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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Covid19

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with symptomatic, diagnostically confirmed COVID-19, per RT-PCR or antigen assay of respiratory tract sample. Patient must have either become symptomatic or found positive by RT-PCR or antigen assay within 5 days, whichever is greater, of randomization. Patients must fill out a baseline questionnaire which is reviewed by study personnel to determine eligibility. Males and females ≥age 18 years. Oxygen saturation by pulse oximeter ≥92% on room air Negative urine or serum pregnancy test (if woman of childbearing potential). 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. Ability to complete the daily diary independently. The patient must give informed consent Exclusion Criteria: Patient is in need of acute hospitalization per clinician assessment. Pregnant or nursing women. Unwillingness or inability to comply with procedures required in this protocol. Patient requires supplemental oxygen. 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. 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Upamostat 200 mg<br>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<br>* 1 capsule comprising 200 mg of upamostat and 1 capsule comprising matching placebo.<br>|
| Experimental: Part A: Upamostat 400 mg<br>Each day participants will receive two 200 mg doses of upamostat, for a total of 14 days. | Drug: Part A: Upamostat 400 mg<br>* 2 capsules, each capsule comprising 200 mg of upamostat<br>|
| Placebo Comparator: Part A: Placebo<br>Each day participants will receive two matching placebos, for a total of 14 days. | Drug: Part A and B: Placebo<br>* 1 or 2 capsules, each capsule a matching placebo<br>|
| Experimental: Part B: Upamostat<br>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<br>* 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.<br>|
| Placebo Comparator: Part B: Placebo<br>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<br>* 1 or 2 capsules, each capsule a matching placebo<br>|

What is the study measuring?
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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 |