Various Treatments for Critically Ill COVID-19 Patients

(I-SPY_COVID Trial)

Recruiting in Palo Alto (17 mi)

+28 other locations

Overseen by Laura Esserman, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: QuantumLeap Healthcare Collaborative

Disqualifiers: Pregnancy, Liver disease, Kidney disease, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

How is the drug combination used in the clinical trial for critically ill COVID-19 patients unique?

The clinical trial uses a combination of drugs like Apremilast, Aviptadil, and Remdesivir, which are not standard treatments for COVID-19. This combination is unique because it includes drugs with different mechanisms, such as anti-inflammatory effects and antiviral properties, potentially offering a broader approach to managing severe COVID-19 symptoms. ^{1 2 3 4 5}

Research Team

Laura Esserman, MD

Principal Investigator

University of California, San Francisco

Carolyn Carolyn, MD

Principal Investigator

University of California, San Francisco

Kathleen Liu, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Eligibility Criteria

Adults hospitalized with severe COVID-19 needing high oxygen or on ventilators can join. They must have confirmed SARS-CoV-2 infection and give consent. Excluded are those with serious liver disease, long-term nursing home residents, pregnant/breastfeeding women, late-stage kidney disease patients on dialysis, certain heart conditions, or expected to transfer out within 72 hours.

Inclusion Criteria

I am hospitalized and on high flow oxygen or intubated for COVID-19 treatment.

Confirmation of SARS-CoV-2 infection by PCR or Rapid antigen testing for SARS-CoV-2 infection prior to randomization

Informed consent provided by the patient or health care proxy

Exclusion Criteria

I am receiving care focused on my comfort.

My doctor thinks I have a 50% or higher chance of passing away in the next six months due to my chronic conditions.

My heart's pumping ability is very weak, or I have unstable chest pain.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Participants receive investigational agents or standard of care for critically ill COVID-19 patients

4 weeks

Daily monitoring (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Weekly visits (in-person)

Observational Component

Collection of clinical data and blood samples for biomarker analysis

Up to 60 days

Treatment Details

Interventions

• Apremilast (Phosphodiesterase 4 Inhibitor)
• Aviptadil (Vasoactive Intestinal Peptide Receptor Agonist)
• Aviptadil Acetate (Vasoactive Intestinal Peptide Receptor Agonist)
• Celecoxib (COX-2 Inhibitor)
• Celecoxib Famotidine (COX-2 Inhibitor, Histamine H2 Receptor Antagonist)
• Cenicriviroc (CCR5 Antagonist)
• Cyclosporine (Immunomodulator)
• Cyproheptadine (Antihistamine)
• Dexamethasone (Corticosteroid)
• dornase alfa (Mucolytic Agent)
• Famotidine (Histamine H2 Receptor Antagonist)
• IC14 (Integrin Antagonist)
• Icatibant (Bradykinin B2 Receptor Antagonist)
• Imatinib Mesylate (Tyrosine Kinase Inhibitor)
• narsoplimab (Complement Inhibitor)
• Narsoplimab (Complement Inhibitor)
• Pulmozyme (Mucolytic Agent)
• Remdesivir (Antiviral)

Trial Overview The trial is testing multiple drugs like Remdesivir and Dexamethasone in critically ill COVID-19 patients using an adaptive platform design to quickly find treatments that reduce death rates and the need for mechanical ventilation.

Participant Groups

Group I: Narsoplimab + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + 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.

Group II: Imatinib + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects will be administered standard of care + 800 mg imatinib 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.

Group III: Imatinib (PENDING ACTIVATION) Experimental Treatment 1 Intervention

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.

Group IV: Icatibant + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + icatibant subcutaneously, 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.

Group V: IC14 + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + IC14 intravenously , 4 mg/kg on day 1, followed by 2 mg/kg on days 2, 3, 4

Group VI: Dornase + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

For Non-intubated subjects: Subjects administered standard of care + dornase, 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: Subjects administered standard of care + dornase, 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.

Group VII: Cyproheptadine + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + cyproheptadine via 4 mg tablet, with dosing regimen of 8 mg every 8 hours daily for ten (10) days.

Group VIII: Cyclosporine + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + modified cyclosporine at an oral dose of 5mg/kg per day administered in two divided doses daily for 5-days.

Group IX: Cenicriviroc + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + cenicriviroc orally , 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.

Group X: Celecoxib/famotidine + Standard of Care (CLOSED) Experimental Treatment 4 Interventions

Subjects administered standard of care + celecoxib/famotidine orally . 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.

Group XI: Aviptadil + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + aviptadil (inhalation via nebulizer), 100 µg three times (TID) daily for a maximum of 14 days

Group XII: Apremilast + Standard of Care (CLOSED) Experimental Treatment 3 Interventions

Subjects administered standard of care + apremilast orally , 30 mg bid × 14 days.

