Conditions: Bioequivalence
Keywords: COVID-19 drug treatment Antiviral Agents Favipiravir Novagenix Farmagen
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 30
Healthy volunteers: yes

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.

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: FAVIRA 200 MG Film Tablet intervention 2: AVIGAN 200 MG Film Tablets
Intervention descriptions: intervention 1: FAVIRA is containing 200 mg favipiravir manufactured by Novelfarma, Turkey. intervention 2: AVIGAN is containing 200 mg favipiravir manufactured by Toyama, Japan

Protocol document:
Prot_SAP_000.pdf: 
Study Code: NOV2020/01923  NCT04400682 
 
Date: 12.05.2020  
Clinical Study Protocol                                                                                                     Version: 1.0 
                                                
 
 
Page 1of 65 
 
 
 
 
CLINICAL STUDY PROTOCOL 
“CONFIDENTIAL” 
 
 
 
Principal Investigator: 
Prof. Dr. Muradiye Nacak   
 
Clinical Center: 
 
Gaziantep Üniversitesi FARMAGEN GCP  
Center, Gaziantep –Turkey 
 
 
Sponsor: 
 
Novelfarma İlaç San. ve Tic. Ltd. Şti.  
 
 
İstanbul-Turkey 
 
Contract Research Organisation:  Novagenix Bioanalytical Drug R&D Centre, 
Ankara - Turkey 
 
 
 
 
 
 
NOTE: No part of this document may be reproduced. The document should be treated as the confidential property of  Novelfarma İlaç San. ve 
Tic. Ltd.Şti. and Novagenix Bioanalytical Drug R&D Centre. Not divulged to unauthorised persons in any form, including publications and 
presentations, without written consent of Novelfarma İlaç San. ve Tic. Ltd.Şti. and Novagenix Bioanalytical Drug R&D Centre. 
 
OPEN-LABEL, RANDOMISED, SINGLE ORAL DOSE, 
TWO-PERIOD, CROSS-OVER TRIAL TO ASSESS THE 
BIOEQUIVALENCE OF FAVIRA 200 MG FILM KAPLI 
TABLET (TEST DRUG) IN COMPARISON WITH  
AVIGAN 200 MG FILM TABLET (REFERENCE DRUG) 
IN HEALTHY MALE SUBJECTS UNDER FASTING 
CONDITIONS 


Study Code: NOV2020/01923 
                                                   
 
 
      Date: 12.05.2020 
Clinical Study Protocol 
 
 
 
 
 
 
 
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  STUDY SYNOPSIS 
 
Study Title: 
Open-label, randomised, single oral dose, two-period, cross-over trial  
to assess to bioequivalence of Favira 200 mg Film Kaplı Tablet (Test 
Drug) in comparison with Avigan 200 mg Film Tablet (Reference 
Drug) in healthy male subjects under fasting conditions 
 
Study Code: 
NOV2020/01923 
 
Drugs: 
Test Drug*: “Favira 200 mg Film Kaplı Tablet” containing 200 mg 
favipiravir (Novelfarma-Turkey).  
 
 
 *: This drug is manufactured by Pharma Plant İlaç San. ve Tic. Ltd. Şti.-Turkey  
 
  
 
 
Reference Drug**: “Avigan 200 mg Film Tablet” containing 200 mg 
favipiravir (Toyama  Chemical  Industry Co.Ltd./Japan). 
 
 
 
**:This drug is manufactured and licenced by Toyama Chemical Industry Co Ltd.-
Japan.   
 
 
    
 
Dosage: 
Once daily 200 mg in a period. 
 
Indication: 
Bioequivalence study 
 
Study Design: 
Single-dose, open-label, randomised, two period, cross-over study. 
 
Variables:  
Pharmacokinetics: 
 
 Primary variables: AUC0-tlast and Cmax  
                                         Secondary variables: AUC0-, tmax, t1/2 
Safety and Tolerability: Adverse events, clinical laboratory, medical 
examinations  
 
Sample Size:                 
30 volunteers will be included. Drop-outs will not be replaced. 
  
   
 
Subjects: 
20 - 40 aged healthy male volunteers, normal weight according to the 
BMI 
 
Sponsor: 
Novelfarma İlaç San. ve Tic. Ltd. Şti. -Turkey 
 
Phase: 
 
I (Bioequivalence study) 
 
Planned Initiation:  
2Q 2020 (inclusion of first subject) 
 
Planned Duration: 
9 days (approximately) including the wash-out period of 48 hours and 
the time between last blood sampling in the last period to the final 
examination tests. 
 
 
 


Study Code: NOV2020/01923 
                                                   
 
 
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Clinical Study Protocol 
 
 
 
 
 
 
 
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Primary Endpoint:   
AUC0-tlast and Cmax of favipiravir 
 
Secondary Endpoint:  
AUC0-∞, t1/2, tmax of favipiravir 
 
Safety Endpoints: 
Adverse events, clinical and laboratory examinations. 
 
Principal Investigator:       Prof. Dr. Muradiye Nacak 
 
Co-investigators:  
İsmail Taner Ezgi, MD 
 
Erol Durucu, MD 
                                            Gaziantep Üniversitesi, FARMAGEN-GCP Center, Gaziantep- Turkey 
 
Analytics: 
     
Plasma concentrations of favipiravir will be analysed in LC system 
with appropriate detection system. 
 
GCP Statement: 
 
This study will be conducted to compliance with Good Clinical 
Practice (ICH-GCP), the Declaration of Helsinki (with amendments) 
and local legal and regulatory requirements. 
 
Blood Sampling:  
The samples will be drawn in the clinical study period: at pre-
dose* and at 0.17, 0.25, 0.50, 0.75, 1.00, 1.33, 1.66, 2.00, 2.50, 3.00, 
3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 14.00, 24.00 hours post-dose (1 x 8 
mL each; totally 19 blood sample points) 
 
 
 
* Note:  
1. Only in Period I; at t0 the blood sample amount will be 20 mL. 
2. Not to have difficulty to draw blood through catheter; the cannula will be 
kept patent by injecting approximately 0.5 mL of 5 IU/mL of heparin in 
normal saline solution at determined blood sampling points. In such 
cases, before collecting the blood samples at the first blood sampling 
points after heparin administration, first 0.5 mL blood will be discarded. 
The aim of this procedure is to eliminate the possible effect of heparin on 
favipiravir analysis [for   details see section 13.7 (Blood Sampling for Drug 
Analysis)] 
 
 
Wash-out duration: 
    At least 48 hours. 
 
Acceptance Range: 
 80% - 125% for Cmax and AUC0-tlast of favipiravir. 


Study Code: NOV2020/01923 
                                                   
 
 
      Date: 12.05.2020 
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1.  THE PARTIES of PROJECT 
 
Study Code:                       
NOV2020/01923 
 
Study Title: 
Open-label, randomised, single oral dose, two-period, cross-over trial to 
assess bioequivalence of  Favira 200  mg Film Kaplı Tablet (Test Drug) in 
comparison with Avigan 200 mg Film Tablet (Reference Drug) in healthy 
male subjects under fasting conditions 
 
 
Sponsor: 
Novelfarma İlaç San. Ve Tic. Ltd. Şti.   
 
