Covid-19 living Data

Favipiravir vs Standard care/Placebo (RCT)

Mild outpatients

Study Dabbous HM, Scientific Reports, 2021 has been retracted on September 18, 2021. The study was excluded from the analysis and grade assessment by October 10 the latest.

FOREST PLOTS -2023-02-23

Studies description

Trial NCT04464408
Publication Bosaeed M, Clin Microbiol Infect (2022) (published paper)
Dates: 2020-07-23 to 2021-08-04
Funding: Public/non profit (King Abdullah International Medical Research Center (KAIMRC).)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Saudi Arabia Follow-up duration (days): 28
Inclusion criteria	18 years and above, from community settings diagnosed with mild COVID-19 (confirmed by positive PCR test for SARS2-CoV) enrolled within 5 days of disease onset (mild COVID-19 case defined as a patient with mild illness (with or without respiratory symptoms), oxygen saturation >94% at room air, and can be managed at home with appropriate therapy)
Exclusion criteria	hospitalized moderate or severe COVID-19 cases pregnant or breastfeeding females those who used favipiravir or participated in other interventional drugs clinical study within 30 days prior to the first dose of the study treatment hematologic malignancy, advanced (stage 4-5) chronic kidney disease (including dialysis therapy), severe liver damage (Child-Pugh score C or AST> 5 times the upper limit), HIV patients with history of gout or hyperuricemia (two times above the upper limit of normal) patients with sensitivity/allergy to favipiravir cases with clinical prognostic non-survival, palliative care, or in a deep coma
Interventions
	Treatment Favipiravir Initial dose: 1800 mg twice daily (9 tablets) Maintenance dose: 800 mg twice daily (4 tablets) for 5-7 days
	Control Placebo
Participants
	Randomized participants : Favipiravir=122 Placebo=123
	Characteristics of participants N= 245 Mean age : NR 155 males Severity : Mild: n= 245/ Asymptomatic: n=0
Primary outcome
	In the register PCR negative [ Time Frame: 15 days ]
	In the report Time from start of treatment to viral clearance defined as the conversion of SARS-CoV-2 RT-PCR from positive to negative within 15 days
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the registry and statistical plan were available for data extraction and risk of bias assessment. The trial (n = 245) did not achieve its target sample size (n = 576) because recruitment was terminated due to futility at the interim analysis. There is no change from the trial registration in the intervention and control treatments. The primary outcome indicated in registry reflects the primary outcome reported in the paper.

