Covid19
Conditions
Keywords
Master Protocol, Outpatient
Brief summary
The overall objective of this study is to efficiently evaluate the clinical efficacy and safety of different investigational therapeutics among adults who have COVID-19 but are not yet sick enough to require hospitalization. The overall hypothesis is that through an adaptive trial design, potential effective therapies (single and combination) may be identified for this group of patients. COVID-19 Outpatient Pragmatic Platform Study (COPPS) is a pragmatic platform protocol designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain) or improve clinical outcomes (Clinical Domain). To be included into the platform, every investigational product will collect data for both Domain primary endpoints. Individual treatments to be evaluated in the platform will be described in separate sub-protocols.
Detailed description
The platform study allows investigational products with objectives either: evaluating viral shedding (Virology Domain); and COVID-19 related Clinical Outcomes (Clinical Domain). The primary objective for investigational products within the Viral Domain is: A. To evaluate the efficacy of each therapeutic intervention in addition to standard supportive care (SSC) compared with SSC in reducing viral shedding of SARS-CoV-2 virus in outpatients with COVID-19 disease. The primary objective for investigational products within for the Clinical Domain is: B. To evaluate the efficacy of each therapeutic intervention in addition to SSC as compared to SSC in improving sustained clinical outcomes in outpatients with COVID-19 disease. Secondary objectives are: 1. The objective of the non-assigned domain an investigational product is under. 1. If under Clinical Domain, reduction in viral shedding. 2. If under Viral Domain, time to sustained resolution of symptoms. 2. To evaluate the efficacy of each therapeutic intervention in reducing SARS-CoV-2 related hospitalizations, ED visits, or death in outpatients with COVID-19 disease. 3. To assess the development of antibodies against SARS-CoV-2 4. To evaluate the safety and tolerability of each therapeutic intervention compared with placebo (supportive care).
Interventions
DRUGAcebilustat
100 mg capsule administered orally once daily
DRUGCamostat
200 mg (2 x 100 mg tablet) administered orally four times daily (800 mg total daily dose).
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Outpatient setting 2. Age ≥ 18 years and ≤ 80 years at the time of the assessment 3. Able and willing to understand the study, adhere to all study procedures, and provide written informed consent 4. Initial diagnosis of COVID-19 disease as defined by an FDA-cleared molecular diagnostic assay positive for SARS-CoV-2 with no more than 72 hours from the initial swab used in the diagnosis to the time of commencing informed consent. 5. At baseline, at least two symptoms should have mild or higher severity score, where at least one of the mild symptoms is not cough, fatigue, or loss of smell/taste OR at least one symptom has a moderate or higher severity score on the COVID Outpatient Symptom Scale (COSS). 6. Participant's COVID-19 related symptom onset occurred within 7 days prior to time of randomization. 7. Other inclusion criteria specific to the investigational product that may, in the eyes of the investigator, be deemed necessary.