Saray Mahallesi Dr. Adnan Büyükdeniz Caddesi. Akkom Ofis Park No:2 
Kelif Plaza Kat:19 , 34768 
                              
Ümraniye, İstanbul-Turkey 
 
Phone: +90 216 365 51 00 
 
Fax: +90 216 365 51 10 
 
Contract Research 
 
Organisation: 
Novagenix Bioanalytical Drug R&D Centre 
 
Esenboğa Yolu 25. Km. 06970 Akyurt, Ankara-Turkey 
 
Phone: +90 312 398 10 81 
  
Fax: +90 312 398 07 18 
  
 
Clinical Facility: 
        Gaziantep Üniversitesi FARMAGEN GCP Center  
 
Gaziantep Üniversitesi Teknoloji Geliştirme Bölgesi (Teknopark),  
 
 Burç Yolu, Şahinbey 27260, Gaziantep-Turkey 
 
 Phone: +90 342 360 62 62 
 
 Fax: +90  342 360 64 57 
 
 
Monitor*:                
Halime Bekdik  
 
 
*: for the absence of principal monitor, the monitoring will be done by Novagenix's authorized personnel.  
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to investigator(s), co-
investigator(s), potential investigator(s) and appropriate Ethics Committee(s). No disclosure should take place without 
the written authorization from Novagenix Bioanalytical Drug R&D Centre and  Novelfarma İlaç San. ve Tic. Ltd. Şti., 
except to the extent necessary to obtain informed consent from potential volunteers. 


Study Code: NOV2020/01923 
                                                   
 
 
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2.  TABLE OF CONTENTS
1.  
THE PARTIES OF PROJECT 
4 
2.  
TABLE OF CONTENTS 
5 
3.  
RESPONSIBILITIES, SIGNATURES AND ADDRESSES 
7 
4.  
LIST OF ABBREVIATIONS AND TERMS 
10 
5.  
SUMMARY AND SCHEDULE FOR THE CLINICAL TRIAL 
11 
5.1. SUMMARY 
11 
5.2. SCHEDULE 
14 
6. STUDY FLOW CHART 
15 
7. INTRODUCTION 
17 
7.1. CHEMICAL AND PHARMACEUTICAL PROPERTIES 
17 
7.2. PHARMACOLOGICAL PROPERTIES 
17 
7.3. PHARMACOKINETICS 
17 
7.4. INDICATIONS 
18 
7.5. CONTRAINDICATIONS 
18 
7.6. ADVERSE REACTIONS 
18 
7.7. CAUTIONS AND PRECAUTIONS 
20 
7.8. INTERACTIONS 
20 
8.     OBJECTIVE OF THE TRIAL 
23 
9. BENEFIT-RISK EVALUATION 
23 
10.  
DESIGN 
23 
11.  
SELECTION OF VOLUNTEERS 
24 
11.1. INCLUSION CRITERIA 
24 
11.2. EXCLUSION CRITERIA 
25 
11.3. OTHER CONDITIONS 
26 
11.4. CODING SUBJECTS 
26 
12.  
MEDICATION 
27 
12.1. STUDY MEDICATION 
27 
12.1.1. Test Drug: 
28 
12.1.2. Reference Drug: 
28 
12.2. BLINDING 
28 
12.2.1. For Clinical Phase 
28 
12.2.2. For Analytical Phase 
28 
12.3. DOSAGE, DURATION OF TREATMENT 
28 
12.4. COMPLIANCE 
29 
12.5. HANDLING AND DRUG ACCOUNTABILITY 
29 
12.6. CONCOMITANT MEDICATION 
29 
12.7. RESCUE MEDICATION 
29 
12.8. STORAGE OF STUDY MEDICATION 
30 
13. STUDY PROCEDURE 
31 
13.1. GENERAL PROCEDURE 
31 
13.2. SPECIAL PROCEDURES 
33 
13.3. DAILY ACTIVITIES DURING THE TRIAL 
33 
13.4. RESTRICTIONS 
34 
13.5. DRUG ADMINISTRATION 
35 
13.6. DIETARY REGIMEN 
35 
13.7. BLOOD SAMPLING FOR DRUG ANALYSIS 
36 
13.8. ENDPOINT(S) FOR THE STUDY 
37 
14. PREMATURE DISCONTINUATION 
38 
14.1. WITHDRAWAL OF VOLUNTEERS 
38 
14.2. REPLACEMENT OF DROP-OUTS 
38 


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14.3. EARLY TERMINATION OF THE STUDY 
39 
14.4. DROP-OUT SAMPLES 
39 
15.  
ADVERSE EVENTS 
40 
15.1. DEFINITION OF ADVERSE EVENT / SERIOUS ADVERSE EVENT / ADVERSE DRUG REACTION / UNEXPECTED 
ADVERSE DRUG REACTION 
40 
15.2. RELATIONSHIP TO THE STUDY MEDICATION 
40 
15.3. REPORTING AND DOCUMENTATION OF ADVERSE EVENT(S) 
42 
16.  
STUDY DOCUMENTATION 
43 
16.1. INVESTIGATOR'S FILE 
43 
16.2. CASE REPORT FORM (CRF) 
44 
17.  
ANALYTICAL EVALUATION 
45 
17.1. REANALYSIS OF STUDY SAMPLES 
45 
17.2. INCURRED SAMPLE REANALYSIS 
45 
18.  PHARMACOKINETIC EVALUATION 
46 
19. 
STATISTICAL PROCEDURES 
47 
19.1. TARGET VARIABLES 
47 
19.1.1. Primary Target Variables 
47 
19.1.2. Secondary Target Variables 
47 
19.2. CALCULATION OF SAMPLE SIZE 
48 
19.3. RANDOMISATION 
48 
19.4. DOCUMENTATION OF THE DATA 
48 
19.5. INTERIM EVALUATION 
49 
20. 
ETHICAL CONSIDERATIONS 
50 
20.1. ETHICAL CONDUCT OF THE STUDY 
50 
20.2. ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
50 
20.3. VOLUNTEER INFORMATION AND INFORMED CONSENT 
51 
21. 
GOOD CLINICAL PRACTICE 
53 
21.1. LEGAL REQUIREMENTS 
53 
21.2. PREVENTIVE MEASURES TO REDUCE BIAS 
54 
21.3. INVESTIGATOR'S OBLIGATIONS 
54 
21.4. ADHERENCE TO THE PROTOCOL 
54 
21.5. DATA HANDLING PROCEDURES 
55 
21.6. MONITORING 
55 
21.7. AUDITING 
56 
21.8. CONFIDENTIALITY 
56 
21.9. INSURANCE 
57 
21.10. SUBJECT PAYMENT 
57 
21.11 QUALIFICATION OF THE INVESTIGATOR 
57 
22. 
PROTOCOL AMENDMENTS 
58 
22.1. PROTOCOL MODIFICATIONS 
58 
22.2. PROTOCOL VIOLATIONS 
58 
23. 
REPORTS 
59 
23.1. ARCHIVING 
59 
24. 
COMMUNICATION OF STUDY RESULTS 
60 
25.  CONTRACT AND COSTS 
60 
26. 
FINAL REGULATIONS 
61 
27. 
REFERENCES 
62 
28. 
LOCATION OF STUDY DOCUMENTATION 
64 
29. 
APPENDICES 
65 


Study Code: NOV2020/01923 
                                                   
 
 
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3.  RESPONSIBILITIES, SIGNATURES AND ADDRESSES 
We, herewith, confirm that the study protocol, CRFs and appendices contains all the information and rules necessary to 
conduct the study according to GCP regulations and that the study will be carried out and documented in complete 
compliance with this study protocol. The legal regulations and described agreements will be observed. The study 
medication will be used only for the purpose of the clinical trial. The clinical investigator will be informed about the 
pharmacological/toxicological tests and all new knowledge about the drug as well as about any newly occurring, hitherto 
unknown adverse events of test and reference drug. 
 
Principal lnvestigator: 
Prof. Dr. Muradiye Nacak 
FARMAGEN GCP Center                                                      
Phone: +90 342 360 62 62 
                                                                 
Fax: +90 342 360 64 57 
 
E-mail: m.nacak@farmagenarge.com 
 
Date and Signature:  
 
 
 
 
_________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: NOV2020/01923 
                                                   
 
 
      Date: 12.05.2020 
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Sponsor Representative:  
  
Ecz. Yasin Alp 
                                                                          Novelfarma İlaç San. Ve Tic. Ltd. Şti.   
Addresses: Saray Mah. Dr. Adnan Büyükdeniz Cad. 
Akkom Ofis Park No:2 Kelif Plaza Kat:19, 34768 
Ümraniye/İstanbul  
                                                                           Phone: +90 216 365 51 00 
                                                                           Fax: +90 216 365 51 10 
                                                                           E-mail: yasinalp@novelfarma.com 
 
  
Date and Signature:  
 
 
 
 
 
 
_________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Code: NOV2020/01923 
                                                   
 
 
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Project Manager:  
Onursal Sağlam 
          
Novagenix Bioanalytical Drug R&D Centre  
 
 
 
Phone: +90 312 398 10 81/117 
 
 
 
Fax: +90 312 398 07 18 
 
 
 
E-mail: osaglam@novagenix.com 
 
Date and Signature: 
 
 
 
_________________________________________ 
 
 
 
Bioanalytical Laboratory Manager: 
 
Berrak Güney 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                 
Phone: +90 312 398 10 81/138 
                                                                
Fax: +90 312 398 07 18 
 
Date and Signature:  
 
 
 
_________________________________________ 
 
 
 
 
 
Data Management Responsible:                
  Erkin Alkan 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                 
Phone: +90 312 398 10 81/126 
                                                                
Fax: +90 312 398 07 18 
 
Date and Signature:  
 
 
 
_________________________________________ 
 
 
 
 
 
Statistical Calculation Responsible:                             Emel Doğan Kurtoğlu, PhD. 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                 
Phone: +90 312 398 10 81/127 
                                                                
Fax: +90 312 398 07 18 
 
Date and Signature:  
 
 
 
_________________________________________ 
 
 
 
Quality Assurance Manager:                
Çiğdem Özer 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                
Phone: +90 312 398 10 81/125 
                                                                 
 
Fax: +90 312 398 07 18 
 
Date and Signature:    
 
 
 
 
________________________________________ 


Study Code: NOV2020/01923 
                                                   
 
 
      Date: 12.05.2020 
Clinical Study Protocol 
 
 
 
 
 
 
 
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4.  LIST OF ABBREVIATIONS AND TERMS 
AE / ADR  
Adverse Event / Adverse Drug Reaction 
ALP 
Alkaline Phosphatase 
ALT / AST  
Alanin- / Aspartate Aminotransferase 
AUC                              
Area under the curve 
AUC 0-24 
Area under the plasma concentration-time curve from zero up to 24 hours 
AUC0-tlast  
Area under the plasma concentration-time curve from zero up to the last measurable concentration 
AUC0-  
Area under the plasma concentration-time curve from zero up to infinity with extrapolation of the terminal 
phase  
BMI  
Body Mass Index (body weight in relation to height and age): 
 
   
weight (kg) 
 
BMI =     
height(m)2 
BP 
Blood Pressure 
Cmax 
Maximum plasma concentration 
CBC                             
Complete Blood Count 
CDER 
Center for Drug Evaluation and Research 
CPMP  
Committee for Proprietary Medicinal Products 
CRF  
Case Report Form 
CRO  
Contract Research Organization 
CV  
Coefficient of Variation 
DBP                             
Diastolic Blood Pressure 
EC  
Ethics Committee 
ECG  
Electrocardiogram 
EGFR 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration  
GCP  
Good Clinical Practice 
GGT  
Gamma-Glutamyl transferase 
GLP  
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HBsAg  
Hepatitis B Surface Antigen 
HBV                             
Hepatitis B Virus 
HCV                            
Hepatitis C Virus 
HCV-Ab 
Antibodies against Hepatitis C Virus 
HIV                              
Human Immunodeficiency Virus 
HIV-Ab  
Antibodies against Human Immunodeficiency Virus 
HR                             
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITF  
Investigator's Trial File 
LC 
Liquid Chromatography 
log  
Logarithmic 
MAOI 
Monoamine oxidase inhibitor 
MoH 
Ministry of Health 
MRT  
Mean Residence Time 
n  
Number (observations; volunteers; sampling points; etc.) 
NA 
Not Applicable 
PR  
Pulse rate 
PTH 
Parathyroid hormone 
SAE 
Serious Adverse Event 
SBP                             
Systolic Blood Pressure  
SD  
Standard Deviation 
SGOT                         
Serum Glutamic Oxaloacetic Transaminase 
SGPT                        
Serum Glutamic Pyruvic Transaminase  
SOP 
Standard Operating Procedures 
t1/2  
Terminal elimination half-life 
 tmax  
Time to reach maximum concentration 
 UADR 
Unexpected Adverse Drug Reaction  
 λz 
Terminal rate constant 
 


Study Code: NOV2020/01923 
                                                   
 
 
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5.  SUMMARY AND SCHEDULE FOR THE CLINICAL TRIAL 
5.1. Summary 
 
Title: 
Open-label, randomised, single oral dose, two-period, cross-over trial  
to assess to bioequivalence of Favira 200 mg Film Kaplı Tablet (Test 
Drug) in comparison with Avigan 200 mg Film Tablet (Reference 
Drug) in healthy male subjects under fasting conditions 
 
 
Study objective: 
The aim of this study is to evaluate the pharmacokinetic profiles and 
the relative bioavailability of favipiravir from the test product (Favira 
200 mg Film Kaplı Tablet, Novelfarma-Turkey) in comparison with 
the reference product (Avigan 200 mg Film Tablet, Toyama Chemical 
Industry Co Ltd.-Japan) under fasting conditions. The primary 
objective is to demonstrate the bioequivalence of test and reference 
products. 
 
  
Test Drug*:  
“Favira 200 mg Film Kaplı Tablet” containing 200 mg  favipiravir  
(Novelfarma-Turkey). 
 
 
 
*: This drug is manufactured by Pharma Plant İlaç San. ve Tic. Ltd. Şti. - 
Turkey  
  
Reference Drug**:  
 “Avigan 200 mg Film Tablet” containing 200 mg favipiravir (Toyama 
Chemical Industry Co Ltd.-Japan). 
 
 
 
 **: This drug is manufactured and licenced by Toyama Chemical Industry Co 
Ltd.-Japan.    
 
Dosage: 
Once daily 200 mg favipiravir in a period 
 
Indication: 
Bioequivalence study 
 
Study design: 
Single dose, open-label, randomised, two period, cross-over study. 
 
Variables: 
 Pharmacokinetics: 
 
  Primary variables: AUC0-tlast and Cmax of favipiravir 
                                       
Secondary variables: AUC0-, tmax, t1/2 of favipiravir 
 Safety and Tolerability: Adverse events, clinical laboratory, medical        
examinations 
  
Sample size: 
30 volunteers will be included. Drop-outs will not be replaced.   
  
 
 
Subject selection criterion:  20 - 40 aged healthy male volunteers. Normal weight according to the 
BMI. 
 
 
 
Blood sampling:  
 
The samples will be drawn in the clinical study period: at pre-
dose* and at 0.17, 0.25, 0.50, 0.75, 1.00, 1.33, 1.66, 2.00, 2.50, 3.00, 
3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 14.00, 24.00 hours post-dose (1 x 
8 mL each; totally 19 blood sample points) 


Study Code: NOV2020/01923 
                                                   
 
 
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* Note:  
1. Only in Period I; at t0 the blood sample amount will be 20 mL. 
2. 
Not to have difficulty to draw blood through catheter; the cannula 
will be kept patent by injecting approximately 0.5 mL of 5 IU/mL 
of heparin in normal saline solution at determined blood sampling 
points. In such cases, before collecting the blood samples at the 
first blood sampling points after heparin administration, first 0.5 
mL blood will be discarded. The aim of this procedure is to 
eliminate the possible effect of heparin on favipiravir analysis [for   
details see section 13.7 (Blood Sampling for Drug Analysis)] 
 
Route of   
Administration: 
 
Oral 
 
Duration of Treatment:  
9 days (approximately) including the wash out period of 48 hours and 
the time between last blood sampling in the last period to the final 
examination tests. 
 
Duration of Wash-out:  
At least 48 hours. 
 
 
Procedure:  
In the 1st period, each volunteer will receive after an overnight fasting 
in random order one single oral dose of 200 mg favipiravir product 
(either 1 tablet of the test drug or 1 tablet of the reference drug). Blood 
samples will be drawn immediately before the dosing and at 0.17, 0.25, 
0.50, 0.75, 1.00, 1.33, 1.66, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 
8.00, 10.00, 14.00, 24.00 hours after the dosing. In the 2nd period there 
will be the same procedure. 
 
Analysis of favipiravir: 
Plasma concentrations of favipiravir will be analysed in LC system. 
 
Statistical analysis: 
Statistical analysis will be performed using Phoenix WinNonlin 
(Version 8.1, Certara L.P.) or above. Analysis of Variance (ANOVA), 
two one-sided tests and 90% confidence intervals for the geometric 
mean ratios (test/reference) of Cmax and AUC0-tlast will be calculated. 
 
Acceptance range: 
Cmax 
: 80-125 % (ln-transformed) 
 
AUC0-tlast : 80-125 % (ln-transformed)  
Evaluation of 
bioequivalence: 
In order to investigate the bioequivalence of all products, the 90% 
confidence intervals will be calculated for the geometric mean ratios of 
test and reference for Cmax and AUC0-tlast of favipiravir. These 
confidence intervals will then be compared with the corresponding 
acceptance ranges. 
 
 
In order to achieve a better approximation to a normal distribution, 
Cmax and AUC0-tlast data for favipiravir will be logarithmically 
transformed (base e) before analysis. The sources of variation will be 
treatments, periods, sequences and subjects within the sequence. 
Evaluation of treatment, period, sequence and subject (nested within 
sequence) effects at 5% level of significance will be performed. From 
the result, the two one-sided hypothesis at the 5% level of significance 
will be tested by constructing the 90% confidence interval for the 


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geometric mean ratios of test/reference products. The confidence 
interval is calculated by retransformation of the shortest confidence 
interval for the difference of the ln-transformed mean values. 
Differences in tmax will be evaluated non-parametrically. 
 
Sponsor: 
 Novelfarma İlaç San. ve Tic. Ltd. Şti. 
   Representative: Ecz. Yasin Alp 
 
Protocol code: 
NOV2020/01923 
 
Phase: 
I (Bioequivalence study) 
 
Planned initiation: 
2Q 2020 (inclusion of first subject) 
 
Planned duration: 
9 days (approximately) including the wash out period of 48 hours and 
the time between last blood sampling in the last period to the final 
examination tests.   
 
Primary Endpoint:   
AUC0-tlast and Cmax favipiravir 
 
Secondary Endpoint:  
AUC0-∞, t1/2, tmax of favipiravir 
 
Safety Endpoints: 
Adverse events, clinical and laboratory examinations. 
 
Principal Investigator: 
Prof. Dr. Muradiye Nacak 
 
Co-investigators:             İsmail Taner Ezgi, MD 
                                        
  Erol Durucu, MD 
                                              Gaziantep Üniversitesi, FARMAGEN-GCP Center, Gaziantep- Turkey 
 
Analytical laboratory: 
Novagenix Bioanalytical Drug R&D Centre 
  
Esenboğa Yolu 25. km. Akyurt 
  
06970 Ankara, Turkey 
 
GCP statement: 
This study will be performed in compliance with Good Clinical Practice 
(ICH-GCP), the Declaration of Helsinki (with amendments) and local 
legal and regulatory requirements. 


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5.2. Schedule 
Estimated time frame for each step is given below: 
X -Contract signed 
Y -Ethics Committee and the Ministry of Health (MoH) approvals 
W -End of clinical part of trial 
Q -End of Analytical Analysis 
Z -End of Statistical Analysis 
 
Approvals:  
X + 1-1½ month 
 
Enrollment of volunteers:  
Y + ½ month 
 
Clinical trial, monitoring:  
Y + ½ months 
 
Evaluation of plasma samples:  
W + 2-3 months 
 
Data input, statistical evaluation  Q + ¼ month 
 
Final Report (Draft)  
 
Z + ½ month  
 


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6. STUDY FLOW CHART 
 
SCREENING AND ISOLATION 
PERIOD I 
PERIOD II 
*Final 
examination 
Study Day: 
1st DAY 
screening   
2nd  DAY 
(isolation) 
3rd  DAY 
(isolation) 
4th DAY 
(isolation) 
5th DAY 
Hospitaliz
ation day 
(Day 0) 
6th DAY 
1st  dosing 
day and 
blood 
sampling 
(Day 1) 
7th DAY 
blood 
sampling 
(t24.00) 
Wash-out 
day/  
(Day 2) 
8th DAY 
2nd   
dosing 
day and 
blood 
sampling 
(Day 3) 
9th DAY 
blood 
sampling 
(t24.00) 
(Day 4) 
9th DAY 
Final 
examination 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
Covid-19 PCR 
Test# 
● 
 
 
 
● 
 
 
 
 
● 
Inclusion criteria 
● 
 
 
 
 
 
 
 
 
 
Demography 
(Birth date, ethnic 
group, gender, 
height, weight, 
BMI) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Medical/Surgical 
history 
● 
 
 
 
 
 
 
 
 
 
HBsAg, anti-HCV, 
HIV 
● 
 
 
 
 
 
 
 
 
 
ECG 
● 
 
 
 
 
 
 
 
 
● 
Clinical 
examination 
(Physical 
examination) 
● 
 
 
 
 
 
 
 
 
 
● 
Clinical chemistry, 
haematology, 
urinalysis 
● 
 
 
 
 
 
 
 
 
● 
Blood pressure, 
pulse rate 
● 
● 
● 
● 
● 
 
● 
 
 
● 
Body 
temperature° 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Drug abuse 
screening** 
● 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
● 
 
 
 
 
 
 
 
 
 
Check of 
restrictions, diet 
 
 
 
 
● 
● 
● 
● 
 
 
Exclusion criteria 
and Withdrawal of 
volunteers 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Hospitalization 
day 
 
 
 
 
● 
 
 
 
 
 
Randomisation 
● 
 
 
 
 
 
 
 
Drug 
administration 
 
 
 
 
 
● 
 
● 
 
 
Blood sampling*** 
(0-24.00 h) 
 
 
 
 
 
● 
● 
● 
● 
 
 
Adverse event 
questioning**** 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
*  The final examination will be carried out on the day of last blood sampling . 
# Two Covid-19 PCR tests will be applied on screening day. 
° Body temperature monitoring will be performed at the following times: at “screening/isolation days”,  
  “hospitalisation day (Day 0)”, “during study period” and “final  examination”.  
**  For amphetamines, cannabinoids, benzodiazepines, cocaine, opioids, and barbiturates.  
***Blood sampling points (for each period): at pre-dose (20 mL only in Period I)  and at 0.17, 0.25, 0.50, 


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0.75, 1.00, 1.33, 1.66, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 14.00, 24.00 hours post-dose (1 x 8 
mL each; totally 19 blood sample points) 
Note:  
1. 
Only in Period I; at t0 the blood sample amount will be 20 mL. 
2. 
Not to have difficulty to draw blood through catheter; the cannula will be kept patent by injecting approximately 0.5 mL of 5 
IU/mL of heparin in normal saline solution at determined blood sampling points. In such cases, before collecting the blood 
samples at the first blood sampling points after heparin administration, first 0.5 mL blood will be discarded. The aim of this 
procedure is to eliminate the possible effect of heparin on favipiravir analysis. [for   details see section 13.7 (Blood Sampling 
for Drug Analysis)] 
****Adverse event questioning: at “screening/isolation days”, hospitalisation day (Day 0) and at  pre-dose, 
1.00, 4.00, 8.00, 14.00, 24.00 hours post-dose in each period.  


