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

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ClinicalTrials.gov Identifier: NCT04723537
Recruitment Status : Recruiting
First Posted : January 25, 2021
Last Update Posted : April 15, 2021
Sponsor:
Information provided by (Responsible Party):
RedHill Biopharma Limited

Tracking Information
First Submitted Date  ICMJE January 18, 2021
First Posted Date  ICMJE January 25, 2021
Last Update Posted Date April 15, 2021
Actual Study Start Date  ICMJE February 16, 2021
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 2, 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. Sustained recovery is recovery, per below definition, maintained for at least 28 days or through end of study, whichever comes first. [ 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, i.e., the same level per symptom questionnaire;
      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 (mild). 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.
Original Primary Outcome Measures  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Upamostat, a Serine Protease Inhibitor, or Placebo for Treatment of COVID-19 Disease
Official Title  ICMJE 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, PCR-positive 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 after 2, 4 and 8 weeks on study; additional televisits will also be conducted. At the home 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Covid19
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 21, 2021)
310
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with symptomatic, diagnostically confirmed COVID-19, per RT-PCR assay of respiratory tract sample.
  2. Patient must have either become symptomatic or found positive by RT-PCR 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. At baseline the laboratory parameters listed below are not worse than NCI CTCAE v5.0 grade 2, with exceptions noted below:

    • Bilirubin ≤ 1.5 times upper limit of normal (ULN; grade 1 only)
    • AST (SGOT), ALT (SGPT) ≤ 5.0 x ULN,
    • Serum creatinine ≤ 1.5 X ULN (grade 1)
    • Albumin ≥ 2.0 g/dL
  6. Acceptable hematologic status:

    • Absolute neutrophil count ≥1000 cells/mm3
    • Platelet count ≥50,000 plt/mm3
    • Hemoglobin ≥ 8.0 g/dL
  7. Clinically acceptable blood sugar control in the opinion of the investigator.
  8. INR and partial thromboplastin time (PTT) each ≤ 1.5 X ULN (i.e., grade 1), unless patient is taking dabigatran or heparin.
  9. Oxygen saturation by pulse oximeter ≥92% on room air
  10. Negative pregnancy test (if woman of childbearing potential).
  11. 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.
  12. Ability to complete the daily diary independently.
  13. 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, chloroquine, hydroxychloroquine, azithromycin or other specific antiviral therapy for COVID-19 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Danielle Abramson, PhD 978-376-2156 danielle@redhillbio.com
Contact: Danielle Fisher, MHS, ACRP-CP dafisher@fhiclinical.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04723537
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party RedHill Biopharma Limited
Study Sponsor  ICMJE RedHill Biopharma Limited
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Terry Plasse, MD RedHill Biopharma Limited
PRS Account RedHill Biopharma Limited
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP