Covid19
Conditions
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.
Interventions
DRUGPart A: Upamostat 200 mg
1 capsule comprising 200 mg of upamostat and 1 capsule comprising matching placebo.
DRUGPart A: Upamostat 400 mg
2 capsules, each capsule comprising 200 mg of upamostat
DRUGPart A and B: Placebo
1 or 2 capsules, each capsule a matching placebo
DRUGPart 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.
Sponsors
RedHill Biopharma Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B | 57 days | This is a qualitative measure that takes into account safety and tolerability 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospitalization or Death For COVID With Presence of Concerning Conditions | 57 days | — |
| Time to Sustained Recovery From Symptomatic Illness for Part A (Protocol Definition) | 57 days | Sustained recovery was defined as recovery maintained for at least 14 or 28 days (two analyses), or through end of study, whichever comes first. A patient was considered to have recovered once he or she met the following criteria: 1. is afebrile (\<38.0°C core temperature/37.5°C oral 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), 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). |
| Time to Sustained Recovery From Symptomatic Illness - Part A (SAP Definition) | 57 days | First day at which there are no symptoms, and no occurrence of any symptoms for at least 14 days or until end of study, whichever came first. Mild symptoms which were noted as preexisting conditions were excluded from this calculation. For example, if a patient noted preexisting shortness of breath, mild shortness of breath was excluded from the calculation of no symptoms. |
| Hospitalization or Death From Any Cause by End of Study | 57 days | — |
| Proportion of Patients Who Are PCR-negative at Day 8 From the Start of Treatment | 8 days | — |
| Proportion of Patients Who Are PCR-negative at Day 57 From the Start of Treatment | 57 days | — |
| Changes in D-dimer Levels, From Baseline to Day 57 | 57 days | — |
| Development of New Disease-related Symptoms and/or Pneumonia on Study | 57 days | — |
Countries
South Africa, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Part A: Upamostat 200 mg: 1 capsule comprising 200 mg of upamostat and 1 capsule comprising matching placebo. | 20 |
| Part A: Upamostat 400 mg Each day participants will receive two 200 mg doses of upamostat, for a total of 14 days.
Part A: Upamostat 400 mg: 2 capsules, each capsule comprising 200 mg of upamostat | 21 |
| Part A: Placebo Each day participants will receive two matching placebos, for a total of 14 days.
Part A and B: Placebo: 1 or 2 capsules, each capsule a matching placebo | 20 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Medical monitor decision, sponsor decision and other | 1 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Upamostat 400 mg | Part A: Placebo | Part A: Upamostat 200 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 18 Participants | 18 Participants | 55 Participants |
| Age, Continuous | 50.0 years | 46.0 years | 40.5 years | 47.0 years |
| Race/Ethnicity, Customized Hispanic/Latino | 10 participants | 7 participants | 10 participants | 27 participants |
| Race/Ethnicity, Customized Non-Hispanic/Non-Latino | 11 participants | 13 participants | 10 participants | 34 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 16 Participants | 18 Participants | 51 Participants |
| Region of Enrollment South Africa | 0 participants | 0 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 21 participants | 20 participants | 19 participants | 61 participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 14 Participants | 34 Participants |
| Sex: Female, Male Male | 12 Participants | 9 Participants | 6 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 | 0 / 20 |
| other Total, other adverse events | 19 / 20 | 20 / 21 | 17 / 20 |
| serious Total, serious adverse events | 0 / 20 | 1 / 21 | 0 / 20 |
Outcome results
Primary
Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B
This is a qualitative measure that takes into account safety and tolerability 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.