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7. INTRODUCTION 
7.1. Chemical and Pharmaceutical Properties 
 
Favipiravir is an antiviral compound with a wide range of antiviral activity against 
various influenza virus strains. Chemically, it is 6-Fluoro-3-hydroxypyrazine-2-
carboxamide and its molecular formula is C5H4FN3O2. Its molecular weight is 157.10. 
 
Figure 1. Chemical Structure of Favipiravir 
 
 
Favipiravir is a white to light yellow powder. It is sparingly soluble in acetonitrile and 
in methanol, and slightly soluble in water and in ethanol. 
 
 
7.2. Pharmacological Properties 
 
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.  
 
 
7.3. Pharmacokinetics 
 
Absorption and Distribution 
 
Following oral administration favipiravir reaches peak plasma concentrations in 
approximately 0.5 hours. After a single 200 mg dose of oral favipiravir tablet to 
Japanese healty volunteers Cmax and AUC0-t were 8.39 µg/ml and 19.67 µg.h/ml 
respectively. The Cmax of favipiravir was linear in the dose range from 30 to 1200 mg, 
while the AUC values at the dose of ≥600 mg remained higher than the value expected 
from the dose-proportional relationship. It is reported thah the pharmacokinetics in the 
dose range in which the pharmacokinetic profiles were linear were compared between 
healthy adult subjects in Japan and the US (when the doses were normalized on the 
basis of a body weight of 60 kg). 
 
When oral tablet of favipiravir was given with a high-fat meal a decrease in Cmax  and 
AUC was observed. 


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Favipiravir is 53.4%-54.4% bound to plasma proteins.  
 
Metabolism and Excretion 
Favipiravir M1 and glucuronide conjugate of favipiravir (M2) were found in the human 
plasma and urine obtained after single-dose administration.  
The elimination of favipiravir largely depends via renal excretion with a mean plasma 
elimination half-life (t½) of 1.5 hours.  
 
 
Some pharmacokinetics parameters of oral Favipiravir tablet are shown in the following 
table: 
 
tmax  
(h) 
Cmax 
(µg/mL) 
Protein binding 
(%) 
t½  
(h) 
Excretion  
0.5 
8.39 (200 mg single 
dose) 
53.4-54.4 
1.5 
via renal excretion 
 
 
     7.4. Indications 
 
Favipiravir is indicated for the treatment of highly pathogenic influenza virus infections 
(limited to patients in whom other influenza antiviral drugs are ineffective or not 
sufficiently effective) 
 
 
7.5. Contraindications 
 
Favipiravir is contraindicated in the patients with a history of hypersensitivity to 
favipiravir or any ingredient of the drug. Also it is contraindicated in women who are 
known or suspected as being pregnant. 
 
 
7.6. Adverse Reactions 
 
The main adverse events of favipiravir seen during the development of the product for 
influenza include mild to moderate diarrhoea, abdominal pain, headache and 
asymptomatic elevations of blood uric acid, decrease of neutrophil count, increase of 
AST (GOT), increase of ALT (GPT). 
 
 
 
 
 
 
 
 


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Adverse reactions observed in Japanese clinical studies and the global phase III clinical 
study (studies conducted with dose levels lower than the approval dosage) are shown in 
the table below with frequency. 
 
 
≥ 1%  
%0.5 - < 1 
< 0.5% 
Hypersensitivity 
 
rash 
eczama, pruritus 
Hepatic 
AST (GOT) 
increased,ALT (GPT) 
increased, 
γ-GTP 
increased 
 
Blood ALP 
increased, blood 
bilirubin 
increased 
Gastrointestinal 
Diarrhoea 
(4.79%) 
Nausea, 
vomiting, 
abdominal 
pain 
Abdominal 
discomfort, 
duodenal ulcer, 
haematochezia, 
gastritis 
Hematologic 
Neutrophil 
count 
decreased, 
white blood 
cell count 
decreased 
 
White blood cell 
count increased, 
reticulocyte count 
decreased, 
monocyte 
increased 
Metabolic disorders 
Blood uric 
acid increased 
(4.79%), 
blood 
triglycerides 
increased 
Glucose urine 
present 
Blood potassium 
decreased 
Respiratory 
 
 
Asthma, 
oropharyngeal 
pain, rhinitis, 
nasopharyngitis 
Others 
 
 
Blood CK (CPK) 
increased, blood 
urine present, 
tonsil polyp, 
pigmentation, 
dysgeusia, bruise, 
vision blurred, 
eye pain, vertigo, 
supraventricular 
extrasystoles 
 


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Clinically significant adverse reactions such as, shock, anaphylaxis, pneumonia, 
hepatitis fulminant, hepatic dysfunction, jaundice, toxic epidermal necrolysis (TEN), 
oculomucocutaneous syndrome (Stevens-Johnson syndrome), acute kidney injury 
decrease of white blood cell, neutrophil count and platelet count, neurological and 
psychiatric 
symptoms 
(consciousness 
disturbed, 
abnormal 
behavior, 
deliria, 
hallucination, delusion, convulsion, etc.) haemorrhagic colitis have been reported with 
other anti-influenza virus agents. 
 
 
7.7. Cautions and Precautions 
 
 
Administration of favipiravir should be started promptly after the onset of influenza-like 
symptoms. 
 
Favipiravir use is limited with cases in which other influenza antiviral drugs are 
ineffective or not sufficiently effective. 
 
Favipiravir should be administered with care in patients with gout or a history of gout, 
and patients with hyperuricaemia. 
 
Increase of plasma level of favipiravir has been reported in patients with liver function 
impairment in pharmacokinetic study. Necessity of the dose adjustment of favipiravir in 
those patients should be considered. 
 
Although the causal relationship is unknown, psychoneurotic symptoms such as 
abnormal behavior after administration of anti-influenza virus agents including 
favipiravir have been reported. 
 
In case of bacterial infection or suspected to be bacterial infection, appropriate measures 
should be taken, due to favipiravir is not effective in bacterial infections. 
 
7.8. Interactions 
In vitro drug-drug interaction 
(a)Inhibitory effect against human cytochrome P-450 (CYP) 
In the in vitro CYP inhibition study, the inhibitory effects of favipiravir against major 
human hepatic CYP isoforms (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) activity were 
investigated in human liver microsome. As a result, favipiravir inhibited the CYP2C8 
activity in a concentration-dependent manner. The metabolic activities of the other CYP 
isoforms in the presence of favipiravir at the maximum concentration were all ≥60% of 
the control. M1, the major metabolite of favipiravir, decreased the CYP2E1 activity to 
72.6% of the control at the maximum concentration, but hardly inhibited activities of 
other CYP isoforms for any isoforms. 
 
In the case of concomitant use of favipiravir with repaglinide, CYP2C8 substrate drugs, 
it cannot be ruled out that the risk of hypoglycemia, a serious adverse drug reaction, is 
increased. In the case of concomitant use of favipiravir with paclitaxel, it cannot be 
ruled out that the risk of white blood cell decreased and peripheral neuropathy, serious 
adverse drug reactions, is increased. 


