Bioequivalence Study of Favipiravir 200 mg Film Tablet (Novelfarma, Turkey) Under Fasting Conditions

• Sponsor: Novelfarma Ilaç San. ve Tic. Ltd. Sti. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04400682
• Collaborator: Novagenix Bioanalytical Drug R&D Center (Other), Farmagen Ar-Ge Biyot. Ltd. Sti (Other)
• Enrollment: 30
• Locations: 2
• Arms: 2
• Actual Duration (Days): 21
• Patients Per Site: 15
• Patients Per Site Per Month: 21.7

Study Details

Study Description

Brief Summary

A single dose of Reference product containing 200 mg favipiravir and a single dose of Test product containing 200 mg favipiravir or vice versa; administered with 240 mL of water at room temperature, in each period under fasting conditions with current pandemic precautions.

Condition or Disease	Intervention/Treatment	Phase
Bioequivalence	Drug: FAVIRA 200 MG Film Tablet; Drug: AVIGAN 200 MG Film Tablets	Phase 1

Detailed Description

Favipiravir is a drug with a mechanism of action different from that of the existing influenza antiviral drugs and effective against all types and sub-types of human influenza A, B and C viruses in vitro, showing anti-viral activity against various influenza virus strains including avian and swine viruses. Favipiravir also has shown anti-viral activity even against amantadine, oseltamivir and zanamivir-resistant influenza viruses in vitro. The mechanism of action of favipiravir is the selective inhibition of RNA polymerase by favipiravir ribosyl triphosphate formed by cellular enzymes in the influenza virus leading to antiviral activity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Open-label, Randomised, Single Oral Dose, Two-period, Cross-over Trial to Assess to Bioequivalence of Favira 200 mg FT in Comparison With Avigan 200 mg FT in Healthy Male Subjects Under Fasting Conditions
• Actual Study Start Date: May 28, 2020
• Actual Primary Completion Date: Jun 5, 2020
• Actual Study Completion Date: Jun 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FAVIRA then AVIGAN Participants first received Favira 200 mg FT manufactured by Novelfarma in a fasting state. After a washout period of 48 hours, they then received Avigan FT200 mg manufactured by Toyama Chemical Industry Co.Ltd./ Japan in a fasting state.	Drug: FAVIRA 200 MG Film Tablet; FAVIRA is containing 200 mg favipiravir manufactured by Novelfarma, Turkey.; Other Names: FAVIRA 200 MG FT ; Drug: AVIGAN 200 MG Film Tablets; AVIGAN is containing 200 mg favipiravir manufactured by Toyama, Japan; Other Names: AVIGAN 200 mg FT
Experimental: AVIGAN then FAVIRA Participants first received Avigan FT 200 mg manufactured by Toyama Chemical Industry Co.Ltd./Japan in a fasting state. After a washout period of 48 hours, they then received Favira 200 mg FT manufactured by Novelfarma in a fasting state.	Drug: FAVIRA 200 MG Film Tablet; FAVIRA is containing 200 mg favipiravir manufactured by Novelfarma, Turkey.; Other Names: FAVIRA 200 MG FT ; Drug: AVIGAN 200 MG Film Tablets; AVIGAN is containing 200 mg favipiravir manufactured by Toyama, Japan; Other Names: AVIGAN 200 mg FT

Outcome Measures

Primary Outcome Measures

1. AUC0-tlast [0 to 24 hours post dose]

   AUC0-tlast of favipiravir will be obtained from plasma concentrations

2. Favipiravir Cmax [0 to 24 hours post dose]

   Favipiravir Cmax Cmax of favipiravir will be obtained from plasma concentrations

Secondary Outcome Measures

1. AUC0-inf of Favipiravir [0 to 24 hours post dose]

   AUC0-inf of favipiravir will be obtained from plasma concentrations

2. Tmax of Favipiravir [0 to 24 hours post dose]

   tmax of favipiravir will be obtained from plasma concentrations

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 40 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy Caucasian male subjects aged between 20 and 40 years,

