Various Treatments for Critically Ill COVID-19 Patients

(I-SPY_COVID Trial)

Recruiting at 30 trial locations

Overseen By Sheetal Gandotra, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: QuantumLeap Healthcare Collaborative

Disqualifiers: Pregnancy, Liver disease, Kidney disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks

1500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find effective treatments for critically ill COVID-19 patients. Researchers are testing various medications, including Apremilast (Otezla), Aviptadil (RLF-100 or ZYESAMI), Celecoxib (Celebrex), and others, to determine if they can lower death rates and reduce the need for ventilators. Participants are hospitalized COVID-19 patients requiring high-flow oxygen or ventilator support. Each participant receives a combination of standard care and one of the tested treatments. The goal is to identify which treatments significantly impact patient recovery. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Past research has shown apremilast to be quite safe. A study analyzing its long-term use found it well-tolerated over five years, with common side effects being mild, such as headaches and nausea. It does not increase the risk of contracting COVID-19 or worsen infections.

Aviptadil has also been studied and appears safe. It sometimes causes diarrhea and flushing, but serious side effects are rare. Safety assessments confirm it is generally well-tolerated.

Studies have shown that celecoxib and famotidine are safe. Celecoxib, even at higher doses, does not present increased safety risks. Famotidine is also safe at high doses and may help reduce COVID-19 symptoms.

Cenicriviroc seems to have a good safety profile. Research indicates it is as safe as a placebo.

Cyclosporine is typically used for other conditions and is considered safe for critically ill patients. Studies suggest it may help reduce symptoms without major safety issues.

Cyproheptadine has been tested in COVID-19 patients and found to be safe, with no serious side effects in trials.

Dornase alfa has been used in clinical trials and seems to have a safety profile similar to standard treatments. Common side effects include mild respiratory issues.

Famotidine alone has been tested and found to be safe, showing some promise in improving symptoms.

IC14 has been studied in severe COVID-19 cases and does not show major safety concerns. It is well-tolerated according to research data.

Icatibant has been used in patients with COVID-19 without significant safety issues. No serious side effects have been reported.

Imatinib mesylate is generally safe and has been used in other conditions. It is under study for COVID-19, and no major safety issues have been reported.

Narsoplimab has been included in trials for severe COVID-19 without new safety concerns. It is considered safe for use in critically ill patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for critically ill COVID-19 patients because they offer different mechanisms of action compared to standard options like remdesivir and dexamethasone. For instance, Narsoplimab targets the lectin pathway of complement activation, which is a unique approach in managing severe COVID-19 symptoms. Cyclosporine, traditionally used as an immunosuppressant, may help by calming the immune response that can get out of control in severe COVID-19 cases. Aviptadil, administered via inhalation, acts by protecting lung cells and reducing inflammation. These novel approaches could offer additional benefits over current treatments, potentially improving outcomes for patients in critical condition.

What evidence suggests that this trial's treatments could be effective for critically ill COVID-19 patients?

Research is exploring various treatments for critically ill COVID-19 patients. In this trial, participants may receive different treatments as part of separate study arms. Apremilast, which participants may receive, has been safe for other conditions, but its effects on COVID-19 remain under study. Aviptadil, another treatment option, is used for lung issues and may help lungs recover faster, though it hasn't significantly improved outcomes in severe COVID-19 cases. The combination of Celecoxib and famotidine might help some COVID-19 patients, but its exact effectiveness is unclear. Cenicriviroc could help by blocking inflammation pathways, but more research is needed. Cyclosporine has shown potential in reducing virus symptoms in other conditions and is being considered for COVID-19. Cyproheptadine, known for reducing serotonin, might help improve breathing in severe cases. Dornase alfa hasn't shown significant improvement in severe cases but might reduce the virus's spread in the body. IC14 did not show significant benefits in severe COVID-19 patients. Icatibant might help by blocking a protein that causes inflammation in COVID-19. Imatinib has shown mixed results, with concerns about its effectiveness in severe cases. Narsoplimab showed promise in reducing the risk of death and inflammation in some patients. Each treatment has potential but requires more research to confirm its effectiveness. ^{1 4 6 7 8}

Who Is on the 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

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Apremilast
• Aviptadil
• Aviptadil Acetate
• Celecoxib
• Celecoxib Famotidine
• Cenicriviroc
• Cyclosporine
• Cyproheptadine
• Dexamethasone
• dornase alfa
• Famotidine
• IC14
• Icatibant
• Imatinib Mesylate
• narsoplimab
• Narsoplimab
• Pulmozyme
• Remdesivir

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis
• Behçet’s disease

Approved in European Union as Otezla for:

• Psoriatic arthritis
• Plaque psoriasis
• Behçet’s disease

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+

University of Florida Health

Collaborator

Trials

10

Recruited

4,200+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

Wake Forest University Health Sciences

Collaborator

Trials

1,432

Recruited

2,506,000+

Sanford Health

Collaborator

Trials

53

Recruited

2,067,000+

Published Research Related to This Trial

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]

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]

Tocilizumab has been identified as an effective biologic treatment for critically ill COVID-19 patients, particularly those suffering from severe lung injury.

In a case series involving five critically ill COVID-19 patients, the use of tocilizumab was associated with notable changes in clinical profiles and laboratory biomarkers, suggesting potential benefits in their treatment outcomes.

NCBI (Pubmed)

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. ElSeirafi, MM., Hasan, HM., Sridharan, K., et al.[2020]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8656447/

Incidence and prognosis of COVID‐19 in patients with ...

These results demonstrate that apremilast use for psoriasis did not increase the risk of contracting SARS‐CoV‐2 infection compared to the ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7300475/

Clinical efficacy, speed of improvement and safety of ...

We signal that 58% of patients achieved Psoriasis Area and Severity Index (PASI) 50, and 19% PASI 75 improvement in the first 8 weeks of treatment.

3.

nature.com

nature.com/articles/s41598-024-54424-y

Prevalence, outcomes and associated factors of SARS ...

COVID-19 vaccine is an important tool against SARS-CoV-2 infection, with protection effectiveness as high as 95%, but due to breakthrough ...

4.

publications.ersnet.org

publications.ersnet.org/content/erj/60/suppl66/2180

Safety and efficacy of apremilast in adults hospitalized with ...

Most pts had a COVID-19 clinical severity score of 4 (48%) or 3 (29%) (range: 1–8, 1=death). Median (95% CI) time to confirmed clinical recovery through Day 29 ...

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S0022202X21016547

Assessing the Risk and Outcome of COVID-19 in Patients ...

We analyzed the quality of papers dealing with the risk and outcomes of COVID-19 in patients with psoriasis and psoriatic arthritis receiving biologic therapies ...

6.

fda.gov

fda.gov/media/180626/download

NDA/BLA Multi-Disciplinary Review and Evaluation (Otezla)

Overall, the quality of data submitted is adequate to characterize the safety and efficacy of apremilast for treatment of moderate to severe ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10266699/

Apremilast Long-Term Safety Up to 5 Years from 15 Pooled ...

We analyzed longer-term safety and tolerability of apremilast 30 mg twice daily across three indications for up to 5 years, focusing on adverse events of ...

8.

dermatologytimes.com

dermatologytimes.com/view/apremilast-use-during-covid-19

Apremilast Use During COVID-19

“Nonetheless, we believe this study suggests apremilast does not increase the risk of URTI or nasopharyngitis compared to placebo and may be ...