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(b) Induction action on CYPs 
In the in vitro CYP induction study, the effects of favipiravir on human hepatic CYP 
isoforms (CYP1A2, 2C9, 2C19, 3A4) were investigated in fresh human primary 
hepatocytes. As a result, favipiravir increased the expression of the CYP isoforms up to 
1.7 times (mean) in the concentration range examined, and this induction rate of 
favipiravir was ≤6.6% of those of the positive controls (omeprazole, rifampicin). 
 
(c) Inhibitory effect against Aldehyde Oxidase (AO) 
In the in vitro inhibition study, the inhibitory effects of favipiravir against the AO 
activity were investigated in human hepatic cytosol. As a result, the residual metabolic 
activity (phthalazone formation activity) of phthalazine, a substrate of AO, decreased 
favipiravir concentration (20-6000 μmol/L) and preincubation time (0-60 minutes)-
dependently. the risk of concomitant use of favipiravir with AO inhibitors may not be 
high. Currently, a drug interaction study of favipiravir with raloxifene hydrochloride, an 
AO inhibitor, is under preparation, and if the risk of concomitant use is suggested by 
this study, precautions will be provided in the package insert.  
 
Based on the currently available pharmacokinetic data, drugs that act as AO substrates 
and would require special attention are hydralazine hydrochloride, which shows a high 
relative contribution of AO, and famciclovir and sulindac, whose effect may be 
decreased by concomitant favipiravir. 
A drug interaction study with hydralazine hydrochloride is under preparation, and if the 
risk of concomitant use is suggested by this study, precautions will be provided in the 
package insert. 
 
(d) Inhibitory effect against Xanthine Oxidase (XO) 
In the in vitro inhibition study, the inhibitory effects of favipiravir against the XO 
activity were investigated in human hepatic cytosol. As a result, favipiravir did not 
inhibit the metabolism of 1-methylxanthine, a metabolite of theophylline (substrate of 
XO), concentration or preincubation time-dependently. 
 
(e) Interaction with acetaminophen 
In the in vitro inhibition study, the inhibitory effects of favipiravir and M1 against 
acetaminophen metabolism were investigated in human liver S9. As a result, favipiravir 
did not inhibit the glucuronide conjugation metabolism of acetaminophen in the 
concentration range examined, but inhibited the sulfate conjugation metabolism. M1 did 
not inhibit glucuronide or sulfate conjugation metabolism of acetaminophen in the 
concentration range examined. Favipiravir is expected to be concomitantly used with 
acetaminophen in the treatment of influenza infection in many patients. The results from 
this study can serve as important information for clinical use of favipiravir and therefore 
should be included in the package insert for information provision. When the results are 
obtained from other interaction studies ongoing or to be conducted, relevant information 
should be provided to healthcare providers in clinical practice appropriately. 
 
 
 
 
 


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(f) Interaction with oseltamivir 
In the in vitro inhibition study, the inhibitory effects of favipiravir and M1 against 
oseltamivir metabolism were investigated in human liver S9. As a result, favipiravir 
inhibited deesterification of oseltamivir in the concentration range examined, but IC50 
values were high. M1 did not inhibit deesterification of oseltamivir in the concentration 
range examined. 
 
(g) P-gp transportation 
A membrane fraction from the human MDR1 expressing cells was used to investigate 
P-gp’s substrate recognition. As a result, favipiravir and M1 did not increase the 
adenosinetriphosphatase (ATPase) activity concentration-dependently, suggesting that 
neither of them will act as a substrate of P-gp.  
 
In vivo drug-drug interaction 
(a) Theophylline  
Favipiravir and/or theophylline were administered to 10 healthy adult Japanese male 
subjects. For combination therapy with theophylline, subjects received a certain 
regimen. Both favipiravir and theophylline were administered between the meals. It is 
found that the combination therapy with theophylline affected the pharmacokinetics of 
favipiravir and M1. On the other hand, both parameter ratios of theophylline fell within 
the above range. 
 
(b) Oseltamivir  
Favipiravir and/or oseltamivir phosphate were administered to 10 healthy adult 
Japanese male subjects in a certain regimen. Both favipiravir and oseltamivir phosphate 
were administered between the meals. There were no significant differences in the 
cumulative urinary excretion rate or CLr of M1 and oseltamivir carboxylate up to 12 
hours after dosing between the monotherapy and combination therapy. When any new 
relevant finding becomes available after marketing of favipiravir; however, it is 
necessary to provide the information to healthcare providers in clinical practice 
appropriately. 
 
(c) Oral Contraseptive 
In studies conducted according to the proposed dosage regimen, only 1 subject 
concomitantly used favipiravir and oral contraceptives and reported rhinitis and 
dysgeusia as adverse events, which were not considered specific to favipiravir or ethinyl 
estradiol. 
 
(d) Pyrazinamide 
Blood uric acid levels increased in all the subjects treated with favipiravir with 
pyrazinamide, although the effect on the blood drug concentration was not significant. 
As a serious adverse event, hepatic function abnormal was reported as well. Hence, it is 
necessary to collect post-marketing information about patients to whom favipiravir is 
administered in combination with pyrazinamide. 
 
 
 
 


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8.     OBJECTIVE OF THE TRIAL 
The aim of this study is to evaluate the pharmacokinetic profiles and the relative 
bioavailability of favipiravir of the Test Drug (Favira 200 mg Film Kaplı Tablet, 
Novelfarma-Turkey) in comparison with Reference Drug (Avigan 200 mg Film Tablet, 
Toyama Chemical Industry Co Ltd.-Japan) under fasting conditions. The primary objective 
is to demonstrate the bioequivalence of all products. 
 
9. BENEFIT-RISK EVALUATION 
For the approval of any product, its efficacy and safety has to be proved. There are two 
possibilities to do this for a new generic product: either by proving therapeutic equivalence or 
by proving bioequivalence with a marketed reference on the basis of comparison of relative 
bioavailability. The first option requires huge numbers of patients and a long period of 
administration of either the test or the reference product. A bioequivalence trial on the basis of 
bioavailability is therefore generally accepted as the better alternative. This trial is conducted 
with the aim to investigate whether any differences concerning the rate and extent of 
absorption exist between the test and the reference products. 
 
10.  DESIGN 
In this open-label, randomised, single-dose, two period, cross-over  study, 30 healthy male 
subjects (intention to treat population) will receive one single oral dose of 200 mg favipiravir 
(one tablet of the test drug or one tablet of the reference drug) after an overnight fasting in 
each period according to a sequence determined by randomisation [In each study period, 
subjects will take different products (either one dose of Test Drug or one dose of Reference 
Drug)]. 
Data of the subjects who have completed the study according to the Clinical Study Protocol 
(per protocol population for pharmacokinetic evaluation) will be used for analytical, 
pharmacokinetic and statistical evaluation. 
 
Test Drug: “Favira 200 mg Film Kaplı Tablet” is manufactured by Pharma Plant İlaç San. 
ve Tic. Ltd. Şti., Turkey and will be licensed by Novelfarma İlaç San. ve Tic. Ltd. Şti., Turkey. 
 
Reference Drug: “Avigan 200 mg Film Tablet” is manufactured and licenced by Toyama 
Chemical Industry Co Ltd.-Japan.    
 
In study period, the subjects will be admitted to the FARMAGEN Clinical Unit in the evening 
(18:00) prior to morning of the administration of medication after screening and isolation 
period as described in Appendix VII. 
  
Volunteers will be confined to the clinical unit and dosing will occur under conditions of 
hospitalization. Medications will be orally administered at approximately at 8:00 (t=0) 
after an overnight fasting (at least 10 hours in fasting). The lunch will be 4 hours post 
dosing and the dinner will be 10 hours post dosing. Blood sampling for the determination 
of favipiravir plasma concentrations will be drawn at specified time points. In study 
period including wash-out period, volunteers will be hospitalized in FARMAGEN Clinic 
Unit. After taking the last blood sample in 2nd period and carried out the post-study and 
final examination, the subjects will be allowed to leave the clinic. 
 