2. Non smokers or smoking maximum 5 cigarettes a day, those who won't smoke or drink coffee during the study period,

3. Two Negative Covid-19 PCR test results.

4. Negative alcohol breath test results,

5. Normal physical examination at screening visit,

6. Having the Body Mass Index ranged between 18.5-30 kg/m2 (see Appendix I) which is in the desirable range according to the age,

7. Ability to communicate adequately with the investigator himself or his representatives,

8. Ability and agreement to comply with the study requirements,

9. Normal blood pressure and heart rate measured under stabilised conditions at the screening visit after at least 5 minutes of rest under supine position: SBP within 100 to 140 mmHg, DBP within 60 to 90 mmHg and HR within 50 to 90 bpm,

10. Normal/ acceptable 12-lead electrocardiographic results at least after 5 minutes of rest,

11. Laboratory results within normal range or clinically non-significant (CBC, glucose, urea, uric acid, creatinine, estimated GFR (eGFR), total bilirubin, sodium, potassium, calcium, chloride, SGOT (AST), SGPT (ALT), GGT, alkaline phosphatase, total protein and urinalysis), drug addiction scanning in urine results in negative (amphetamine, barbiturate, benzodiazepine, cannabinoid, cocaine, opiate),

12. Understanding of the study and agreement to give a written informed consent according to section 20.3.

13. Understanding of that he and his partner will use a practice adequate contraception during the study and at least 7 days after the study.

14. Volunteer's compliance with isolation rules defined at study protocol.

Exclusion Criteria:

1. Who have atopic constitution or asthma or known allergy for favipiravir and/or any other ingredients of the products.

2. Who have positive Covid-19 PCR test result.

3. Any history or presence of clinical relevance of cardiovascular, neurological, musculoskeletal, haematological, hepatic, gastrointestinal, renal, pulmonary, endocrinological, metabolism or psychiatric disease, any type of porphyria.

4. Symptomatic or asymptomatic orthostatic hypotension at screening or before the first drug administration defined by a decrease of SBP more than 20 mmHg or DBD more than 10 mmHg occurs between sitting/supine to standing position subject will be excluded (if it deemed necessary by the investigator),

5. Presence or history of malabsorption or any gastrointestinal surgery except appendectomy or except herniotomy.

6. Subjects who have given more than 400 mL blood within the last two months before the first drug administration and subjects who have participated to any drug research within the last two months before the first drug administration.

7. Subjects suspected to have a high probability of non-compliance to the study procedure and/or completion of the study according to the investigator's judgement.

8. Subjects who used any of prescribed systemic or topical medication (including OTC medication) within 2 weeks (or six elimination half lives of this medication, whichever is longer) before the initiation of the study (except single doses of analgesics which have no drug interaction with study product).

9. Use of any vitamins or herbal products within 7 days prior to the initial dose of the study medication.

10. History of allergic response to heparin.

11. Subjects who have any chronic disease which might interfere with absorption, distribution, metabolism or excretion of the drug.

12. Subjects who regular consumed of beverages or food containing methylxanthines (e.g. coffee, tea, cola, caffeine, chocolate, sodas,) equivalent to more than 500 mg methylxanthines per day.

13. Subjects who has taken any grapefruit or grapefruit juice during 7 days prior to drug administration, during the study.

14. History of drug abuse.

15. History of alcohol abuse and/or regular use of more than 2 units of alcohol per day or 10 units per week and/or positive alcohol breath test results (Note: one unit of alcohol equals 250 mL beer, 125 mL wine or 25 mL spirits).

16. Positive blood test for HBV, HCV and HIV.

17. Who have relationship to the investigator.

18. Who are not suitable to any of inclusion criteria.

19. History of difficulty of swallowing.

20. Intake of depot injectable solutions (including study medications) within 6 months before start of the study.

21. Intake of enzyme-inducing, organotoxic or long half-life drugs within 4 weeks before start of the study.

22. Special diet due to any reason, e.g. vegetarian.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novagenix Drug R&D Center	Akyurt	Ankara	Turkey	06970
2	Farmagen Ar-Ge Biyot. Ltd. Sti.	Sahinbey	Gaziantep	Turkey	27000

Sponsors and Collaborators

• Novelfarma Ilaç San. ve Tic. Ltd. Sti.
• Novagenix Bioanalytical Drug R&D Center
• Farmagen Ar-Ge Biyot. Ltd. Sti

Investigators

• Principal Investigator: Muradiye Nacak, MD,PhD, Farmagen Ar-Ge Biyot. Ltd. Sti
• Study Chair: Taner Ezgi, MD, Farmagen Ar-Ge Biyot. Ltd. Sti

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 12, 2020
• Informed Consent Form - May 11, 2020

More Information

Publications

None provided.

