Leidos-Enabled Adaptive Protocol for Clinical Trials (LEAP-CT) in Hospitalized Patients With COVID-19 (Addendum 1)

Study Overview
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Brief Summary
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This study is designed to test the efficacy and safety of combinations of two well-understood agents - famotidine and celecoxib in patients hospitalized with moderate-to-severe COVID-19 (based on World Health Organization [WHO] Ordinal Scale for Clinical Improvement). Both famotidine and celecoxib separately demonstrate clinical activity in mitigating COVID-19 disease symptoms or severity, and appear to have separate and complementary mechanisms of action.

Detailed Description
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Participants will be randomly assigned, in a 1:1 ratio, to one of two regimens, with 202 subjects per group as follows: Group 1 (study product) subjects will receive 80 mg famotidine by mouth (PO) 4 times per day (QID) + 400 mg celecoxib as a first dose, followed by 200 mg celecoxib PO, 2 times per day (BID), for 5 days. Following this 5-day period, subjects will continue their famotidine treatment for an additional 9 days. Group 2 (reference therapy) subjects will receive matching placebos QID and BID, for 5 days. Following this 5-day period, subjects will continue to receive matching famotidine placebo, QID, for an additional 9 days. Safety, efficacy and pharmacokinetics of famotidine and celecoxib will be evaluated. All participants will receive the standard of care (SOC), which typically consists of remdesivir, decadron (dexamethasone), lovenox, tociluzimab, and convalescent plasma. At the discretion of the investigator, study treatment can be stopped and dexamethasone initiated in study participants who require supplemental oxygen (WHO 5) as outlined in the NIH COVID-19 Treatment Guidelines. Investigators are required to stop study treatment and initiate dexamethasone, as indicated in participants who require high-flow oxygen (WHO 6), non-invasive ventilation (NIV; WHO 6), invasive mechanical ventilation (WHO 7-8) or extracorporeal membrane oxygenation (ECMO; WHO 9), in accordance with the NIH COVID-19 Treatment Guidelines. The NIH COVID-19 Treatment Guidelines recommend against the use of dexamethasone only in hospitalized patients not requiring supplemental oxygen (WHO 4).

Official Title
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A Phase 2 Randomized, Single-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of the Combination of Famotidine and Celecoxib as a Treatment in Moderate-to-severe Patients Hospitalized for COVID-19

Conditions
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2019 Novel Coronavirus Disease, 2019 Novel Coronavirus Infection, 2019-nCoV Disease, 2019-nCoV Infection, COVID-19 Pandemic, COVID-19 Virus Disease, COVID-19 Virus Infection, Covid19, Coronavirus Disease 2019, SARS-CoV-2 Infection, SARS-CoV-2 Acute Respiratory Disease, COVID-19

Intervention / Treatment
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* Drug: Famotidine
* Drug: Celecoxib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants must be at least 18 years of age, inclusive, at the time of signing the informed consent form. Confirmed COVID-19 or symptom onset within 7 days of hospitalization, as shown by medical history, physical exam, and laboratory tests (PCR), and who have been hospitalized for COVID-19 at WHO Grade 4-5. Contraceptive use by men or women should be consistent with Appendix 4 of the Master Protocol (LDOS-21-001). Capable of understanding and providing a signed informed consent form. Reliable access to the internet. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Pregnant or breastfeeding History of HIV Ongoing treatment that cannot be temporarily discontinued during the study: anti-inflammatory treatment (nonsteroidal anti-inflammatory drugs [NSAIDS]);corticosteroids; antimalarials; antiarrhythmics; tricyclic antidepressants; natalizumab; quinolones; macrolides; and agalsidase alfa and beta drugs dependent on gastric pH for absorption, e.g., dasatinib, delavirdine, mesylate, cefditoren, and fosamprenavir; tizanidine (CYP1A2) substrate; drugs that interfere with hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]); angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or beta-blockers; diuretics; digoxin Ongoing famotidine, celecoxib, or other COVID-19 clinical investigational treatment(s) within the past 30 days or current participation in another investigational clinical trial History of immunosuppression History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs Rejection of participation at the discretion of the Principal Investigator or Sponsor Any contraindication for famotidine or celecoxib treatment: a. Famotidine or celecoxib hypersensitivity; b. Retinopathy, visual field or visual acuity disturbances; c. History of cardiovascular disease, such as congestive heart failure, QT prolongation, bradycardia (<50 bpm), ventricular tachycardia, other arrhythmias, as determined at screening electrocardiogram (ECG) or medical history; d. Potassium <3 mEq/L (milliequivalent/liter) as determined at Visit 1; e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 upper normal limit, as determined at Visit 1; f. Previous myocardial infarction; e. Myasthenia gravis; h. Psoriasis or porphyria; i. Glomerular clearance, 60 mL/min; j. Previous history of severe hypoglycemia; k. Known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history or experience with other CYP2C9 substrates, such as warfarin and phenytoin; l. Moderate or severe hepatic impairment, e.g., Child-Pugh Class B or C.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects randomized 1:1, study drug:placebo
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (Study Product)<br>Subjects will receive 80 mg famotidine (PO) QID and 400 mg celecoxib as a first dose, followed by 200 mg (PO) BID celecoxib, for 5 days. Following this 5-day period, subjects will continue their famotidine treatment for an additional 9 days. | Drug: Famotidine<br>* 80 mg tablet, QID for 14 days<br>* Other names: Pepcid;Drug: Celecoxib<br>* 400 mg (initial dose), then 200 mg capsule, BID for 5 days<br>* Other names: Celebrex;|
| Placebo Comparator: Group 2 (Reference Therapy)<br>Subjects will receive matching placebos QID and BID, for 5 days. Following this 5-day period, subjects will continue to receive matching famotidine placebo, QID, for an additional 9 days. | Drug: Placebo<br>* tablet, QID for 14 days; capsule, BID for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-to-event to achieve WHO level ≤3 | Evaluation of the time-to-event to achieve a WHO level score ≤3 | 30 days | 
| Death rate | Evaluation of the time-to-event where all-cause mortality occurs | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital discharge to chronic palliative care | Measured incidence of hospital discharge to chronic palliative care | 30 days | 
| Hospital discharge with no additional medical care | Measured incidence of hospital discharge with no additional medical care required | 30 days | 
| Related adverse events (AEs) and serious adverse events (SAEs) | Measured incidence of related AEs and SAEs | 90 days | 
| Study discontinuation due to related AEs or SAEs | Measured incidence of study discontinuation due to related AEs or SAEs | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, COVID, COVID19, SARS-CoV-2