Upamostat, a Serine Protease Inhibitor, or Placebo for Treatment of COVID-19 Disease

Phase 2/3 Study of Upamostat, a Serine Protease Inhibitor, or Placebo for Treatment of COVID-19 Disease

A 2-part, multicenter, Phase 2/3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of upamostat in adult patients with COVID-19 disease who do not require inpatient care.

Study Overview

• Status: Suspended
• Conditions: Covid19
• Intervention / Treatment: Drug: Part A: Upamostat 200 mg; Drug: Part A: Upamostat 400 mg; Drug: Part A and B: Placebo; Drug: Part B: Upamostat 200 or 400 mg

Detailed Description

Patients will be seen in a medical facility (ER or COVID-19 clinic) for initial evaluation. Consenting, diagnostically-confirmed COVID-19 patients not in need of hospitalization per investigator assessment and who meet all other inclusion and exclusion criteria will be randomized to treatment and provided with medication and home monitoring devices, and instructed in drug administration and use of the devices. They will take medication daily for two weeks, complete a smartphone-based questionnaire, provide additional monitoring information via devices provided periodically over an 8-week period. Patients will be seen at home by a study nurse or return to the clinic after 2, 4 and 8 weeks on study ("follow up" visits); additional televisits will also be conducted. At the follow up visits nasal swab specimens for COVID-19 PCR and blood specimens for safety labs and disease markers will be collected.

In part A of the study, patients will be randomized 1:1:1 to one of two doses of upamostat or placebo. Based on safety results of part A, a dose for part B will be selected, and patients will be randomized 3:2 to active vs placebo.

• Study Type: Interventional
• Enrollment (Anticipated): 310
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• South Africa
  • Benoni, South Africa, 1500
    • Worthwhile Clinical Trials
  • Cape Town
    • Kraaifontein, Cape Town, South Africa, 7570
      • Langeberg Medical Centre - Clinical Trials
  • Gauteng
    • Roodepoort, Gauteng, South Africa, 1724
      • Roodepoort Medicross Clinical Trial Research Centre
    • Vereeniging, Gauteng, South Africa, 1935
      • FCRN Clinical Trial Centre
  • Natal
    • KwaZulu, Natal, South Africa, 4092
      • PJ Sebastian
  • Pretoria
    • Arcadia, Pretoria, South Africa, 0001
      • Global Clinical Trials PTY (LTD)
• United States
  • Florida
    • Cutler Bay, Florida, United States, 33157
      • Beautiful Minds Clinical Research
    • Hialeah, Florida, United States, 33013
      • Research in Miami Inc.
    • Miami, Florida, United States, 33122
      • Angels Clinical Research Institute
    • Miami Springs, Florida, United States, 33166
      • South Florida Research Phase I-Iv, Inc.
  • Michigan
    • Bay City, Michigan, United States, 48706
      • Great Lakes Research Group
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital, emergency department
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Bronx, New York, United States, 10456
      • Prime Global Research
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • On-Site Clinical Solutions
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland
  • Texas
    • Dallas, Texas, United States, 75235
      • Southwest Family Medicine Research

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients with symptomatic, diagnostically confirmed COVID-19, per RT-PCR or antigen assay of respiratory tract sample.
2. Patient must have either become symptomatic or found positive by RT-PCR or antigen assay within 5 days, whichever is greater, of randomization.
3. Patients must fill out a baseline questionnaire which is reviewed by study personnel to determine eligibility.
4. Males and females ≥age 18 years.
5. Oxygen saturation by pulse oximeter ≥92% on room air
6. Negative urine or serum pregnancy test (if woman of childbearing potential).
7. Females of childbearing potential and males with female partners of childbearing potential must agree to use acceptable contraceptive methods during the study and for at least two months after the last dose of study medication.
8. Ability to complete the daily diary independently.
9. The patient must give informed consent

Exclusion Criteria:

