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

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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Covid19	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	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 310 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2/3 Study of Upamostat, a Serine Protease Inhibitor, or Placebo for Treatment of COVID-19 Disease
• Actual Study Start Date: February 16, 2021
• Estimated Primary Completion Date: September 2021
• Estimated Study Completion Date: September 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. 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)
2. 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
3. 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.
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. Part B - Mortality [ Time Frame: 57 days ]
    Mortality within 57 days of the start of study medication
12. Part B - Adverse events [ Time Frame: 57 days ]
    Adverse events

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Danielle Abramson, PhD; 978-376-2156; danielle@redhillbio.com

Contact: Danielle Fisher, MHS, ACRP-CP; dafisher@fhiclinical.com

Locations

United States, Florida

RecioMed Clinical Research Network, Inc.; Not yet recruiting

Boynton Beach, Florida, United States, 33472

Contact: Diana de la Torre 561-880-0170 diana@reciomed.com

Principal Investigator: Luis Pena-Hernandez, MD

South Florida Research Phase I-IV, Inc.; Recruiting

Miami Springs, Florida, United States, 33166

Contact: Lisbelle Revoredo 305-418-0847 lrevoredo@southfloridatrials.com

Principal Investigator: Belkis Delgado, MD, CPI

Floridian Research Institute; Not yet recruiting

Miami, Florida, United States, 33145

Contact: Milene Garcia 786-391-1137 mgarcia@floridianresearch.com

Principal Investigator: Gretel Trullenque, MD

United States, Michigan

Henry Ford Hospital, emergency department; Recruiting

Detroit, Michigan, United States, 48202

Contact: Timothy Asmar 313-404-9110 TAsmar2@hfhs.org

Principal Investigator: Joseph B Miller, MD

United States, Ohio

University Hospitals Cleveland; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Melinda Caraballo, RN 833-788-7425 Melinda.Caraballo@UHhospitals.org

Principal Investigator: Grace A McComsey, MD, FIDSA

United States, Texas

DM Clinical Research; Recruiting

Tomball, Texas, United States, 77375

Contact: Amar Syed amar@apdcr.com

Principal Investigator: Najmuddin Karimjee, MD

Sponsors and Collaborators

RedHill Biopharma Limited

Investigators

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

More Information

• Responsible Party: RedHill Biopharma Limited
• ClinicalTrials.gov Identifier: NCT04723537
• Other Study ID Numbers: RHB-107-01
• First Posted: January 25, 2021
• Last Update Posted: April 15, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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