Trial NCT04600895
Publication PRESECO - Golan Y, Clin Infect Dis (2022) (published paper)
Dates: 2020-11-30 to 2021-10-20
Funding: Private (The conduct of this clinical trial and the preparation of this manuscript were supported by Appili Therapeutics, Inc., Halifax, NS, Canada.)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA (27 sites), Brazil (7 sites) and Mexico (6 sites) Follow-up duration (days): 28
Inclusion criteria	Age 18 years or older Mild-to-moderate COVID-19 First positive reverse transcription polymerase chain reaction (RT-PCR) or Rapid Antigen assay within 3 days of enrollment First symptoms within 5 days of enrollment Having at least 2 moderate or severe COVID-19 symptoms signing an informed consent COVID-19-related symptoms included runny nose, sore throat, shortness of breath, cough, tiredness, body aches, headache, chills, feeling feverish, nausea, diarrhea, and vomiting. Early in the trial, taste or smell changes were included in the entry criteria, however, later, based on an evolving understanding of COVID-19 symptom time course, taste and smell were excluded. Subjects enrolled based solely on taste and smell changes were not analyzed Males must be sterile, OR agree not to donate semen AND agree to strictly adhere to contraceptive measures (e.g., condom use) during the study and for 7 days following the last dose of study treatment 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 treatment Females must agree to stop breast-feeding prior to first dose of study drug and through 7 days after completing therapy Females must have a negative pregnancy test at screening
Exclusion criteria	O2 saturation <94% Shortness of breath at rest Heart rate ≥125 beats per minute COVID-19 symptoms first presented >5 days prior to randomization Requirement for hospitalization at the time of enrollment Participation in another trial or use of any experimental treatment for COVID-19 Treatment with high steroid dose, i.e., >30 mg/day prednisolone equivalent (excluding stable chronic treatment) or remdesivir or anyone receiving SARS-CoV-2 monoclonal antibodies within 3 months prior to enrollment Known sepsis or organ dysfunction/failure Known infection with a respiratory virus other than SARS-CoV-2 (e.g., Influenza) or any known bacterial infection (affecting the respiratory system or any other system) Inability to adhere to study requirements For premenopausal women: unwilling or unable to use effective birth control measures Known allergy to favipiravir Known end-stage kidney disease or requiring hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) Known liver impairment greater than Child-Pugh A Psychiatric illness that is not well controlled (defined as stable on a regimen for more than one year) Known elevated uric acid levels in the past year or taking uric acid lowering medications (allopurinol, febuxostat) History of hereditary xanthinuria or history of xanthine urolithiasis History of gout or actively being treated for gout
Interventions
	Treatment Favipiravir Initial dose: 1800 mg orally twice daily on Day 1 -Maintenance dose: 800 mg orally twice daily on Days 2–10
	Control Placebo
Participants
	Randomized NR Analyzed 1211 participants Favipiravir=610 Placebo=601
	Characteristics of participants N= 1211 Mean age : NR 543 males Severity : Mild: n= 1211/ Asymptomatic: n=0
Primary outcome
	In the register Time to sustained clinical recovery [Time Frame: From Day 0 to Day 28]: The endpoint will be considered to have been met at the earliest time point at which the subject has reached Sustained Alleviation of Symptoms (Symptoms related to smell or taste are not included in the primary endpoint) reported by the patient have reached a severity of "0 - none" or "1 - mild" in assessments for 4-point scale assessments and not known to have redeveloped any COVID-19 associated signs and symptoms (not including reduced sense of taste or smell) in a severity beyond mild for 4 consecutive days when assessed from the start of study treatment to day 28. To meet the primary endpoint, subjects must survive with no hospitalization to day 28.
	In the report Time to Sustained Clinical Recovery, calculated as the number of days from start of study medication to sustained symptom alleviation, defined by: Oxygen saturation ≥94% at rest, and Oral temperature <38.0°C, and all COVID-19-associated symptoms reaching a score of mild or none for 4 consecutive days.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article and its supplement, the study registry was used in data extraction and risk of bias assessment. The study achieved the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome.

Trial NCT04346628
Publication Holubar M, Clin Infect Dis (2022) (published paper)
Dates: 2020-07-08 to 2021-03-23
Funding: Public/non profit (Anonymous donors to Stanford University)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Single center / USA Follow-up duration (days): 28
Inclusion criteria	Asymptomatic or symptomatic adults without respiratory distress positive SARS-CoV-2 RT-PCR collected within 72 hours of enrollment
Exclusion criteria	Individuals who required renal replacement therapy liver impairment immunocompromised or taking immunosuppressing medications pregnant or breast-feeding
Interventions
	Treatment Favipiravir Initial dose: 1800 mg orally twice a day on day 1 - Maintenance dose: 800 mg orally twice a day on days 2-10.
	Control Placebo
Participants
	Randomized participants : Favipiravir=75 Placebo=74
	Characteristics of participants N= 149 Mean age : NR 66 males Severity : Mild: n= 135/ Asymptomatic: n=14
Primary outcome
	In the register Time until cessation of oral shedding of SARS-CoV-2 virus [ Time Frame: Up to 28 days ] Time in days from randomization to the first two negative results of nasal and/or oropharyngeal swab.
	In the report SARS-CoV-2 shedding cessation, defined as the time from enrollment to the first of two consecutive negative nasal RT-PCRs
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the preprint and published articles, the supplemental data and study registry were used in data extraction and risk of bias assessment. The protocol and statistical analysis plan were not available. The registry primary outcome reflects the reported primary outcome. Some outcomes (e.g. mortality, hospitalization, adverse events) are reported in the paper, but were not pre-specified in the trial registry. The trial (n = 149) achieved its original target sample size (n = 120), but with 116 PCR-positive patients (days 1-3) did not achieve the amended target sample size for PCR-positive patients (n = 120). This study was updated on May 11th, 2022 with data extracted from the final published report. This study was updated on August 8th, 2022 with data obtained from contact with authors. This study was updated on November 4th, 2022 with data extracted from the registry.