1. Patient is in need of acute hospitalization per clinician assessment.
2. Pregnant or nursing women.
3. Unwillingness or inability to comply with procedures required in this protocol.
4. Patient requires supplemental oxygen.
5. Patient is currently receiving, has received within the past 7 days or is expected to receive during the course of the study remdesivir, or other specific antiviral or anticytokine therapy for COVID-19, other than therapeutic monoclonal antibodies allowed or approved in the region in which the patient lives, or systemic corticosteroid equivalent to ≥20 mg daily prednisone/3 mg dexamethasone daily.
6. Patient is currently receiving or has received within 30 days prior to screening any other investigational agent for any indication, including approved agents given for investigational indications (e.g., anti-cytokine treatments).
7. Patient is currently taking or is expected to start taking warfarin, apixaban (Eliquis), or rivaroxaban (Xarelto). Patients may be taking or start on study dabigatran (Pradaxa), standard or low molecular weight heparin.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Upamostat 200 mg; Each day participants will receive a single 200 mg dose of upamostat along with a single matching placebo, for a total of 14 days.	Drug: Part A: Upamostat 200 mg; 1 capsule comprising 200 mg of upamostat and 1 capsule comprising matching placebo.
Experimental: Part A: Upamostat 400 mg; Each day participants will receive two 200 mg doses of upamostat, for a total of 14 days.	Drug: Part A: Upamostat 400 mg; 2 capsules, each capsule comprising 200 mg of upamostat
Placebo Comparator: Part A: Placebo; Each day participants will receive two matching placebos, for a total of 14 days.	Drug: Part A and B: Placebo; 1 or 2 capsules, each capsule a matching placebo
Experimental: Part B: Upamostat; Based on dose selected from Part A, each day participants will receive EITHER a single 200 mg dose of upamostat OR two 200 mg doses of upamostat, for a total of 14 days.	Drug: Part B: Upamostat 200 or 400 mg; Based on dose selection from Part A, "Part B Upamostat" will be EITHER a single 200 mg dose of upamostat OR two 200 mg doses of upamostat, for a total of 14 days.
Placebo Comparator: Part B: Placebo; Based on dose selected from Part A, each day participants will receive EITHER a single matching placebo OR two matching placebos, for a total of 14 days.	Drug: Part A and B: Placebo; 1 or 2 capsules, each capsule a matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A - Determination of the safety and tolerability of two dose levels and selection of an upamostat dose for part B	Safety and tolerability will be determined based on the relative incidence and severity (CTCAE v 5.0 criteria) of adverse events, both clinical and laboratory (SOC=investigations) in each active treatment group as compared to placebo. In addition, toxicities (i.e., adverse events considered at lease possible related to study medication) resulting in dose reductions or discontinuation of therapy will be tabulated and compared among treatment groups.	57 days
Part B - Comparison between upamostat and placebo in time to sustained recovery from symptomatic illness.	Sustained recovery: recovery maintained for at least 14 or 28 days or through EOS, whichever comes first (assessed in part A and a decision reached as to which period to use for definition of sustained recovery in part B). A patient will be considered to have recovered after meeting the following criteria: 1) is afebrile for at least 48 hours without use of antipyretics; 2) all symptoms have resolved or returned to pre- illness levels, except for: a. fatigue, anosmia, ageusia or dysgeusia, which may be persistent at level similar to that during the acute illness; b. chest pain, cough or dyspnea which if persistent must be at least one grade lower than at the start of treatment and no worse than grade 1 (mild).	57 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part B - Hospitalization or death from any cause by end of study	Hospitalization or death from any cause within 8 weeks after the first dose of study medication	57 days
Part A and at Interim Analysis in Part B - assessment of risk of hospitilization or death	Assessment of risk of hospitilization or death as a function of the presence, number and severity of concerning conditions will be undertaken. This information may be used to develop a definition of very high risk for calculation of the incidence of hospitilization or death in the high risk/very high risk population in part B	57 days
Part B - Proportion of patients who are PCR-negative at various time points during the study.	Proportion of patients who are PCR-negative at days 8, 15, 29 and 57 from the start of treatment (landmark analyses)	57 days
Part B - Time to resolution of individual disease-related symptoms present at baseline	Time to resolution of individual disease-related symptoms present at baseline	57 days
Part B - Development of new disease-related symptoms on study	Development of new disease-related symptoms on study will be captured using the same questionnaire as is being used to capture resolution of symptoms.	57 days
Part B - Development of pneumonia on study	Incidence of pneumonia during study among patients without baseline pneumonia	57 days
Part B - Changes in laboratory markers of disease severity	Changes in oxygen saturation from baseline to time points at which these are measured on study	57 days
Part B - Changes in laboratory markers of disease severity	Changes in CRP from baseline to time points at which these are measured on study	57 days
Part B - Changes in laboratory markers of disease severity	Changes in lymphocyte count from baseline to time points at which these are measured on study	57 days
Part B - Changes in laboratory markers of disease severity	Changes in cardiac troponin from baseline to time points at which these are measured on study	57 days
Part B - Changes in laboratory markers of disease severity	Changes in D-dimer levels from baseline to time points at which these are measured on study	57 days
Part B - Adverse events	Adverse events	57 days

Collaborators and Investigators

• Sponsor: RedHill Biopharma Limited
• Investigators: Study Director: Terry Plasse, MD, RedHill Biopharma Limited

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2021
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: January 18, 2021
• First Submitted That Met QC Criteria: January 21, 2021
• First Posted (Actual): January 25, 2021

Study Record Updates

• Last Update Posted (Actual): August 5, 2022
• Last Update Submitted That Met QC Criteria: August 2, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: RHB-107-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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