An overview of the study procedures is given in the Study Flow Chart provided in 
section 6. 


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11.  SELECTION OF VOLUNTEERS 
11.1. Inclusion Criteria 
Only volunteers fulfilling all of the following criteria should be enrolled in the present 
trial: 
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. 
 
 


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11.2. Exclusion Criteria 
Volunteers presenting any of the following exclusion criteria will not be included in the trial: 
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. 


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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.  
 
11.3. Other Conditions 
Diseases present at entry into the study are regarded as concomitant illnesses and 
generally as an exclusion criteria. Illnesses occurring during the study period 
(intercurrent illnesses) are to be regarded as adverse events and will be documented on 
a separate page (“adverse event form” and “drop-out sheet”) in the Case Report Forms 
(CRF) (see Appendix II). 
 
11.4. Coding Subjects 
 
The subject screening number will be also assigned as the subject code throughout the 
study. A volunteer code will be assigned to each subject. 


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12.  MEDICATION 
12.1. Study Medication 
The study medications will be supplied together with certificates of analysis by the 
company responsible for manufacturing the product, Pharma Plant İlaç San. ve Tic. 
Ltd. Şti.-Turkey. The packaging and labelling will be done according to the GMP and 
GCP requirements.  
The reference drug is manufactured and licenced by Toyama Chemical Industry Co 
Ltd.-Japan. All study drugs, together with relative documentation, will be supplied to 
FARMAGEN- Good Clinical Practice and Research Center by SPONSOR after 
approval of the study protocol by MoH. After arriving study drugs to clinical 
center, the clinic schedule will be determined. The delivery address for study 
medication is: 
 
Prof. Dr. Muradiye Nacak 
Gaziantep Üniversitesi FARMAGEN GCP Center 
Gaziantep Üniversitesi Teknoloji Geliştirme Bölgesi (Teknopark), 
Burç Yolu, Şahinbey 27260, Gaziantep-TURKEY 
 
 
 
 
 
   
 


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12.1.1. Test Drug: 
Active substance:  
Favipiravir 
Formulation: 
 
Film Coated Tablet for oral administration 
Strength: 
 
200 mg 
Manufacturer:                   
Pharma Plant İlaç San. ve Tic. Ltd. Şti.-Turkey 
 
Marketing Authorisation Holder:  
Novelfarma İlaç San. ve Tic. Ltd. Şti.-Turkey  
       Trade name: 
Favira 200 mg Film Kaplı Tablet  
       Batch Number: 
FAV-20/A 
       Expiry Date: 
03.2022 
       Storage requirements:      
Store below 25°C at room temperature. 
       Certificate of analysis: 
To be provided by the Sponsor together with medication 
 
 12.1.2. Reference Drug: 
Active substance:  
Favipiravir   
Formulation: 
 
Film Tablet for oral administration 
Strength: 
 
200 mg  
Manufacturer:                   
Toyama  Chemical  Industry Co.Ltd./Japan 
 Marketing Authorisation Holder: 
Toyama  Chemical  Industry Co.Ltd./Japan 
Batch Number: 
RF1042 
        Expiry Date: 
10.2022 
Trade name: 
 
 Avigan 200 mg Film Tablet  
Storage requirements:      
Store below 25°C at room temperature. 
Certificate of analysis: 
To be provided by the Sponsor together with medication 
   
  12.2. Blinding 
 
12.2.1. For Clinical Phase 
This trial is planned as open-labelled in clinical phase. Investigator will have the 
information of which subject will take which product [Test or Reference] in which 
period. Also, the subjects will have the information about the products which will be 
administered in each study period. 
12.2.2. For Analytical Phase 
This trial is planned as fully blinded in analytical phase. The exact list will be in a 
sealed envelope and this envelope will be opened at Novagenix in a “Project 
Evaluation Meeting” when all laboratory analyses are over. Once the sealed envelope 
is opened, no more reanalyse or data change/exclusion will be allowed. 
12.3. Dosage, Duration of Treatment 
 
 All volunteers will receive once daily either 200 mg favipiravir of the test drug (in 
one period) or 200 mg favipiravir of the reference drug (in one period) according to 
the randomisation table. The instructions for intake of the study medication are given 
in section 13.5 and separately on a sheet to be kept in the room where administration 
takes place.  


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12.4. Compliance 
On each day of administration and/or sampling the identity of the volunteer will be 
confirmed by checking the Identity Card. Administration of the study medication will 
be performed by the investigator or co-investigator and supervised by a second 
medical professional to ensure the correctness of drug administration. Also, a 
Novagenix personnel (monitor) will attend during this procedure. The administration 
of the study medication is to be followed by a mouth check, to be documented in the 
CRF and certified by the Investigator. 
12.5. Handling and Drug Accountability 
The study medication will be packed and labelled according to GMP requirements. 
The study medication will be provided by the Sponsor together with certificates of 
analysis in a sufficient quantity for the needs of the whole trial. The Sponsor is 
responsible for keeping an appropriate amount of each study medication at the facility 
in order to allow repeated pharmaceutical analysis.  
The investigator will confirm receipt of study medication in writing, including all 
follow-up supplies. The investigator will administer the study medication only to 
volunteers included in the study by following the procedures set out in the study 
protocol, as given in chapter 13.2. All drug supplies (test and reference medication, 
unused medication, empty blisters) have to be returned to sponsor after completion of 
the study. It is not allowed to use the study medication for any other purpose. 
12.6. Concomitant Medication 
Concomitant medication is generally not allowed for the duration of the trial. If this is 
considered  necessary for the volunteer's welfare, it may be given at the decision of the 
investigator. The volunteers have to inform the investigator about any intake of other 
drugs in the course of the trial. If necessary, for the treatment of ordinary pain (e.g. 
headache), some analgesics  which have no drug interaction with study products, may 
be given by investigator.  Any intake of concomitant medication has to be documented 
in the Case Report Form (“concominant medication form”, “adverse event form” and 
“drop-out sheet”) specifying the substance, dose, time and reason for use of 
concomitant medication and may be regarded as an exclusion criterion. 
12.7. Rescue Medication 
No specific rescue medication is planned for the present trial since it is not a 
therapeutic trial and the safety / tolerability profiles of the administered drug substance 
are well known. 


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12.8. Storage of Study Medication 
The investigator will be responsible for proper storage of the investigational products. 
All drug supplies must be stored in a dry place at room temperature and separately 
from normal hospital/practice stocks, locked and only accessible for authorized 
personnel, in accordance with the manufacturer's instructions. All supplies must be 
accounted for at the end of the study. A drug inventory form is to be filled in for this 
purpose. 