Time frame: 57 days
Population: All patients entered
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Upamostat 200 mg | Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B | Safe and well tolerated | 20 Participants |
| Part A: Upamostat 200 mg | Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B | Dose reductions or discontinuation of therapy | 0 Participants |
| Part A: Upamostat 400 mg | Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B | Safe and well tolerated | 21 Participants |
| Part A: Upamostat 400 mg | Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B | Dose reductions or discontinuation of therapy | 0 Participants |
| Part A: Placebo | Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B | Safe and well tolerated | 20 Participants |
| Part A: Placebo | Part A - Determination of the Safety and Tolerability of Two Dose Levels and Selection of an Upamostat Dose for Part B | Dose reductions or discontinuation of therapy | 0 Participants |
Secondary
Changes in D-dimer Levels, From Baseline to Day 57
Time frame: 57 days
Population: Patient with D dimer results at end of study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Upamostat 200 mg | Changes in D-dimer Levels, From Baseline to Day 57 | -0.21 ug/ml | Standard Deviation 0.27 |
| Part A: Upamostat 400 mg | Changes in D-dimer Levels, From Baseline to Day 57 | -0.64 ug/ml | Standard Deviation 0.81 |
| Part A: Placebo | Changes in D-dimer Levels, From Baseline to Day 57 | 0.01 ug/ml | Standard Deviation 0.41 |
Secondary
Development of New Disease-related Symptoms and/or Pneumonia on Study
Time frame: 57 days
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Upamostat 200 mg | Development of New Disease-related Symptoms and/or Pneumonia on Study | 17 Participants |
| Part A: Upamostat 400 mg | Development of New Disease-related Symptoms and/or Pneumonia on Study | 12 Participants |
| Part A: Placebo | Development of New Disease-related Symptoms and/or Pneumonia on Study | 16 Participants |
Secondary
Hospitalization or Death For COVID With Presence of Concerning Conditions
Time frame: 57 days
Population: Patient with concerning conditions per NIAID guideline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Upamostat 200 mg | Hospitalization or Death For COVID With Presence of Concerning Conditions | 0 Participants |
| Part A: Upamostat 400 mg | Hospitalization or Death For COVID With Presence of Concerning Conditions | 0 Participants |
| Part A: Placebo | Hospitalization or Death For COVID With Presence of Concerning Conditions | 2 Participants |
Secondary
Hospitalization or Death From Any Cause by End of Study
Time frame: 57 days
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Upamostat 200 mg | Hospitalization or Death From Any Cause by End of Study | 0 Participants |
| Part A: Upamostat 400 mg | Hospitalization or Death From Any Cause by End of Study | 1 Participants |
| Part A: Placebo | Hospitalization or Death From Any Cause by End of Study | 3 Participants |
Secondary
Proportion of Patients Who Are PCR-negative at Day 57 From the Start of Treatment
Time frame: 57 days
Population: Patients with PCR results
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Upamostat 200 mg | Proportion of Patients Who Are PCR-negative at Day 57 From the Start of Treatment | 16 Participants |
| Part A: Upamostat 400 mg | Proportion of Patients Who Are PCR-negative at Day 57 From the Start of Treatment | 12 Participants |
| Part A: Placebo | Proportion of Patients Who Are PCR-negative at Day 57 From the Start of Treatment | 17 Participants |
Secondary
Proportion of Patients Who Are PCR-negative at Day 8 From the Start of Treatment
Time frame: 8 days
Population: Patients with PCR results
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Upamostat 200 mg | Proportion of Patients Who Are PCR-negative at Day 8 From the Start of Treatment | 9 Participants |
| Part A: Upamostat 400 mg | Proportion of Patients Who Are PCR-negative at Day 8 From the Start of Treatment | 10 Participants |
| Part A: Placebo | Proportion of Patients Who Are PCR-negative at Day 8 From the Start of Treatment | 7 Participants |
Secondary
Time to Sustained Recovery From Symptomatic Illness for Part A (Protocol Definition)
Sustained recovery was defined as recovery maintained for at least 14 or 28 days (two analyses), or through end of study, whichever comes first. A patient was considered to have recovered once he or she met the following criteria: 1. is afebrile (\<38.0°C core temperature/37.5°C oral 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), 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).
Time frame: 57 days
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Upamostat 200 mg | Time to Sustained Recovery From Symptomatic Illness for Part A (Protocol Definition) | 19.0 days |
| Part A: Upamostat 400 mg | Time to Sustained Recovery From Symptomatic Illness for Part A (Protocol Definition) | 27.0 days |
| Part A: Placebo | Time to Sustained Recovery From Symptomatic Illness for Part A (Protocol Definition) | 19 days |
Secondary
Time to Sustained Recovery From Symptomatic Illness - Part A (SAP Definition)
First day at which there are no symptoms, and no occurrence of any symptoms for at least 14 days or until end of study, whichever came first. Mild symptoms which were noted as preexisting conditions were excluded from this calculation. For example, if a patient noted preexisting shortness of breath, mild shortness of breath was excluded from the calculation of no symptoms.
Time frame: 57 days
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Upamostat 200 mg | Time to Sustained Recovery From Symptomatic Illness - Part A (SAP Definition) | 29.5 days |
| Part A: Upamostat 400 mg | Time to Sustained Recovery From Symptomatic Illness - Part A (SAP Definition) | 38.0 days |
| Part A: Placebo | Time to Sustained Recovery From Symptomatic Illness - Part A (SAP Definition) | 38.0 days |
Post Hoc
Time to Sustained Recovery From Severe Symptoms - Part A
Time frame: 57 days
Population: Patients with severe symptoms at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Upamostat 200 mg | Time to Sustained Recovery From Severe Symptoms - Part A | 4.0 days |
| Part A: Upamostat 400 mg | Time to Sustained Recovery From Severe Symptoms - Part A | 3.0 days |
| Part A: Placebo | Time to Sustained Recovery From Severe Symptoms - Part A | 8.0 days |