I-SPY_COVID: I-SPY COVID-19 TRIAL: An Adaptive Platform Trial for Critically Ill Patients
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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. 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). All patients who start high-flow oxygen (WHO COVID-19 level 5; > 6L oxygen by nasal prongs or mask) will be entered in an observational registry which will only require extraction of medical record data. Registry participants will be asked to sign a consent form for the backbone treatment and a specific investigational agent arm to which they are assigned. The primary endpoint will be time to recover to a durable level 4 (or less) on the WHO COVID-19 ordinal scale for clinical improvement. 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. The trial will begin enrollment with two investigational agents and quickly increase to four study arms as the pace of enrollment increases. 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 50 patients. It is anticipated that 10 investigational agents can be evaluated in the span of 4-6 months, depending on the time course of COVID-19 infections across the US. 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 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. Information about agents disposition will be as follows:
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Remdesivir plus standard of care See the Full EUA Prescribing Information for complete dosage, administration, and preparation instructions. Remdesivir is available as a concentrated solution. The recommended dose for adults weighing 40 kg and higher is a single loading dose of 200 mg on Day 1 followed by once- daily maintenance doses of 100 mg from Day 2. The optimal duration of treatment for COVID-19 is unknown. For patients requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO), the recommended total treatment duration is 10 days. For patients not requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days for a total treatment duration of up to 10 days. Administer remdesivir via IV infusion over 30 to 120 minutes. |
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:
|
| Experimental: Pulmozyme plus remdesivir Nebulized aerosol medication that is inhaled recombinant DNAse. Dosing for high-flow nasal cannula (HFNC) 2.5 mg/2.5 mL nebulized BID; for mechanical ventilation (MV) 5.0 mg/10 mL nebulized BID. Treatment course is 14 days total (return to room air or baseline oxygen use for 24hours, 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:
Drug: Pulmozyme
For high-flow nasal cannula (HFNC) 2.5 mg/2.5 mL nebulized BID; for mechanical ventilation (MV)5.0 mg/ 10 mL nebulized BID. Treatment course is 14 days total, return to room air or baseline oxygen use for 24 hours, or until hospital discharge, whichever comes first.
Other Names:
|
| Experimental: IC14 plus remdesivir Monoclonal antibody that blocks CD14, a cell surface and soluble protein that acts as a cofactor in triggering innate immune inflammation to pathogen- and damage-associated molecular patterns. Dosing: 4 mg/kg/day on Day 1, then 2 mg/kg/day on Days 2-4 as an IV infusion over 2 hours via peripheral or central vein. Additional Exclusions: Pre-existing thrombocytopenia (platelets <50,000/mm3); presence of serious coexisting infection, defined as HIV infection not virally suppressed and with pre-hospitalization CD4 counts ≤ 500 cell/mm3; or active tuberculosis or a history of inadequately treated tuberculosis; or active hepatitis B or hepatitis C viral infection (for questions, consult chaperones). |
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:
Drug: IC14
4 mg/kg/day on Day 1, then 2 mg/kg/day on Days 2-4 as an IV infusion over 2 hours via peripheral or central vein
Other Names:
|
| Experimental: Celecoxib & Famotidine plus remdesivir Histamine-2 (H2) receptor antagonist and inverse agonist acts via a well-documented mechanism of action involving histamine H2 receptor blockade as well as interference with mast cell autocrine amplification of activation and degranulation which may reduce the proinflammatory response. The course of treatment is a total of 21 days. High dose 80 mg PO/PNGT four times daily (QID) for 7 days. Upon completion of the high dose, subjects should receive a lower 40 mg PO twice daily (BID) for a course of 14 days. Subjects will continue regimen upon discharge should it occur prior to 21 days from initiation of medication. |
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:
Drug: Celecoxib Famotidine
Clecoxib = 400 mg PO/ PNGT BID for 7 days. Famotidine = The course of treatment is a total of 21 days. High dose80 mg PO/PNGT four times daily (QID) for 7 days. Upon completion of the high dose, subjects should receive a lower 40 mg PO twice daily (BID) for a course of 14 days. For those with a serum Cr corresponding to an eGFR 30-59 mL/min/1.73m2, reduce the dose to 40 mg PO QID for 7 days, followed by 20 mg PO twice BID for 14 days. Stop at hospital discharge if a subject is discharged before day 21.
