COVID-19, Sars-CoV2
Conditions
Brief summary
The objective of this study is to evaluate the efficacy of oral favipiravir plus standard of care treatment (SOC) compared with placebo plus SOC in reducing the duration of shedding of SARS-CoV2 virus in patients with mild or asymptomatic COVID-19.
Interventions
DRUGFavipiravir
Favipiravir administered orally, 1800 mg on the first dose (day 1) followed by 800 mg twice daily for the next 9 days (days 2-10).
DRUGPlacebo
Placebo to match favipiravir administered orally through day 10.
OTHERStandard of care treatment
Standard of care treatment for COVID-19 infection
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of COVID-19 disease: * If symptomatic, presence of mild to moderate symptoms without signs of respiratory distress, with positive for SARS-CoV-2 diagnostic assay within 72 hours prior to.informed consent. * If asymptomatic, initial diagnosis obtained no more than 72 hours prior to informed consent * Subject agrees to maintain home or other quarantine as recommended by the study physician, except to visit the study site as required by the protocol * Members of the same household may participate in the study as long as the inclusion and
Exclusion criteria
are met * Males must be sterile, OR agree not to donate semen AND agree to strictly adhere to contraceptive measures during the study and for seven days following the last dose of study medication * Females must be unable to bear children, OR ensure that their male partner is incapable of fathering a child, OR, if of childbearing potential will strictly adhere to contraceptive measures during the study and for seven days following the last dose of study medication * Females must agree to stop breast-feeding prior to first dose of study drug and through seven days after completing therapy * Females must have a negative pregnancy test at screening * Participant agrees to maintain home or other quarantine as recommended by the study physician, except to visit the study site as required by the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time Until Cessation of Oral Shedding of SARS-CoV-2 Virus | Up to 28 days | Time in days from randomization to the first two negative results of nasal and/or oropharyngeal swab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants With Clinical Worsening of COVID-19 Disease | Up to 28 days | Clinical worsening is reported as the number of participants with hospitalization or emergency department (ED) visits. |
| Count of Participants With Development of SARS-CoV-2 Antibodies | Up to 28 days | — |
| Time Until Cessation of Symptoms | Up to 28 days | Time until cessation of symptoms is reported as days until initial resolution and sustained resolution of symptoms. |
| Sars-CoV-2 Viral Load | Up to 28 days | Viral load (nucleic acid) will be assessed by RT-PCR Ct over time. 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. |
| Cmax of Favipiravir | Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration) | Cmax is a pharmacokinetic parameter that measures the maximum concentration of drug in plasma. |
| Cmin of Favipiravir | Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration) | Cmin is a pharmacokinetic parameter that measures the minimum concentration of drug in plasma. |
| Count of Participant With Absence of Development of Any Symptoms | Up to 28 days | This outcome will be assessed in patient who are asymptomatic of COVID-19 infection at the time of enrollment |
Countries
United States
Participant flow
Pre-assignment details
385 participants were assessed for eligibility; 149 participants were enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo In addition to standard of care (SOC) treatment for COVID-19 infection, participants were randomized to receive placebo to match favipiravir for 10 days, and to be evaluated for health outcomes through day 28. | 70 |
