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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Favipiravir | Experimental | In addition to SOC, participants will receive favipiravir for 10 days, and be evaluated for health outcomes through day 28. |
|
| Placebo | Active Comparator | In addition to SOC, participants will receive placebo to match favipiravir for 10 days, and be evaluated for health outcomes through day 28. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Favipiravir | Drug | 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). |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Diagnosis of COVID-19 disease:
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
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yvonne (Bonnie) A Maldonado, MD | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University | Stanford | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35446944 | Result | Holubar M, Subramanian A, Purington N, Hedlin H, Bunning B, Walter KS, Bonilla H, Boumis A, Chen M, Clinton K, Dewhurst L, Epstein C, Jagannathan P, Kaszynski RH, Panu L, Parsonnet J, Ponder EL, Quintero O, Sefton E, Singh U, Soberanis L, Truong H, Andrews JR, Desai M, Khosla C, Maldonado Y. Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial. Clin Infect Dis. 2022 Nov 30;75(11):1883-1892. doi: 10.1093/cid/ciac312. | |
| 33624010 |
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No current plan to share individual participant data (IPD).
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385 participants were assessed for eligibility; 149 participants were enrolled and randomized.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Baseline characteristics were assessed for the symptomatic modified ITT (smITT) Analysis Set (participants who reported at least one symptom other than mild cough, mild fatigue, or decreased taste/smell at baseline), and for the modified ITT (mITT) Analysis Set (participants who were symptomatic with positive RT-PCR result at baseline).
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Favipiravir |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Participants in the smITT Analysis Set and the mITT Analysis Set. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Modified intention-to-treat (mITT) Analysis Set (participants who were symptomatic with positive RT-PCR result at baseline) | Posted | Median | 95% Confidence Interval | days | Up to 28 days |
|
28 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute Respiratory Distress Syndrome (ARDS) | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yvonne A. Maldonado, MD | Stanford University | (650) 723-5682 | bonniem@stanford.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 18, 2021 | Feb 9, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
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| ID | Term |
|---|---|
| C462182 | favipiravir |
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| Placebo | Drug | Placebo to match favipiravir administered orally through day 10. |
|
| Standard of care treatment | Other | Standard of care treatment for COVID-19 infection |
|
| Up to 28 days |
| 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. | Up to 28 days |
| Count of Participants With Development of SARS-CoV-2 Antibodies | Up to 28 days |
| Time Until Cessation of Symptoms | Time until cessation of symptoms is reported as days until initial resolution and sustained resolution of symptoms. | Up to 28 days |
| 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 | Up to 28 days |
| Cmax of Favipiravir | Cmax is a pharmacokinetic parameter that measures the maximum concentration of drug in plasma. | Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration) |
| Cmin of Favipiravir | Cmin is a pharmacokinetic parameter that measures the minimum concentration of drug in plasma. | Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration) |
| Derived |
| Jacobson KB, Rao M, Bonilla H, Subramanian A, Hack I, Madrigal M, Singh U, Jagannathan P, Grant P. Patients With Uncomplicated Coronavirus Disease 2019 (COVID-19) Have Long-Term Persistent Symptoms and Functional Impairment Similar to Patients with Severe COVID-19: A Cautionary Tale During a Global Pandemic. Clin Infect Dis. 2021 Aug 2;73(3):e826-e829. doi: 10.1093/cid/ciab103. |
| Withdrew (medication intolerant) |
|
| Withdrew (declined intervention) |
|
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). |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Participants in the smITT Analysis Set and the mITT Analysis Set. | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Participants in the smITT Analysis Set and the mITT Analysis Set. | Count of Participants | Participants |