Exclusion criteria
1. At screening, the participant needs to be admitted to the hospital or is being evaluated for potential admission. 2. Previous use of experimental drugs that may be active against COVID-19 in the eyes of the investigators. 3. Participant yields a positive urine pregnancy test at screening. 4. Participant is using adrenocorticosteroids (except topical or inhaled preparations or oral preparations equivalent to or less than 10 mg of oral prednisone) or immunosuppressive or immunomodulatory drugs (e.g., immunosuppressants, anticancer drugs, interleukins, interleukin antagonists or interleukin receptor blockers). NOTE: Treatment of study participants following institutional COVID-19 treatment policies or guidelines, including the use of immunomodulatory medications, is permitted. This excludes treatment with agents that have the potential for direct antiviral activity, including convalescent plasma and NO, and co-enrollment into other clinical studies that evaluate investigational agents for COVID-19. 5. Participant has a serious chronic disease (e.g., uncontrolled human immunodeficiency virus \[HIV\], cancer requiring chemotherapy within the preceding 6 months, and/or moderate or severe hepatic insufficiency). 6. Has renal insufficiency including severe renal impairment and ESRD and/or requiring hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). 7. Has liver impairment greater than Child Pugh A. 8. Has a history of alcohol or drug abuse in the previous 6 months. 9. Has a psychiatric disease that is not well controlled where controlled is defined as: stable on a regimen for more than one year. 10. Has taken another investigational drug within the past 30 days. 11. Is deemed by the Investigator to be ineligible for any reason. 12. Additional exclusions may pertain to specific drugs as described in study-specific protocols.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| For Viral Domain: Change in Viral Shedding | 10 days | Change in shedding of SARS-CoV-2 virus through day 10 attained from self-collected nasal swab. Viral load (nucleic acid) was assessed by RT-PCR Ct over time, and is reported here as the average change in Ct values per day. Cycle threshold (Ct) denotes how many PCR cycles are required before the SARS-CoV-2 viral RNA reached a detectable level. Higher Ct values correspond to lower viral copy numbers. For reference, Ct values of 20 correspond to \ 2.12 x 106 viral copies per milliliter, while a Ct value of 40 is undetectable and is considered the lower limit of detection of this RT-PCR test for SARS-CoV-2. |
| For Clinical Domain: Time-to-sustained-resolution | 28 days | Time from randomization to sustained symptom resolution assessed over a 28-day period. Resolution is defined as the first day where no symptoms are self-reported on all succeeding days through and including day 28, not including sense of taste or smell, and defining recovery for fatigue and cough as mild or none. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Full Resolution | 28 days | Defined as the study day where no symptoms are first self-reported. |
| Time to Viral Cessation | 28 days | Defined as the time in days from randomization to the first of two consecutive negative RT-PCR results of self-collected nasal swabs. |
| Number of Participants That Developed Antibodies to SARS-CoV-2 | 28 days | — |
| Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | 28 days | — |
| Time to First Resolution | 28 days | Defined as the first study day where no symptoms are self-reported, not including sense of taste or smell, and defining recovery for fatigue and cough as mild or none. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants receive placebo for 10 or 28 days. | 60 |
| Acebilustat Participants receive acebilustat (100 mg/day) for 28 days. | 60 |
| Camostat Participants receive camostat (800 mg/day) for 10 days. | 2 |
| Total | 122 |
Baseline characteristics
| Characteristic | Acebilustat | Total | Placebo | Camostat |
|---|---|---|---|---|
| Age, Continuous | 41 years STANDARD_DEVIATION 13 | 41 years STANDARD_DEVIATION 13 | 41 years STANDARD_DEVIATION 14 | 29 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 29 Participants | 14 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 92 Participants | 45 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 10 Participants | 5 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized More than one race | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 8 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 43 Participants | 90 Participants | 46 Participants | 1 Participants |
| Region of Enrollment United States | 60 Participants | 122 Participants | 60 Participants | 2 Participants |
| Sex: Female, Male Female | 38 Participants | 79 Participants | 40 Participants | 1 Participants |
| Sex: Female, Male Male | 22 Participants | 43 Participants | 20 Participants | 1 Participants |
| Viral Shedding | 20.5 cycles STANDARD_DEVIATION 6.4 | 21.0 cycles STANDARD_DEVIATION 6.3 | 21.2 cycles STANDARD_DEVIATION 5.8 | 30.8 cycles STANDARD_DEVIATION 13.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 59 | 0 / 2 |
| other Total, other adverse events | 3 / 59 | 1 / 59 | 0 / 2 |
| serious Total, serious adverse events | 0 / 59 | 0 / 59 | 0 / 2 |
Outcome results
Primary
For Clinical Domain: Time-to-sustained-resolution
Time from randomization to sustained symptom resolution assessed over a 28-day period. Resolution is defined as the first day where no symptoms are self-reported on all succeeding days through and including day 28, not including sense of taste or smell, and defining recovery for fatigue and cough as mild or none.