| Favipiravir In addition to SOC treatment for COVID-19 infection, participants were randomized to receive favipiravir for 10 days, and to be evaluated for health outcomes through day 28. Favipiravir was administered orally, 1800 mg on the first dose (day 1) followed by 800 mg twice daily for the next 9 days (days 2-10). | 65 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 4 | 4 |
| Overall Study | Withdrew (declined intervention) | 0 | 1 |
| Overall Study | Withdrew (had personal reasons) | 2 | 5 |
| Overall Study | Withdrew (medication intolerant) | 0 | 3 |
Baseline characteristics
| Characteristic | Placebo | Favipiravir | Total |
|---|---|---|---|
| Age, Continuous mITT analysis set | 43.4 years STANDARD_DEVIATION 12.8 | 42.9 years STANDARD_DEVIATION 12.3 | 43.1 years STANDARD_DEVIATION 12.5 |
| Age, Continuous smITT analysis set | 42.8 years STANDARD_DEVIATION 12.6 | 42.5 years STANDARD_DEVIATION 12 | 42.6 years STANDARD_DEVIATION 12.3 |
| Alanine Aminotransferase (ALT) mITT Analysis Set | 29.0 units/L | 25.0 units/L | 25.5 units/L |
| Alanine Aminotransferase (ALT) smITT Analysis Set | 24.5 units/L | 25.0 units/L | 25.0 units/L |
| Anterior nares RT-PCR Ct mITT Analysis Set | 25.1 cycles | 22.2 cycles | 24.0 cycles |
| Anterior nares RT-PCR Ct smITT Analysis Set | 28.3 cycles | 24.3 cycles | 26.2 cycles |
| Aspartate aminotransferase (AST) mITT Analysis Set | 32.0 units/L | 29.0 units/L | 29.0 units/L |
| Aspartate aminotransferase (AST) smITT Analysis Set | 29.5 units/L | 29.0 units/L | 29.0 units/L |
| Asymptomatic mITT Analysis Set | 1 Participants | 3 Participants | 4 Participants |
| Asymptomatic smITT Analysis Set | 0 Participants | 0 Participants | 0 Participants |
| Body Mass Index mITT Analysis Set | 29.3 kg/m^2 STANDARD_DEVIATION 6 | 27.8 kg/m^2 STANDARD_DEVIATION 5.7 | 28.5 kg/m^2 STANDARD_DEVIATION 5.9 |
| Body Mass Index smITT Analysis Set | 28.9 kg/m^2 STANDARD_DEVIATION 5.9 | 28.0 kg/m^2 STANDARD_DEVIATION 5.8 | 28.4 kg/m^2 STANDARD_DEVIATION 5.8 |
| Comorbid Conditions Chronic lung disease - mITT Analysis Set | 3 Participants | 2 Participants | 5 Participants |
| Comorbid Conditions Chronic lung disease - smITT Analysis Set | 3 Participants | 2 Participants | 5 Participants |
| Comorbid Conditions Diabetes mellitus - mITT Analysis Set | 3 Participants | 7 Participants | 10 Participants |
| Comorbid Conditions Diabetes mellitus - smITT Analysis Set | 4 Participants | 8 Participants | 12 Participants |
| Comorbid Conditions Hypertension - mITT Analysis Set | 5 Participants | 5 Participants | 10 Participants |
| Comorbid Conditions Hypertension - smITT Analysis Set | 8 Participants | 6 Participants | 14 Participants |
| Comorbid Conditions None - mITT Analysis Set | 39 Participants | 41 Participants | 80 Participants |
| Comorbid Conditions None - smITT Analysis Set | 48 Participants | 47 Participants | 95 Participants |
| Creatinine mITT Analysis Set | 0.8 mg/dL | 0.8 mg/dL | 0.8 mg/dL |
| Creatinine smITT Analysis Set | 0.8 mg/dL | 0.8 mg/dL | 0.8 mg/dL |
| Days from symptom onset to randomization mITT Analysis Set | 5 days | 5 days | 5 days |
| Days from symptom onset to randomization smITT Analysis Set | 5 days | 5 days | 5 days |
| Number of symptoms reported at randomization mITT Analysis Set | 6 symptoms | 6 symptoms | 6 symptoms |
| Number of symptoms reported at randomization smITT Analysis Set | 6 symptoms | 6 symptoms | 6 symptoms |
| Oropharyngeal RT-PCR positivity mITT Analysis Set | 50 Participants | 54 Participants | 104 Participants |
| Oropharyngeal RT-PCR positivity smITT Analysis Set | 52 Participants | 53 Participants | 105 Participants |
| Race/Ethnicity, Customized Asian - mITT Analysis Set | 5 Participants | 6 Participants | 11 Participants |
| Race/Ethnicity, Customized Asian - smITT Analysis Set | 7 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized Latinx - mITT Analysis Set | 24 Participants | 26 Participants | 50 Participants |
| Race/Ethnicity, Customized Latinx - smITT Analysis Set | 29 Participants | 28 Participants | 57 Participants |