Other Names:
|
| Experimental: Narsoplimab plus remdesivir 4 mg/kg, given as a 30-minute intravenous infusion (up to maximum of 370 mg/ infusion) twice weekly. If weekend narsoplimab administration is not feasible, administration day can be worked around as long as the intervals do not exceed 2-3 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:
Drug: Narsoplimab
4 mg/kg, given as a 30-minute intravenous infusion (up to maximum of 370 mg/ infusion) twice weekly. If weekend narsoplimab administration is not feasible, administration day can be worked around aslong as the intervals do not exceed 2-3 days
Other Names:
|
| Experimental: Aviptadil plus remdesivir 100μg (microgram) in 1ml normal saline per dose. Drug solution is provided in a syringe for convenient filling of nebulizer and should be used neat (undiluted)1 ml total per dose for intubated and non-intubated subjects. Drug should be administered gradually, and it will take approximately 5 minutes to administer. Drug should be administered q8H, for a maximum of 14 days(maximum 42 doses) |
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:
Drug: Aviptadil Acetate
100μg (microgram)in 1ml normal saline per dose. Drug solution is provided in a syringe for convenient filling of nebulizer and should be used neat (undiluted)
Other Names:
|
| Experimental: Cyclosporine plus remdesivir Dosing: 5mg/kg/ day given PO/NGT in two doses daily for 5 days while hospitalized as inpatients. Prior and after administration through an NGT/OGT, flush the NGT or OGT with 5-10ml of water. See instructions for dose adjustment based on CsA levels. |
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:
Drug: Cyclosporine
5mg/kg/day given PO/NGT in two doses daily for 5 days while hospitalized as inpatients.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Identify agents that will result in substantial improvements to the clinical condition of participants with COVID-19 [Up to 28 days]
Time to achieve durable change in COVID-19 to ordinal level 4 or less for at least 48 hours
Secondary Outcome Measures
- Improvement in disease severity [Up to 60 days]
% of COVID-19 level 5 who never progress to COVID-19 level 6/7
- Health care utilization [Up to 60 days]
Ventilator-free Days
- Frequency of serious AEs [Up to 60 days]
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)
- Mortality [Up to 28 days]
Mortality at 28 days after study enrollment
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or Female, at least 18 years old.
-
Admitted to the hospital and placed on high flow oxygen (greater than 6L by nasal cannula or mask delivery system) or intubated for the treatment of (established or presumed) COVID-19.
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Informed consent provided by the patient or health care proxy.
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Confirmation of SARS-CoV-2 infection by PCR or Rapid antigen testing for SARS-CoV-2 infection prior to randomization.
Exclusion Criteria:
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Pregnant or breastfeeding women.
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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.
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Comfort measures only.
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Acute or chronic liver disease with a Child-Pugh score greater than 11.
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Resident for more than six months at a skilled nursing facility.
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Estimated mortality greater than 50% over the next six months from underlying chronic conditions.
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Time since requirement for high flow oxygen or ventilation greater than 120 hours (5 days).
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Anticipated transfer to another hospital which is not a study site within 72 hours.
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Patients with either end-stage kidney disease or acute kidney injury who are on dialysis.
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Co-enrollment in clinical trials of pharmacologic agents requiring an IND.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama at Birmingham | Birmingham | Alabama | United States | 35294 |
| 2 | UC Davis Medical Center | Davis | California | United States | 95817 |
| 3 | Long Beach Memorial Medical Center | Long Beach | California | United States | 90806 |
| 4 | University of Southern California | Los Angeles | California | United States | 90033 |
| 5 | Hoag Memorial Hospital Presbyterian | Newport Beach | California | United States | 92663 |
| 6 | University of California San Francisco (UCSF) | San Francisco | California | United States | 94115 |
| 7 | University of Colorado | Aurora | Colorado | United States | 80045 |
| 8 | Yale Cancer Center | New Haven | Connecticut | United States | 06510 |
| 9 | Georgetown University | Washington | District of Columbia | United States | 20007 |
| 10 | Emory University | Atlanta | Georgia | United States | 30322 |
| 11 | Northwestern University | Chicago | Illinois | United States | 60611 |
| 12 | University of Iowa | Iowa City | Iowa | United States | 52242 |
| 13 | Kalispell Regional Medical Center | Kalispell | Montana | United States | 59901 |
| 14 | Montefiore Medical Center | Bronx | New York | United States | 10461 |
| 15 | Columbia University Medical Center | New York | New York | United States | 10032 |
| 16 | Wake Forest Baptist Comprehensive Cancer Center | Winston-Salem | North Carolina | United States | 27157 |
| 17 | University of Pennsylvania (U Penn) | Philadelphia | Pennsylvania | United States | 19104 |
| 18 | Main Line Health - Lankenau Medical Center | Wynnewood | Pennsylvania | United States | 19096 |
| 19 | Sanford Health | Sioux Falls | South Dakota | United States | 57109 |
Sponsors and Collaborators
- QuantumLeap Healthcare Collaborative
- University of California, San Francisco
- University of Pennsylvania
- Emory University
- University of Alabama at Birmingham
- University of Colorado, Denver
- University of Southern California
- Yale University
- Columbia University
- Wake Forest University Health Sciences
- Sanford Health
- Long Beach Memorial Medical Center
- Georgetown University
- Kalispell Regional Medical Center
- Montefiore Medical Center
- University of California, Davis
- Hoag Memorial Hospital Presbyterian
- University of Iowa
- Main Line Health
- Northwestern University
Investigators
- Principal Investigator: Carolyn Carolyn, MD, University of California, San Francisco
- Principal Investigator: Kathleen D Liu, MD, University of California, San Francisco
- Principal Investigator: Laura Esserman, MD, University of California, San Francisco
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- I-SPY-COVID