan Health Medical Center
state: Montana
city: Mount Holly
country: United States
facility: Virtua Mount Holly Hospital
state: New Jersey
city: Voorhees
country: United States
facility: Virtua Voorhees Hospital
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Comprehensive Cancer Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital Cleveland Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania (U Penn)
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center (Mainline Health)
state: Pennsylvania
city: Wynnewood
country: United States
facility: Main Line Health - Lankenau Medical Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Health
state: South Dakota
city: Edinburg
country: United States
facility: DHR Health
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Morgantown
country: United States
facility: WVU Medicine
state: West Virginia
Study officials:
affiliation: University of California, San Francisco
name: Carolyn Carolyn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Kathleen D Liu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Laura Esserman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.