Group XIII: Control/Backbone - Remdesivir and Dexamethasone (CLOSED) Active Control 2 Interventions

Participants randomized to the backbone control will be given standard of care (supportive care for ARDS, including remdesivir and, if needed, lung protective ventilation). Because dexamethasone was shown to have benefit in at least one large randomized clinical trial, patients in the backbone control arm should receive dexamethasone for a total of 10 days during the hospitalization or until or hospital discharge. Remdesivir (intravenous): 200-mg loading dose on day 1, followed by a daily maintenance dose of 100-mg on days 2 through 10. Dexamethasone (intravenous): 6 mg intravenous or oral dexamethasone once daily up to 10 days or equivalent for alternate corticosteroid if dexamethasone unavailable.

Apremilast is already approved in Canada, Japan for the following indications:

Approved in Canada as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis

Approved in Japan as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis

Who Is Running the Clinical Trial?

QuantumLeap Healthcare Collaborative

Lead Sponsor

Trials

6

Recruited

7,000+

Corewell Health

Collaborator

Trials

1

Recruited

1,500+

Kalispell Regional Medical Center

Collaborator

Trials

1

Recruited

1,500+

Virtua Health

Collaborator

Trials

4

Recruited

2,900+

Montefiore Medical Center

Collaborator

Trials

468

Recruited

599,000+

Andrew D. Racine

Montefiore Medical Center

Chief Medical Officer since 1992

MD, PhD from New York University; Undergraduate degree from Harvard University

Philip O. Ozuah

Montefiore Medical Center

Chief Executive Officer since 2019

MD, PhD from New York University

University of Florida Health

Collaborator

Trials

10

Recruited

4,200+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

Dr. Katrina Armstrong

Columbia University

Chief Executive Officer

MD from Johns Hopkins University, MS in Epidemiology from Harvard School of Public Health

Dr. Katrina Armstrong

Columbia University

Chief Medical Officer

MD from Harvard Medical School

Wake Forest University Health Sciences

Collaborator

Trials

1,432

Recruited

2,506,000+

Dr. L. Ebony Boulware

Wake Forest University Health Sciences

Chief Medical Officer since 2022

MD from Duke University School of Medicine, MPH from Johns Hopkins Bloomberg School of Public Health

Dr. Julie Ann Freischlag

Wake Forest University Health Sciences

Chief Executive Officer since 2020

BS from University of Illinois, MD from Rush University

Sanford Health

Collaborator

Trials

53

Recruited

2,067,000+

Findings from Research

Convalescent plasma therapy and pharmacological treatments like interferon-α, corticosteroids, and tocilizumab have been used for critically ill COVID-19 patients, but their effectiveness is still debated.

Extracorporeal therapies, including continuous renal replacement therapy (CRRT), therapeutic plasma exchange (TPE), and extracorporeal membrane oxygenation (ECMO), show potential in improving outcomes for critically ill COVID-19 patients, suggesting a need for further investigation into these methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of extracorporeal therapies in critically ill COVID-19 patients. Zhou, Z., Kuang, H., Ma, Y., et al.[2022]

In a study of 694 critically ill COVID-19 patients, treatments with lopinavir-ritonavir, hydroxychloroquine, or their combination resulted in fewer organ support-free days compared to no antiviral therapy, indicating worse outcomes for those receiving these treatments.

The study found that all three antiviral interventions were associated with higher in-hospital mortality rates compared to the control group, suggesting that these treatments may be harmful rather than beneficial for critically ill patients with COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Arabi, YM., Gordon, AC., Derde, LPG., et al.[2022]

In a study of 107 critically ill COVID-19 patients, those treated with favipiravir (FVP) had a significantly shorter median ICU stay (6.6 days) compared to those treated with lopinavir/ritonavir (LPV/r) who stayed for a median of 9 days, suggesting FVP may be more effective in managing severe cases.

The mortality rates were similar between the two treatment groups, with 66.2% of patients in the FVP group and 54.8% in the LPV/r group dying, indicating that while FVP may reduce ICU stay, its impact on mortality requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observational study of the effects of Favipiravir vs Lopinavir/Ritonavir on clinical outcomes in critically Ill patients with COVID-19. Kocayiğit, H., Özmen Süner, K., Tomak, Y., et al.[2022]

In a study of 226 critically ill COVID-19 patients, those treated with oseltamivir experienced faster viral load clearance (11 days) compared to those who did not receive the drug (16 days), indicating its potential efficacy in managing severe cases.

Patients receiving oseltamivir also had a shorter duration of mechanical ventilation (6.5 days vs. 8.5 days) and lower odds of developing hospital-acquired pneumonia, suggesting additional benefits without significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of oseltamivir use in critically ill patients with COVID-19: A multicenter propensity score-matched study. Aljuhani, O., Korayem, GB., Altebainawi, AF., et al.[2023]

References

1. China pubmed.ncbi.nlm.nih.gov

Application of extracorporeal therapies in critically ill COVID-19 patients. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of tocilizumab in critically ill adults with COVID-19 infection in Bahrain: A report of 5 cases. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Observational study of the effects of Favipiravir vs Lopinavir/Ritonavir on clinical outcomes in critically Ill patients with COVID-19. [2022]

5. Saudi Arabia pubmed.ncbi.nlm.nih.gov

The effect of oseltamivir use in critically ill patients with COVID-19: A multicenter propensity score-matched study. [2023]