|
| Region of Enrollment | Participants in the smITT Analysis Set. | Count of Participants | Participants |
|
| Body Mass Index | Participants in the smITT Analysis Set and the mITT Analysis Set. | Mean | Standard Deviation | kg/m^2 |
|
| Comorbid Conditions | Participants in the smITT Analysis Set and the mITT Analysis Set with available data. | Count of Participants | Participants |
|
| Asymptomatic | Participants in the smITT Analysis Set and the mITT Analysis Set. | Count of Participants | Participants |
|
| Days from symptom onset to randomization | Participants in the smITT Analysis Set and the mITT Analysis Set. | Median | Inter-Quartile Range | days |
|
| Number of symptoms reported at randomization | Participants in the smITT Analysis Set and the mITT Analysis Set. | Median | Inter-Quartile Range | symptoms |
|
| Symptoms at randomization | Participants in the smITT Analysis Set and the mITT Analysis Set. | Count of Participants | Participants |
|
| Received at least one dose of COVID-19 vaccine | Participants in the smITT Analysis Set and the mITT Analysis Set. | Count of Participants | Participants |
|
| Seropositive | Participants in the smITT Analysis Set and the mITT Analysis Set. | Count of Participants | Participants |
|
| Anterior nares RT-PCR Ct | 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. RT-PCR: reverse transcription-polymerase chain reaction. | Participants in the smITT Analysis Set and the mITT Analysis Set. | Median | Inter-Quartile Range | cycles |
|
| Oropharyngeal RT-PCR positivity | Participants in the smITT Analysis Set and the mITT Analysis Set. | Count of Participants | Participants |
|
| Aspartate aminotransferase (AST) | Participants in the smITT Analysis Set and the mITT Analysis Set. | Median | Inter-Quartile Range | units/L |
|
| Alanine Aminotransferase (ALT) | Participants in the smITT Analysis Set and the mITT Analysis Set. | Median | Inter-Quartile Range | units/L |
|
| Creatinine | Participants in the smITT Analysis Set and the mITT Analysis Set. | Median | Inter-Quartile Range | mg/dL |
|
| Uric acid | Participants in the smITT Analysis Set and the mITT Analysis Set. | Median | Inter-Quartile Range | mg/dL |
|
|
|
|
| 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. | mITT Analysis Set (participants who were symptomatic with positive RT-PCR result at baseline) | Posted | Median | Inter-Quartile Range | cycles | Up to 28 days |
|
|
|
| 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. | Intention-to-treat (ITT) analysis set | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
|
| Secondary | Count of Participants With Development of SARS-CoV-2 Antibodies | ITT analysis set; participants with available data at each time point are included in the analysis | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
| Secondary | Time Until Cessation of Symptoms | Time until cessation of symptoms is reported as days until initial resolution and sustained resolution of symptoms. | 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) | Posted | Median | Inter-Quartile Range | days | Up to 28 days |
|
|
|
|
| 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 | smITT Analysis Set (participants reported at least one symptom other than mild cough, mild fatigue, or decreased taste/smell at baseline) | Posted | Count of Participants | Participants | Up to 28 days |
|
|
|
| Secondary | Cmax of Favipiravir | Cmax is a pharmacokinetic parameter that measures the maximum concentration of drug in plasma. | Data were not collected for this outcome measure. | Posted | Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration) |
|
|
| Secondary | Cmin of Favipiravir | Cmin is a pharmacokinetic parameter that measures the minimum concentration of drug in plasma. | Data were not collected for this outcome measure. | Posted | Days 1 and 10 (samples taken 30 minutes prior to and 1 hour following favipiravir administration) |
|
|
| 0 |
| 74 |
| 1 |
| 74 |
| 0 |
| 74 |
| EG001 | 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). | 0 | 75 | 0 | 75 | 0 | 75 |
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| D014777 |
| Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| Male |
|
| Day 10 |
|
| Day 28 |
|
| Fisher Exact |
| 0.56 |
A p-value of 0.05 would have been considered statistically significant. |
| Superiority |
| Day 28 |
|
|
Difference in days until sustained resolution of symptoms |
| Cox proportional hazards model |
| 0.59 |
A p-value of 0.05 would have been considered statistically significant. |
| Hazard Ratio (HR) |
| 0.87 |
| 2-Sided |
| 95 |
| 0.52 |
| 1.45 |
Hazard ratio adjusted for age and sex |
| Superiority |