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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: COVID-19; Covid19; Coronavirus Disease 2019; SARS-CoV-2 Infection; SARS-CoV-2 Acute Respiratory Disease; COVID-19 Pandemic; COVID-19 Virus Infection; COVID-19 Virus Disease; 2019 Novel Coronavirus Disease; 2019 Novel Coronavirus Infection; 2019-nCoV Disease; 2019-nCoV Infection
• Intervention / Treatment: Drug: Famotidine; Drug: Celecoxib; Drug: Placebo

Detailed Description

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).

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Brian A Roberts, MS, PMP; Phone Number: 240-529-0455; Email: brian.a.roberts@leidos.com
• Study Contact Backup: Name: Tilly Lawrence, BSN, RN; Phone Number: 240-529-0497; Email: tilly.lawrence@leidos.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

  1. drugs dependent on gastric pH for absorption, e.g., dasatinib, delavirdine, mesylate, cefditoren, and fosamprenavir;
  2. tizanidine (CYP1A2) substrate;
  3. drugs that interfere with hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]);
  4. angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or beta-blockers;
  5. diuretics;
  6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1 (Study Product); 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; 80 mg tablet, QID for 14 days; Other Names: Pepcid; Drug: Celecoxib; 400 mg (initial dose), then 200 mg capsule, BID for 5 days; Other Names: Celebrex
Placebo Comparator: 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.	Drug: Placebo; tablet, QID for 14 days; capsule, BID for 5 days

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) endpoint-Assess area under the curve	Measure area under the curve (AUC) for famotidine and celecoxib combination in 10 patients per group	14 days
Pharmacokinetic (PK) endpoint-Assess time to maximum plasma concentration	Measure time to maximum plasma concentration (tmax) for famotidine and celecoxib combination in 10 patients per group	14 days
Pharmacokinetic (PK) endpoint-Assess maximum serum concentration	Measure maximum serum concentration (Cmax) for famotidine and celecoxib combination in 10 patients per group	14 days
Exploratory endpoint-Incidence of symptom reduction	Cumulative incidence of clinically significant symptom reduction (severity and duration) using COVID-19 Symptom Score	14 days
Exploratory endpoint-Incidence of clinical improvement	Cumulative incidence of clinically significant symptom reduction (severity and duration) using WHO Ordinal Scale for Clinical Improvement	14 days
Special Assessment - High-resolution computed tomography (HRCT), 20 patients/group, change from baseline	HRCT scan of the chest	Study Day 1 (baseline), Day 16 (discharge), 30 days after first dose, and 90 days after first dose
Special Assessment - Total lung capacity (TLC), 20 patients/group, change from baseline	TLC	Study Day 1 (baseline), 16 (discharge), 30 days after first dose, and 90 days after first dose
Special Assessment - Prostaglandin E2 (PGE2), 20 patients/group, change from baseline	PGE2 testing	Study Day 1 (baseline), 16 (discharge), 30 days after first dose, and 90 days after first dose
Special Assessments - Urinalysis, 20 patients/group, change from baseline	Urinalysis	Study Day 1 (baseline) and 16 (discharge)

Collaborators and Investigators

• Sponsor: Leidos Life Sciences
• Collaborators: United States Department of Defense
• Investigators: Study Director: Tilly Lawrence, BSN, RN, Leidos, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2023
• Primary Completion (Actual): February 7, 2023
• Study Completion (Actual): February 7, 2023

Study Registration Dates

• First Submitted: October 7, 2021
• First Submitted That Met QC Criteria: October 18, 2021
• First Posted (Actual): October 20, 2021

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; COVID; COVID19
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Coronavirus Infections; Infections; Communicable Diseases; Virus Diseases; Respiration Disorders; Respiratory Tract Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gastrointestinal Agents; Cyclooxygenase 2 Inhibitors; Anti-Ulcer Agents; Histamine Antagonists; Histamine Agents; Histamine H2 Antagonists; Celecoxib; Famotidine
• Other Study ID Numbers: LDOS-21-001-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: It is not yet known if there will be a plan to make individual participant data (IPD) available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No