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

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.

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.