| Race/Ethnicity, Customized Native Hawaiian/ Pacific Islander - mITT Analysis Set | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian/ Pacific Islander - smITT Analysis Set | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Other/Unknown - mITT Analysis Set | 6 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized Other/Unknown - smITT Analysis Set | 7 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized White - mITT Analysis Set | 21 Participants | 19 Participants | 40 Participants |
| Race/Ethnicity, Customized White - smITT Analysis Set | 26 Participants | 22 Participants | 48 Participants |
| Received at least one dose of COVID-19 vaccine mITT Analysis Set | 2 Participants | 0 Participants | 2 Participants |
| Received at least one dose of COVID-19 vaccine smITT Analysis Set | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 70 Participants | 65 Participants | 135 Participants |
| Seropositive mITT Analysis Set | 4 Participants | 6 Participants | 10 Participants |
| Seropositive smITT Analysis Set | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male mITT Analysis Set Female | 29 Participants | 28 Participants | 57 Participants |
| Sex: Female, Male mITT Analysis Set Male | 28 Participants | 31 Participants | 59 Participants |
| Sex: Female, Male smITT Analysis Set Female | 37 Participants | 32 Participants | 69 Participants |
| Sex: Female, Male smITT Analysis Set Male | 33 Participants | 33 Participants | 66 Participants |
| Symptoms at randomization Cough/dyspnea - mITT Analysis Set | 44 Participants | 42 Participants | 86 Participants |
| Symptoms at randomization Cough/dyspnea - smITT Analysis Set | 48 Participants | 47 Participants | 95 Participants |
| Symptoms at randomization Fatigue - mITT Analysis Set | 41 Participants | 40 Participants | 81 Participants |
| Symptoms at randomization Fatigue - smITT Analysis Set | 51 Participants | 47 Participants | 98 Participants |
| Symptoms at randomization Fever - mITT Analysis Set | 2 Participants | 1 Participants | 3 Participants |
| Symptoms at randomization Fever - smITT Analysis Set | 3 Participants | 1 Participants | 4 Participants |
| Symptoms at randomization Headache - mITT Analysis Set | 37 Participants | 40 Participants | 77 Participants |
| Symptoms at randomization Headache - smITT Analysis Set | 45 Participants | 43 Participants | 88 Participants |
| Symptoms at randomization Joint pain - mITT Analysis Set | 18 Participants | 20 Participants | 38 Participants |
| Symptoms at randomization Joint pain - smITT Analysis Set | 20 Participants | 22 Participants | 42 Participants |
| Symptoms at randomization Myalgias - mITT Analysis Set | 36 Participants | 36 Participants | 72 Participants |
| Symptoms at randomization Myalgias - smITT Analysis Set | 42 Participants | 38 Participants | 80 Participants |
| Uric acid mITT Analysis Set | 4.5 mg/dL | 4.4 mg/dL | 4.5 mg/dL |
| Uric acid smITT Analysis Set | 4.5 mg/dL | 4.4 mg/dL | 4.5 mg/dL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 74 | 0 / 75 |
| other Total, other adverse events | 0 / 74 | 0 / 75 |
| serious Total, serious adverse events | 1 / 74 | 0 / 75 |
Outcome results
Primary
Time Until Cessation of Oral Shedding of SARS-CoV-2 Virus
Time in days from randomization to the first two negative results of nasal and/or oropharyngeal swab.
Time frame: Up to 28 days
Population: Modified intention-to-treat (mITT) Analysis Set (participants who were symptomatic with positive RT-PCR result at baseline)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time Until Cessation of Oral Shedding of SARS-CoV-2 Virus | 13 days |
| Favipiravir | Time Until Cessation of Oral Shedding of SARS-CoV-2 Virus | 14 days |
p-value: 0.2495% CI: [0.48, 1.2]Cox proportional hazards model
Secondary
Cmax of Favipiravir
Cmax is a pharmacokinetic parameter that measures the maximum concentration of drug in plasma.
Time frame: Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration)
Population: Data were not collected for this outcome measure.
Secondary
Cmin of Favipiravir
Cmin is a pharmacokinetic parameter that measures the minimum concentration of drug in plasma.