Time frame: 28 days
Population: Intent-to-treat analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | For Clinical Domain: Time-to-sustained-resolution | 26 days |
| Acebilustat | For Clinical Domain: Time-to-sustained-resolution | NA days |
| Camostat | For Clinical Domain: Time-to-sustained-resolution | NA days |
Comparison: A two-sided log rank test at the 0.04999 level of significance for the final analysis required 78 events (i.e., sustained symptom resolution) to provide 80% power to detect a hazard ratio of 1.91. Based on previous outpatient COVID-19 trials at Stanford, assumed placebo and treatment arm median time to symptom resolution of 10 and 5 days, respectively, for a total sample size of 120 patients. Participants with missing data lasting through Day 28 were censored on Day 28.p-value: 0.0795% CI: [0.34, 1.04]Cox proportional hazards model
Primary
For Viral Domain: Change in Viral Shedding
Change in shedding of SARS-CoV-2 virus through day 10 attained from self-collected nasal swab. Viral load (nucleic acid) was assessed by RT-PCR Ct over time, and is reported here as the average change in Ct values per day. Cycle threshold (Ct) denotes how many PCR cycles are required before the SARS-CoV-2 viral RNA reached a detectable level. Higher Ct values correspond to lower viral copy numbers. For reference, Ct values of 20 correspond to \ 2.12 x 106 viral copies per milliliter, while a Ct value of 40 is undetectable and is considered the lower limit of detection of this RT-PCR test for SARS-CoV-2.
Time frame: 10 days
Population: Intent-to-treat analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | For Viral Domain: Change in Viral Shedding | 1.6 cycles |
| Acebilustat | For Viral Domain: Change in Viral Shedding | 1.7 cycles |
| Camostat | For Viral Domain: Change in Viral Shedding | 1.0 cycles |
Comparison: A generalized linear mixed effects model with parameterization was utilized to capture the difference in change in viral shedding at day 10 between treatment arms. SARS-CoV2 viral RNA CT values were transformed using a standard Reference curve.p-value: 0.2Linear mixed-effects regression model
Secondary
Number of Participants That Developed Antibodies to SARS-CoV-2
Time frame: 28 days
Population: Participants with available antibody data are included in the analysis. No antibody results data were collected in the Camostat arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants That Developed Antibodies to SARS-CoV-2 | 55 Participants |
| Acebilustat | Number of Participants That Developed Antibodies to SARS-CoV-2 | 53 Participants |
Secondary
Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease.
Time frame: 28 days
Population: Intent-to-treat analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | ED visit | 2 Participants |
| Placebo | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | Hospitalization | 0 Participants |
| Placebo | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | Death | 0 Participants |
| Acebilustat | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | ED visit | 0 Participants |
| Acebilustat | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | Hospitalization | 1 Participants |
| Acebilustat | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | Death | 0 Participants |
| Camostat | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | Hospitalization | 0 Participants |
| Camostat | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | Death | 0 Participants |
| Camostat | Number of Participants With SARS-CoV-2 Related Hospitalizations, Emergency Department (ED) Visits, or Death in Outpatients With COVID-19 Disease. | ED visit | 0 Participants |
Comparison: Difference in incidence of ED visitsp-value: 0.21Fisher Exact
Secondary
Time to First Resolution
Defined as the first study day where no symptoms are self-reported, not including sense of taste or smell, and defining recovery for fatigue and cough as mild or none.
Time frame: 28 days
Population: Intent-to-treat analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Resolution | 11.5 days |
| Acebilustat | Time to First Resolution | 14 days |
| Camostat | Time to First Resolution | NA days |
p-value: 0.0595% CI: [0.38, 1.01]Linear mixed-effects regression model
Secondary
Time to Full Resolution
Defined as the study day where no symptoms are first self-reported.
Time frame: 28 days
Population: Intent-to-treat analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Full Resolution | 13 days |
| Acebilustat | Time to Full Resolution | 15 days |
| Camostat | Time to Full Resolution | NA days |
95% CI: [0.34, 1.01]
Secondary
Time to Viral Cessation
Defined as the time in days from randomization to the first of two consecutive negative RT-PCR results of self-collected nasal swabs.
Time frame: 28 days
Population: Intent-to-treat analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Viral Cessation | NA days |
| Acebilustat | Time to Viral Cessation | NA days |
| Camostat | Time to Viral Cessation | NA days |