• Responsible Party: Novelfarma Ilaç San. ve Tic. Ltd. Sti.
• ClinicalTrials.gov Identifier: NCT04400682
• Other Study ID Numbers: NOV2020/1923; FARGE 367
• First Posted: May 22, 2020
• Last Update Posted: Aug 11, 2020
• Last Verified: Aug 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novelfarma Ilaç San. ve Tic. Ltd. Sti.: COVID-19 drug treatment; Antiviral Agents; Favipiravir; Novagenix; Farmagen
• Additional relevant MeSH terms: Favipiravir

Study Results

Participant Flow

Pre-assignment Detail	46 subjects screened

Arm/Group Title	FAVIRA Then AVIGAN	AVIGAN Then FAVIRA
Arm/Group Description	Participants first received Favira 200 mg FT manufactured by Novelfarma in a fasting state. After a washout period of 48 hours, they then received Avigan FT200 mg manufactured by Toyama Chemical Industry Co.Ltd./ Japan in a fasting state. FAVIRA 200 MG FT: FAVIRA containing 200 mg favipiravir manufactured by Novelfarma, Turkey. AVIGAN 200 mg FT: AVIGAN containing 200 mg favipiravir manufactured by Toyama, Japan	Participants first received Avigan FT 200 mg manufactured by Toyama Chemical Industry Co.Ltd./Japan in a fasting state. After a washout period of 48 hours, they then received Favira 200 mg FT manufactured by Novelfarma in a fasting state. FAVIRA 200 MG FT: FAVIRA containing 200 mg favipiravir manufactured by Novelfarma, Turkey. AVIGAN 200 mg FT: AVIGAN containing 200 mg favipiravir manufactured by Toyama, Japan
Period Title: Period 1
STARTED	15	15
COMPLETED	14	11
NOT COMPLETED	1	4
Period Title: Period 1
STARTED	14	11
COMPLETED	14	11
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	FAVIRA Then AVIGAN	AVIGAN Then FAVIRA	Total
Arm/Group Description	Participants first received Favira 200 mg FT manufactured by Novelfarma in a fasting state. After a washout period of 48 hours, they then received Avigan FT200 mg manufactured by Toyama Chemical Industry Co.Ltd./ Japan in a fasting state. FAVIRA 200 MG FT: FAVIRA containing 200 mg favipiravir manufactured by Novelfarma, Turkey. AVIGAN 200 mg FT: AVIGAN containing 200 mg favipiravir manufactured by Toyama, Japan	Participants first received Avigan FT 200 mg manufactured by Toyama Chemical Industry Co.Ltd./Japan in a fasting state. After a washout period of 48 hours, they then received Favira 200 mg FT manufactured by Novelfarma in a fasting state. FAVIRA 200 MG FT: FAVIRA containing 200 mg favipiravir manufactured by Novelfarma, Turkey. AVIGAN 200 mg FT: AVIGAN containing 200 mg favipiravir manufactured by Toyama, Japan	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31 (2.9)	33 (3.4)	32 (3.15)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	15 100%	15 100%	30 100%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	15 100%	15 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	AUC0-tlast
Description	AUC0-tlast of favipiravir will be obtained from plasma concentrations
Time Frame	0 to 24 hours post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FAVIRA (Novelfarma-Turkey)	AVIGAN (Toyama-Japan)
Arm/Group Description	Participants received an oral single dose of 200 mg favipiravir (Novelfarma-Turkey) in fasting state.	Participants received an oral single dose of 200 mg favipiravir (Toyama-Japan) in fasting state.
Measure Participants	25	25
Least Squares Mean (Standard Deviation) [ng*hr/mL]	10400.038 (2803.269)	9907.948 (2487.955)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FAVIRA (Novelfarma-Turkey), AVIGAN (Toyama-Japan)
	Comments
	Type of Statistical Test	Equivalence
	Comments	0.80-1.25 margins for equivalence
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.0150
	Confidence Interval	(2-Sided) 90%; 0.9897 to 1.0410
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ln(AUClast) : 0.989- 1.0410

2. Primary Outcome

Title	Favipiravir Cmax
Description	Favipiravir Cmax Cmax of favipiravir will be obtained from plasma concentrations
Time Frame	0 to 24 hours post dose

Outcome Measure Data

Analysis Population Description

All of the 25 subjects were included in statistical analysis.

