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

• ClinicalTrials.gov Identifier: NCT04723537
• Recruitment Status: Active, not recruiting
• First Posted: January 25, 2021
• Last Update Posted: November 16, 2021
• Sponsor: RedHill Biopharma Limited
• Information provided by (Responsible Party): RedHill Biopharma Limited

Tracking Information

• First Submitted Date: January 18, 2021
• First Posted Date: January 25, 2021
• Last Update Posted Date: November 16, 2021
• Actual Study Start Date: February 16, 2021
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 18, 2021)

• Part A - Determination of the safety and tolerability of two dose levels and selection of an upamostat dose for part B [ Time Frame: 57 days ]
  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.
• Part B - Comparison between upamostat and placebo in time to sustained recovery from symptomatic illness. [ Time Frame: 57 days ]
  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).

Original Primary Outcome Measures (submitted: January 21, 2021)

• Part A - Determination of the safety and tolerability of two dose levels and selection of an upamostat dose for part B [ Time Frame: 57 days ]
  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.
• Part B - Comparison between upamostat and placebo in time to recovery from symptomatic illness. [ Time Frame: 57 days ]
  A patient will be considered to have recovered once he or she meets the following criteria:

  1. is afebrile (<38.0° C core temperature) for at least 48 hours without use of antipyretics;
  2. all symptoms have resolved or returned to pre- illness levels (e.g., if patient had respiratory compromise prior to the onset of COVID-19), except for:
     1. fatigue, anosmia, ageusia or dysgeusia, which may be persistent at level similar to that during the acute illness
     2. 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. A symptom questionnaire generally following the FDA guidance, Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subject in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment, September, 2020, for both the terms and severity grading, will be used to capture symptomology.

Current Secondary Outcome Measures (submitted: June 18, 2021)

• Part B - Hospitalization or death from any cause by end of study [ Time Frame: 57 days ]
  Hospitalization or death from any cause within 8 weeks after the first dose of study medication
• Part A and at Interim Analysis in Part B - assessment of risk of hospitilization or death [ Time Frame: 57 days ]
  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
• Part B - Proportion of patients who are PCR-negative at various time points during the study. [ Time Frame: 57 days ]
  Proportion of patients who are PCR-negative at days 8, 15, 29 and 57 from the start of treatment (landmark analyses)
• Part B - Time to resolution of individual disease-related symptoms present at baseline [ Time Frame: 57 days ]
  Time to resolution of individual disease-related symptoms present at baseline
• Part B - Development of new disease-related symptoms on study [ Time Frame: 57 days ]
  Development of new disease-related symptoms on study will be captured using the same questionnaire as is being used to capture resolution of symptoms.
• Part B - Development of pneumonia on study [ Time Frame: 57 days ]
  Incidence of pneumonia during study among patients without baseline pneumonia
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in oxygen saturation from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in CRP from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in lymphocyte count from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in cardiac troponin from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in D-dimer levels from baseline to time points at which these are measured on study
• Part B - Adverse events [ Time Frame: 57 days ]
  Adverse events

Original Secondary Outcome Measures (submitted: January 21, 2021)

• Part B - Proportion of patients who are PCR-negative at various time points during the study. [ Time Frame: 57 days ]
  Proportion of patients who are PCR-negative at days 8, 15, 29 and 57 from the start of treatment (landmark analyses)
• Part B - Time to resolution of individual disease-related symptoms present at baseline [ Time Frame: 57 days ]
  Time to resolution of individual disease-related symptoms present at baseline
• Part B - Development of new disease-related symptoms on study [ Time Frame: 57 days ]
  Development of new disease-related symptoms on study will be captured using the same questionnaire as is being used to capture resolution of symptoms.
• Part B - Incidence of pneumonia during study among patients without baseline pneumonia [ Time Frame: 57 days ]
  Incidence of pneumonia during study among patients without baseline pneumonia
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in oxygen saturation from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in CRP from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in lymphocyte count from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in cardiac troponin from baseline to time points at which these are measured on study
• Part B - Changes in laboratory markers of disease severity [ Time Frame: 57 days ]
  Changes in D-dimer levels from baseline to time points at which these are measured on study
• Part B - Hospitalization [ Time Frame: 57 days ]
  Hospitalization within 8 weeks after the first dose of study medication, overall and for COVID-19-related indications
• Part B - Mortality [ Time Frame: 57 days ]
  Mortality within 57 days of the start of study medication
• Part B - Adverse events [ Time Frame: 57 days ]
  Adverse events

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Upamostat, a Serine Protease Inhibitor, or Placebo for Treatment of COVID-19 Disease
• Official Title: Phase 2/3 Study of Upamostat, a Serine Protease Inhibitor, or Placebo for Treatment of COVID-19 Disease
• Brief Summary: 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.

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
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Covid19

Intervention

• Drug: Part A: Upamostat 200 mg
  1 capsule comprising 200 mg of upamostat and 1 capsule comprising matching placebo.
• Drug: Part A: Upamostat 400 mg
  2 capsules, each capsule comprising 200 mg of upamostat
• Drug: Part A and B: Placebo
  1 or 2 capsules, each capsule a matching placebo
• 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.

Study Arms

• 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.
  Intervention: Drug: Part A: Upamostat 200 mg
• Experimental: Part A: Upamostat 400 mg
  Each day participants will receive two 200 mg doses of upamostat, for a total of 14 days.
  Intervention: Drug: Part A: Upamostat 400 mg
• Placebo Comparator: Part A: Placebo
  Each day participants will receive two matching placebos, for a total of 14 days.
  Intervention: Drug: Part A and B: 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.
  Intervention: Drug: Part B: Upamostat 200 or 400 mg
• 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.
  Intervention: Drug: Part A and B: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: January 21, 2021): 310
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2022
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: South Africa, United States

Administrative Information

• NCT Number: NCT04723537
• Other Study ID Numbers: RHB-107-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: RedHill Biopharma Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: RedHill Biopharma Limited
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Terry Plasse, MD; RedHill Biopharma Limited

• PRS Account: RedHill Biopharma Limited
• Verification Date: November 2021