Trial NCT04499677
Publication FLARE - Lowe DM, PLoS Med (2022) (published paper)
Dates: 2020-10-06 to 2021-11-04
Funding: Mixed (LifeArc, UK; Fujifilm Toyama Chemical Co. provided favipiravir and favipiravir placebo free of charge.)
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	Aged between 18 and 70 years Recently (within the last 5 days) developed symptoms of COVID-19 Tested positive for SARS-CoV-2 by PCR Were within 7 days of symptom onset, or who were asymptomatic but had tested positive by PCR within the previous 48 hours
Exclusion criteria	Known hypersensitivity to either drug or their ingredients/excipients Chronic liver or kidney disease Taking concomitant medicines known to interact with the trial treatments Being treated as a hospital inpatient for any condition Pregnant or breastfeeding Participating in another interventional clinical trial (treatment or vaccination) Female participants of childbearing potential were required to provide a negative pregnancy test before commencement of trial medication and on Day 14, and to use highly effective contraceptive measures during the trial Male participants with a female partner of childbearing potential were also required to use highly effective contraception
Interventions
	Treatment LPV/r+FAV Initial dose: 1800 mg FAV + 400/100 mg LPV/r orally twice a day on Day 1 -Maintenance dose: 400 mg FAV + 200/50 mg LPV/r orally 4 times a day on Days 2-7. Lopinavir-Ritonavir Initial dose: 400/100 mg LPV/r orally twice a day on Day 1 -Maintenance dose: 200/50 mg LPV/r orally 4 times a day on Days 2-7. Favipiravir Initial dose: 1800 mg FAV orally twice a day on Day 1 -Maintenance dose: 400 mg orally 4 times a day on Days 2-7.
	Control Placebo
Participants
	Randomized participants : Placebo=60 LPV/r+FAV=61 Lopinavir-Ritonavir =60 Favipiravir=59
	Characteristics of participants N= 240 Mean age : NR 123 males Severity : Mild: n= 239/ Asymptomatic: n=1
Primary outcome
	In the register Upper respiratory tract viral load at Day 5 [ Time Frame: Day 5 from randomisation ] Quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5 of therapy
	In the report Viral load measured by quantitative polymerase chain reaction (PCR) performed on saliva samples at Day 5
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the pre-print article, protocol, statistical analysis plan and prospective study registry were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. The study (n=240) achieved the target sample size (n=240) specified in the trial registry. This study was updated on August 8th, 2022 with data obtained from contact with authors. This study was updated on January 19th, 2023 with data extracted from the published report.

Trial NCT04445467
Publication VIRCO - McMahon JH, EClinicalMedicine (2022) (published paper)
Dates: 2020-07-31 to 2021-09-19
Funding: Mixed (The study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor’s Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.)
Conflict of interest: No

Trial IRCT20211004052664N1
Publication Tehrani S, Mediterr J Infect Microbes Antimicrob (2022) (published paper)
Dates: 2021-04-01 to 2021-09-30
Funding: No specific funding (The authors declared that this study received no financial support.)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Iran Follow-up duration (days): 6
Inclusion criteria	Laboratory confirmation of SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) or imaging findings highly suggestive of COVID-19 Outpatients with moderate severity (respiratory rate <30/min, oxygen saturation >94%, or pulmonary infiltration <50% in both lungs) Age of at least 18 y Agreed to participate in this study oral tolerance to the medication. Additionally, an expert radiologist read the lung computed tomography (CT) scan of the patients. Unilateral and bilateral multilobular infiltrations, especially peripheral, and ground-glass opacities in lung CT scan were considered highly suggestive of COVID-19.
Exclusion criteria	Immunocompromised patients defined as receiving immunosuppressive medications, solid organ transplant, hematopoietic stem cell transplant, infection with human immunodeficiency virus, and active cancer Pregnancy Consumption of other antiviral therapies from symptom onset Severe hypersensitivity or anaphylactic shock after taking favipiravir
Interventions
	Treatment Favipiravir Initial dose: 1600 mg favipiravir orally 2 times a day for the first 24 hours -Maintenance dose: 600 mg orally 2 times a day for the next 4 days.
	Control Standard care
Participants
	Randomized participants : Standard care=40 Favipiravir=38
	Characteristics of participants N= 78 Mean age : NR 43 males Severity : Mild: n= 78/ Asymptomatic: n=0
Primary outcome
	In the register 1) Body temperature; Timepoint: Days 1 (start of treatment), 3, 5 and 7; Method of measurement: Thermometer. 2) Respiratory rate (per minute); Timepoint: Days 1 (start of treatment), 3, 5 and 7; Method of measurement: Physical examination by physician. 3) Oxygen saturation; Timepoint: Days 1 (start of treatment), 3, 5 and 7; Method of measurement: Pulseoxymeter.
	In the report Hospitalization rate during the seven-days follow-up period.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the study registry was used in data extraction. The study achieved the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome does not reflect the reported primary outcome. Adverse events did not seem to be completely reported. The study duration was short.