Time frame: Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration)
Population: Data were not collected for this outcome measure.
Secondary
Count of Participants With Clinical Worsening of COVID-19 Disease
Clinical worsening is reported as the number of participants with hospitalization or emergency department (ED) visits.
Time frame: Up to 28 days
Population: Intention-to-treat (ITT) analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Count of Participants With Clinical Worsening of COVID-19 Disease | Hospitalization | 4 Participants |
| Placebo | Count of Participants With Clinical Worsening of COVID-19 Disease | ED visit | 7 Participants |
| Favipiravir | Count of Participants With Clinical Worsening of COVID-19 Disease | Hospitalization | 0 Participants |
| Favipiravir | Count of Participants With Clinical Worsening of COVID-19 Disease | ED visit | 5 Participants |
Comparison: Difference in hospitalizationsp-value: 0.06Fisher Exact
Comparison: Difference in ED visitsp-value: 0.56Fisher Exact
Secondary
Count of Participants With Development of SARS-CoV-2 Antibodies
Time frame: Up to 28 days
Population: ITT analysis set; participants with available data at each time point are included in the analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Count of Participants With Development of SARS-CoV-2 Antibodies | Baseline | 12 Participants |
| Placebo | Count of Participants With Development of SARS-CoV-2 Antibodies | Day 28 | 47 Participants |
| Favipiravir | Count of Participants With Development of SARS-CoV-2 Antibodies | Baseline | 9 Participants |
| Favipiravir | Count of Participants With Development of SARS-CoV-2 Antibodies | Day 28 | 40 Participants |
Secondary
Count of Participant With Absence of Development of Any Symptoms
This outcome will be assessed in patient who are asymptomatic of COVID-19 infection at the time of enrollment
Time frame: Up to 28 days
Population: smITT Analysis Set (participants reported at least one symptom other than mild cough, mild fatigue, or decreased taste/smell at baseline)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Count of Participant With Absence of Development of Any Symptoms | 2 Participants |
| Favipiravir | Count of Participant With Absence of Development of Any Symptoms | 5 Participants |
Secondary
Sars-CoV-2 Viral Load
Viral load (nucleic acid) will be assessed by RT-PCR Ct over time. 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: Up to 28 days
Population: mITT Analysis Set (participants who were symptomatic with positive RT-PCR result at baseline)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Sars-CoV-2 Viral Load | Day 1 | 25.1 cycles |
| Placebo | Sars-CoV-2 Viral Load | Day 5 | 27.3 cycles |
| Placebo | Sars-CoV-2 Viral Load | Day 10 | 37.3 cycles |
| Placebo | Sars-CoV-2 Viral Load | Day 28 | 40.0 cycles |
| Favipiravir | Sars-CoV-2 Viral Load | Day 28 | 40.0 cycles |
| Favipiravir | Sars-CoV-2 Viral Load | Day 1 | 22.2 cycles |
| Favipiravir | Sars-CoV-2 Viral Load | Day 10 | 40.0 cycles |
| Favipiravir | Sars-CoV-2 Viral Load | Day 5 | 27.9 cycles |
Secondary
Time Until Cessation of Symptoms
Time until cessation of symptoms is reported as days until initial resolution and sustained resolution of symptoms.
Time frame: Up to 28 days
Population: Symptomatic Modified Intention-to-treat (smITT) Analysis Set (participants reported at least one symptom other than mild cough, mild fatigue, or decreased taste/smell at baseline)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time Until Cessation of Symptoms | Initial resolution of symptoms | 14 days |
| Placebo | Time Until Cessation of Symptoms | Sustained resolution of symptoms | 24 days |
| Favipiravir | Time Until Cessation of Symptoms | Initial resolution of symptoms | 15 days |
| Favipiravir | Time Until Cessation of Symptoms | Sustained resolution of symptoms | NA days |
Comparison: Difference in days until initial resolution of symptomsp-value: 0.4395% CI: [0.54, 1.29]Cox proportional hazards model
Comparison: Difference in days until sustained resolution of symptomsp-value: 0.5995% CI: [0.52, 1.45]Cox proportional hazards model