Arm/Group Title	FAVIRA (Novelfarma-Turkey)	AVIGAN (Toyama-Japan)
Arm/Group Description	Participants received an oral single dose of 200 mg favipiravir (Novelfarma-Turkey) in fasting state.	Participants received an oral single dose of 200 mg favipiravir (Toyama-Japan) in fasting state.
Measure Participants	25	25
Least Squares Mean (Standard Deviation) [ng/mL]	5242.459 (1761.452)	4969.881 (1325.164)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FAVIRA (Novelfarma-Turkey), AVIGAN (Toyama-Japan)
	Comments
	Type of Statistical Test	Equivalence
	Comments	0.80 - 1.25 equivalence margin is required.
Statistical Test of Hypothesis	p-Value	0.0033
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.0361
	Confidence Interval	(2-Sided) 90%; 0.9294 to 1.1551
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ln(Cmax) : 0.9294 - 1.1551

3. Secondary Outcome

Title	AUC0-inf of Favipiravir
Description	AUC0-inf of favipiravir will be obtained from plasma concentrations
Time Frame	0 to 24 hours post dose

Outcome Measure Data

Analysis Population Description

All of the 25 subjects were included in statistical analysis

Arm/Group Title	FAVIRA (Novelfarma-Turkey)	AVIGAN (Toyama-Japan)
Arm/Group Description	Participants received an oral single dose of 200 mg favipiravir (Novelfarma-Turkey) in fasting state.	Participants received an oral single dose of 200 mg favipiravir (Toyama-Japan) in fasting state.
Measure Participants	25	25
Least Squares Mean (Standard Deviation) [ng*hr/mL]	10400.038 (2803.269)	10186.389 (2528.923)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FAVIRA (Novelfarma-Turkey), AVIGAN (Toyama-Japan)
	Comments
	Type of Statistical Test	Equivalence
	Comments	0.80 - 1.25 equivalence margin is not required.
Statistical Test of Hypothesis	p-Value	0.0000
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.0108
	Confidence Interval	(2-Sided) 90%; 0.9856 to 1.0366
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Ln(Cmax) : 0.9856 - 1.0366

4. Secondary Outcome

Title	Tmax of Favipiravir
Description	tmax of favipiravir will be obtained from plasma concentrations
Time Frame	0 to 24 hours post dose

Outcome Measure Data

Analysis Population Description

All of the 25 subjects were included in statistical analysis.

Arm/Group Title	FAVIRA (Novelfarma-Turkey)	AVIGAN (Toyama-Japan)
Arm/Group Description	Participants received an oral single dose of 200 mg favipiravir (Novelfarma-Turkey) in fasting state.	Participants received an oral single dose of 200 mg favipiravir (Toyama-Japan) in fasting state.
Measure Participants	25	25
Mean (Standard Deviation) [hr]	0.766 (0.394)	0.770 (0.444)

Adverse Events

Time Frame	9 days
Arm/Group Title	FAVIRA (Novelfarma-Turkey)		AVIGAN (Toyama-Japan
Arm/Group Description	Participants received an oral dose of 200 mg favipiravir (Novelfarma-Turkey) in fasting state.		Participants received an oral dose of 200 mg favipiravir (Toyama-Japan) in fasting state.
All Cause Mortality
	FAVIRA (Novelfarma-Turkey)		AVIGAN (Toyama-Japan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Serious Adverse Events
	FAVIRA (Novelfarma-Turkey)		AVIGAN (Toyama-Japan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	FAVIRA (Novelfarma-Turkey)		AVIGAN (Toyama-Japan
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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