Trial NCT04333589
Publication Zhao H, Int Immunopharmacol (2021) (published paper)
Dates: 2020-03-27 to 2020-05-09
Funding: Public/non profit (Chinese COVID-19 scientific research emergency; China Mega-Project for Infectious Diseases; China Mega-Project for Innovative Drugs)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / China Follow-up duration (days): 30
Inclusion criteria	Over 18 years of age both male and female After the first diagnosis and treatment of COVID-19, the SARS-CoV-2 RNA test of respiratory specimens such as sputum or nasopharyngeal swabs, has been negative for two consecutive times (sampling time interval of at least 24 h), in accordance with China COVID-19 guidelines (7th Edition), discharged During screening visit (follow-up after discharge), the SARS-CoV-2 RNA test of COVID-19 is positive in any one of the following samples: sputum, nasopharyngeal swabs, blood, feces or other specimens. Regardless of whether or not they had symptoms and the severity of symptoms Volunteer to participate in the research and sign the Informed Consent Form.
Exclusion criteria	Allergic to favipiravir Pregnant or lactating women The researchers considered the patient was not suitable to participate in this clinical trial.
Interventions
	Treatment Favipiravir Initial dose: 1600 mg twice a day orally on day 1 -Maintenance dose: 600 mg twice a day orally on days 2-7. Day 8-14 according to clinician's judgement, but no more than 14 days of treatment.
	Control Standard care
Participants
	Randomized participants : Favipiravir=36 Standard care=19
	Characteristics of participants N= 55 Mean age : NR 25 males Severity : Mild: n= / Asymptomatic: n=
Primary outcome
	In the register Viral nucleic acid test negative conversion rate [ Time Frame: 5 months ]
	In the report The primary outcome was time to achieve a consecutive twice (at intervals of more than 24 h) negative RT-PCR result for SARS-CoV-2 RNA in nasopharyngeal swab and sputum sample.
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry and published protocol summary were used in data extraction and assessment of risk of bias. The study was registered retrospectively and did not achieve the target sample size. There are some differences in outcomes reported and follow-up timepoints in the published article and registry and protocol summary.

Methods
	RCT Blinding: triple blinding
	Location : Single center / Australia Follow-up duration (days): 28
Inclusion criteria	adults ≥18 years old with PCR confirmed COVID-19 on nasopharyngeal or combined nose and throat swab onset of COVID-19 related symptoms (one or more of: fever, cough, sore throat, shortness of breath, fatigue, myalgia) in the prior 5 days.
Exclusion criteria	enrolled into another COVID-19 antiviral treatment trial were pregnant or breastfeeding. Female participants of childbearing potential were required to have a negative pregnancy test prior to enrolment chronic liver disease (Child-Pugh C) renal impairment requiring dialysis.
Interventions
	Treatment Favipiravir Initial dose: 1800 mg orally on day 1 -Maintenance dose: 800 mg orally 2 times a day for 14 days
	Control Placebo
Participants
	Randomized participants : Favipiravir=99 Placebo=100
	Characteristics of participants N= 199 Mean age : NR 109 males Severity : Mild: n= 198/ Asymptomatic: n=0
Primary outcome
	In the register Time to virological cure [Time Frame: 14 days]: Time to 2 successive throat (or combined nose/throat) swabs negative for SARS-CoV-2 by nucleic acid testing.
	In the report time to virological cure as defined by 2 successive throat (or combined nose/throat) swabs negative for SARS-CoV-2 by PCR.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, its supplement and the preprint, the study registry and protocol were used in data extraction and risk of bias assessment. The study achieved the target sample size specified in the trial registry and protocol. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome.