Study of the Use of Favipiravir in Hospitalized Subjects With COVID-19

• ClinicalTrials.gov Identifier: NCT04358549
• Recruitment Status: Completed
• First Posted: April 24, 2020
• Results First Posted: March 29, 2022
• Last Update Posted: March 29, 2022
• Sponsor: Fujifilm Pharmaceuticals U.S.A., Inc.
• Information provided by (Responsible Party): Fujifilm Pharmaceuticals U.S.A., Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: COVID-19
• Interventions: Drug: Favipiravir; Other: Standard of Care
• Enrollment: 50

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Favipiravir Treatment Arm	Standard of Care Arm
Arm/Group Description	Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets	Standard of Care for 14 days Standard of Care: Standard of Care for individual study site as determined by each hospital's protocol
Period Title: Overall Study
Started	25	25
ITT Population (Randomized Subjects)	25	25
Safety Population (Patients Who Received Either Favipiravir + SOC or SOC Alone) [1]	24	25
Completed	15	17
Not Completed	10	8
Reason Not Completed
Adverse Event	0	1
Death	1	0
Lost to Follow-up	2	1
Withdrawal by Subject	6	6
Start remdesivir	1	0
[1] One patient randomized in favipiravir + SOC arm withdrew before the first dose of favipiravir.

Baseline Characteristics

Arm/Group Title		Favipiravir Treatment Arm	Standard of Care Arm	Total
Arm/Group Description		Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets	Standard of Care for 14 days Standard of Care: Standard of Care for individual study site as determined by each hospital's protocol	Total of all reporting groups
Overall Number of Baseline Participants		25	25	50
Baseline Analysis Population Description		Intent-to-Treat (ITT) population
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	25 participants	25 participants	50 participants
		55.4 (12.37)	58.9 (13.90)	57.2 (13.14)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants	25 participants	50 participants
	Female	9 36.0%	11 44.0%	20 40.0%
	Male	16 64.0%	14 56.0%	30 60.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants	25 participants	50 participants
	Hispanic or Latino	13 52.0%	14 56.0%	27 54.0%
	Not Hispanic or Latino	12 48.0%	10 40.0%	22 44.0%
	Unknown or Not Reported	0 0.0%	1 4.0%	1 2.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants	25 participants	50 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 4.0%	0 0.0%	1 2.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	4 16.0%	6 24.0%	10 20.0%
	White	17 68.0%	12 48.0%	29 58.0%
	More than one race	3 12.0%	7 28.0%	10 20.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Smoking Status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	25 participants	25 participants	50 participants
	Non-smoker	17 68.0%	14 56.0%	31 62.0%
	Ex-smoker	6 24.0%	11 44.0%	17 34.0%
	Smoker	2 8.0%	0 0.0%	2 4.0%

Outcome Measures

1. Primary Outcome

Title	Time to Viral Clearance
Description	To determine the effect of favipiravir + SOC v. SOC on viral clearance of COVID-19 as measured by nasopharyngeal and oropharyngeal sampling
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Favipiravir Treatment Arm	Standard of Care Arm
Arm/Group Description:	Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets	Standard of Care for 14 days Standard of Care: Standard of Care for individual study site as determined by each hospital's protocol
Overall Number of Participants Analyzed	25	25
Median (90% Confidence Interval); Unit of Measure: days
	16.0; (12.0 to 29.0)	30.0; (12.0 to 31.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Favipiravir Treatment Arm, Standard of Care Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0415
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	14
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Status of Clinical Recovery as Measured by the Study-specific 6-point Ordinal Scale
Description	To determine the clinical benefit of administering favipiravir plus SOC compared to SOC alone, clinical benefit will be measured using a study-specified ordinal scale on Day 15 in adult patients hospitalized with COVID-19.
Time Frame	on Day 15

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Favipiravir Treatment Arm	Standard of Care Arm
Arm/Group Description:	Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets	Standard of Care for 14 days Standard of Care: Standard of Care for individual study site as determined by each hospital's protocol
Overall Number of Participants Analyzed	25	25
Measure Type: Count of Participants; Unit of Measure: Participants
Not Hospitalized	18 72.0%	18 72.0%
Hospitalized, not requiring supplemental oxygen	1 4.0%	3 12.0%
Hospitalized, requiring supplemental oxygen	4 16.0%	1 4.0%
Hospitalized, on non-invasive ventilation or high flow oxygen devices	0 0.0%	0 0.0%
Hospitalized, on invasive mechanical ventilation or ECMO	1 4.0%	0 0.0%
Death	0 0.0%	0 0.0%
Not available	1 4.0%	3 12.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Favipiravir Treatment Arm, Standard of Care Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.653
	Confidence Interval	(2-Sided) 90%; 0.190 to 2.240
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Time to the National Early Warning Score 2 (NEWS2) of 2 or Less, or Hospital Discharge
Description	The NEWS2 is based on a simple aggregate scoring system in which a score is allocated to physiological measurements, already recorded in routine practice, when patients present to, or are being monitored in hospital. Six simple physiological parameters form the basis of the scoring system: respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or new confusion, temperature. The time to aggregate NEWS2 score of ≤ 2 (sustained for at least 72 hours) or hospital discharge is analyzed.
Time Frame	through Day 29

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Favipiravir Treatment Arm	Standard of Care Arm
Arm/Group Description:	Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets	Standard of Care for 14 days Standard of Care: Standard of Care for individual study site as determined by each hospital's protocol
Overall Number of Participants Analyzed	25	25
Median (90% Confidence Interval); Unit of Measure: days
	4.0; (3.0 to 8.0)	7.0; (4.0 to 10.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Favipiravir Treatment Arm, Standard of Care Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9879
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	3
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Characterize the Pharmacokinetics (PK) of Favipiravir in Plasma: Cmax
Description	Measurement of maximum plasma concentration
Time Frame	through Day 14

Outcome Measure Data

Analysis Population Description

PK population: All subjects in the safety population that have at least one result that can be used in the PK summaries.

Arm/Group Title		Favipiravir Treatment Arm
Arm/Group Description:		Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets
Overall Number of Participants Analyzed		23
Median (Full Range); Unit of Measure: µg/mL
Day 1	Number Analyzed	23 participants
		60.9; (22.0 to 84.5)
Day 2	Number Analyzed	23 participants
		47.1; (16.7 to 109)
Day 8	Number Analyzed	20 participants
		51.4; (17.1 to 133)
Day 14	Number Analyzed	17 participants
		50.8; (14.2 to 134)

5. Secondary Outcome

Title	Characterized the Pharmacokinetics (PK) of Favipiravir in Plasma: Cmin
Description	Measurement of minimum plasma concentration
Time Frame	through Day 14

Outcome Measure Data

Analysis Population Description

PK population: All subjects in the safety population that have at least one result that can be used in the PK summaries.

Arm/Group Title		Favipiravir Treatment Arm
Arm/Group Description:		Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets
Overall Number of Participants Analyzed		23
Median (Full Range); Unit of Measure: µg/mL
Day 1	Number Analyzed	23 participants
		3.24; (0.120 to 36.1)
Day 2	Number Analyzed	23 participants
		8.19; (0.152 to 70.2)
Day 8	Number Analyzed	20 participants
		17.1; (1.04 to 88.4)
Day 14	Number Analyzed	17 participants
		15.5; (0.815 to 87.4)

6. Secondary Outcome

Title	Characterized the Pharmacokinetics (PK) of Favipiravir in Plasma: Area Under Curve (AUC 0-24)
Description	Measurement of the area under the curve of plasma concentration versus time profile
Time Frame	through Day 14

Outcome Measure Data

Analysis Population Description

PK population: All subjects in the safety population that have at least one result that can be used in the PK summaries.

Arm/Group Title		Favipiravir Treatment Arm
Arm/Group Description:		Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets
Overall Number of Participants Analyzed		23
Median (Full Range); Unit of Measure: hr*µg/mL
Day 1	Number Analyzed	23 participants
		414; (161 to 1240)
Day 2	Number Analyzed	23 participants
		488; (135 to 2120)
Day 8	Number Analyzed	20 participants
		786; (189 to 2580)
Day 14	Number Analyzed	17 participants
		772; (151 to 2680)

Adverse Events

Time Frame	Until 60 days from Enrollment
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Favipiravir Treatment Arm	Standard of Care Arm
Arm/Group Description	Day 1: favipiravir 1800 mg BID plus Standard of Care (SOC) Days 2-14: 1000 mg BID plus SOC. For subjects with Child-Pugh A liver impairment: Days 2-14: 800 mg BID plus SOC Favipiravir: Favipiravir to be administered as an oral tablet or made into a slurry for subjects who cannot swallow tablets	Standard of Care for 14 days Standard of Care: Standard of Care for individual study site as determined by each hospital's protocol
All-Cause Mortality
	Favipiravir Treatment Arm	Standard of Care Arm
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/24 (4.17%)	0/25 (0.00%)
Serious Adverse Events
	Favipiravir Treatment Arm	Standard of Care Arm
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/24 (8.33%)	3/25 (12.00%)
General disorders
Necrosis *	0/24 (0.00%)	1/25 (4.00%)
Infections and infestations
Osteomyelitis *	1/24 (4.17%)	0/25 (0.00%)
Staphylococcal infection *	1/24 (4.17%)	0/25 (0.00%)
Clostridium difficile infection *	0/24 (0.00%)	1/25 (4.00%)
Urinary tract infection *	0/24 (0.00%)	1/25 (4.00%)
Metabolism and nutrition disorders
Failure to thrive *	0/24 (0.00%)	1/25 (4.00%)
Nervous system disorders
Basal ganglia hemorrhage *	1/24 (4.17%)	0/25 (0.00%)
* Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	4%
	Favipiravir Treatment Arm	Standard of Care Arm
	Affected / at Risk (%)	Affected / at Risk (%)
Total	13/24 (54.17%)	12/25 (48.00%)
Gastrointestinal disorders
Constipation *	0/24 (0.00%)	2/25 (8.00%)
Dyspepsia *	0/24 (0.00%)	2/25 (8.00%)
Nausea *	2/24 (8.33%)	2/25 (8.00%)
Investigations
Blood lactate dehydrogenase increased *	2/24 (8.33%)	0/25 (0.00%)
Gamma-glutamyltransferase increased *	3/24 (12.50%)	0/25 (0.00%)
Inflammatory marker increased *	1/24 (4.17%)	4/25 (16.00%)
Nervous system disorders
Dizziness *	0/24 (0.00%)	2/25 (8.00%)
Headache *	2/24 (8.33%)	1/25 (4.00%)
Renal and urinary disorders
Acute kidney injury *	3/24 (12.50%)	0/25 (0.00%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure *	1/24 (4.17%)	4/25 (16.00%)
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

No publication until earlier of: Sponsor publishes multisite results, Sponsor notice that multisite publication no longer planned, and 18 months after Study close. Submission to Sponsor of proposed publication for 30-45 days prior to submission for publication. Good faith consideration by Site of Sponsor's comments; deletion of any of Sponsor's confidential information. Sponsor may require up to additional 60-day delay to file patent applications for patentable subject matter in the publication.

Results Point of Contact

• Name/Title: Clinical Research Manager
• Organization: FUJIFILM Pharmaceuticals U.S.A., Inc.
• Phone: No phone at site
• EMail: fphucontact@fujifilm.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Finberg RW, Ashraf M, Julg B, Ayoade F, Marathe JG, Issa NC, Wang JP, Jaijakul S, Baden LR, Epstein C. US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19. Open Forum Infect Dis. 2021 Dec 7;8(12):ofab563. doi: 10.1093/ofid/ofab563. eCollection 2021 Dec.

• Responsible Party: Fujifilm Pharmaceuticals U.S.A., Inc.
• ClinicalTrials.gov Identifier: NCT04358549
• Other Study ID Numbers: FAVI-COV-US201
• First Submitted: April 16, 2020
• First Posted: April 24, 2020
• Results First Submitted: March 22, 2022
• Results First Posted: March 29, 2022
• Last Update Posted: March 29, 2022