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13. STUDY PROCEDURE 
13.1. General Procedure 
Volunteers eligible for inclusion within the age limits as defined in section 11.1 will be 
asked for informed consent as described in Appendix VII due to the Covid-19 
outbreak precautions and as described in section 20.3 and will be thereafter screened 
with respect to inclusion and exclusion criteria.  
The initial examination will be carried out on the day of the beginning of the isolation 
as described in Appendix VII. The standard clinical screening includes demographic 
data, brief anamnestic data (medical history with information about relevant previous 
diseases of all body systems), physical examination, determination of body 
temperature, weight and height, standard ECG (12 lead), measurements of blood 
pressure (BP) and pulse rate (PR) after 5 minutes supine rest. 
The standard laboratory screening includes serum levels of “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”. The blood specimen (20 mL# for entry and 12 mL for final) for 
the safety laboratory will be taken under fasting conditions. Total blood sampling for 
both laboratory examinations (entry and final) will be 32 mL. The volunteers will also 
be checked for presence of HBsAg, HCV-Ab and HIV-Ab in serum and Covid-19 
PCR test.  
Clinical laboratory tests will be performed using the auto analyser at a contracted and         
certified laboratory (GAMA Tıp Laboratuvarı-Gaziantep). Covid-19 PCR test will 
be performed at “FARMAGEN-GCP Center, Gaziantep- Turkey”.  
#  At entry examination the blood sample amount will be 20 mL and 8 mL sample of 
20 mL sample will be divided into tubes and one of this tube will be used for the anti-
coagulant validation purpose during the analytical validation process. This plasma 
sample will send to Novagenix with master and back-up samples. 
The following parameters are determined in urine (30 mL): pH, protein, glucose (semi 
quantitatively by means of strip test), ketones, blood, leukocytes, bilirubin, nitrites. If 
the strip test for any urine parameter is positive, a microscopic examination of the 
sediment has to be done. 
At screening volunteers will be requested to provide a urine sample for a drug screen 
which will include “amphetamines, cannabinoids, benzodiazepines, cocaine, opioids 
and barbiturates” and for an alcohol breath test. All laboratory tests will be carried out 
in a certified local laboratory. A list of the normal ranges and units of measurement of 
the laboratory parameters to be determined during the study and the certificate of the 
laboratory will be provided by the investigator before the start of the study. The 
reference ranges and the results of the individual laboratory examination will be 
documented in each CRF. The investigator will be provided with a print-out or 
authorized copy of the original laboratory values. 
If in the course of initial screening any clearly pathological value (laboratory value 
outside reference range, clinically relevant or significant) is observed, this finding will 
be regarded as an exclusion criterion. 


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Laboratory values outside the normal range will be judged by the investigator in a 
written form in the CRF. Single laboratory values outside the normal range will 
generally not be regarded as an exclusion criterion provided that: 
a) they are not accompanied by clinical symptoms, 
b) the context of related laboratory values gives no indication of a pathological 
process and 
c) the investigator regards them as clinically irrelevant in written form in the CRF. 
If any positive result in Covid-19 PCR test is observed, the volunteer will be 
transfer to Gaziantep University Şahinbey Research Hospital, Emergency 
Department* under appropriate conditions immediately. This finding will be 
regarded as an exclusion criterion.  
*Contact Physician: Prof. Dr. Şevki Hakan EREN 
 Gaziantep University Şahinbey Research Hospital,  
  
 
 
          Emergency Department 
  
GSM: 0506 2379579 
The test and reference product will be administered under fasting conditions each in 
a randomised manner in two-period with at least 48 hours wash-out 
period.Volunteers will be treated under hospitalization conditions in study period and 
will be hospitalised at the Clinical Facility (FARMAGEN-Good Clinical Practice and 
Research Center)  from the evening of  Day 0 (hospitalization day) normally until 
taking the last blood sample in 2nd period and carried out the post-study and final 
examination to ensure subjects’ safety as well as standardised trial conditions during 
profiling days (e.g. in view of food and fluid intake, diet, fasting conditions, drug 
administration, clinical and other procedures). Adverse events will be monitored 
throughout the study. The medical care of the volunteers will be guaranteed by the 
presence or stand-by of the investigator or one of the co-investigators throughout the 
clinical phase of this trial. 
The volunteers will come to the clinic from isolation, described at Appendix VII, at 
approximately 18:00 on the day before the treatment (Day 0) and will remain there for 
90 hours. A measurement of body temperature will be performed once a day in the 
mornings during the study period.They will not be allowed to drink water between 1 h 
before to 1 h after administration, except while dosing (the total intake of water on the 
days of dosing will be maximum 1.5 L). The investigator will check on each 
volunteer's wellbeing prior to their discharge from the clinic. If necessary, some 
volunteers will remain at the clinic until any adverse events have resolved. All 
volunteers will be subjected to a post-study and final examination and laboratory tests 
on the day of  last sampling in second period. 
For each volunteer being withdrawn from the study prior to regular termination of the 
individual study period, due to whatever reason, a complete final examination has to 
be performed at the time of withdrawal as far as possible with regard to the volunteer's 
health conditions and as far as necessary with regard to safety aspects. All taken 
plasma samples will be analysed. But will not be included to statistical 
calculations. 


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13.2. Special Procedures 
Special procedures due to the Covid-19 outbreak will be done as described in 
Appendix VII. 
Study drugs will be administered on the Day 1 and Day 3 (as given in the Study Flow 
Chart provided in section 6). The subjects will be fasted overnight (minimum of 10 
hours) and administrations will take place in the morning approximately  at 08:00 a.m. 
and the exact time will be recorded on CRFs. 
The subjects will remain fasting until 4 hours after administration. Subjects are not 
allowed to drink water from 1 h before until 1 h after administration, except that 
while dosing. Subjects will be dosed in sitting position and they will be instructed to 
remain in sitting position in bed for 4 hours after drug administration without lying in 
bed for each period . In this interval (t0.17-t4.00); the blood samples will be performed 
in bed and lunch will be provided on bed.  
During this study all clinical unit personal will be checked daily by Covid-19 PCR test 
for safety 
 
13.3. Daily Activities during the Trial 
Entry examination: 
The entry examination will be carried out on the day of screening of the trial as 
described in Appendix VII. The following parameters will be documented: 
 
Written Informed consent 
 
Inclusion criteria (according to protocol) 
 
Exclusion criteria (according to protocol) 
 
Demographic data (date of birth, height, weight, gender, BMI) 
 
Anamnestic data (medical history, relevant previous diseases) 
 
Clinical screening and examination (clinical state: body temperature, BP, PR, 
ECG, registration of pathological findings, if any, clinical chemistry, Covid-
19 PCR test, haematology, HBsAg, HIV-Ab, HCV-Ab, drug screening, 
alcohol breath test,  urinalysis). 
Period 1: 
 Interview (possible presence of exclusion criteria and/or adverse events)  
 Standardised dinner will be served before dosing on day 0 (between 18:00 p.m. to  
 21:00 p.m.) 
 Blood samples will be collected before dosing on day 1 with separation of plasma. 
 Treatments will be given according to randomised administration [single oral dose of 
1 tablet of the test drug or 1 tablet of the reference drug] with compliance check 
(approximately 08:00 a.m.)   
 Blood sampling (0.17-24.00 hours) will be done after drug administration with 
separation of plasma 
 Standardised lunch will be served at 4 hours after the dosing (between 12:00 p.m.  
to 13:00 p.m.) 


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 Standardised dinner will be served at 10 hours after the dosing (between 18:00 p.m. to 
19:00 p.m.) 
 Standardised light breakfast will be served at approximately 21.30 pm. 
 Questioning for and registration of adverse events at hospitalisation day (Day 0), pre 
dose and 1.00, 4.00, 8.00, 14.00, 24.00 hours post-dose*.  
 Standardised breakfast, lunch, dinner and light breakfast will be served on Day 2 
(including wash-out period)  
Note: Covid-19 PCR test will be done at Day 0. 
 
Period 2: 
 Interview (possible presence of exclusion criteria and/or adverse events)  
 Standardised dinner and light breakfast will be served before dosing day  (at 18:00 
p.m. and 21:30  p.m.respectively) 
 Blood samples will be collected before dosing with separation of plasma. 
 Treatments will be given according to randomised administration [single oral dose of 
1 tablet of the test drug or 1 tablet of the reference drug] with compliance check 
(approximately 08:00 a.m.)   
 Blood sampling (0.17-24.00 hours) will be done after drug administration with 
separation of plasma 
 Standardised lunch will be served at 4 hours after the dosing (between 12:00 p.m.  
to 13:00 p.m.) 
 Standardised dinner will be served at 10 hours after the dosing (between 18:00 p.m. to 
19:00 p.m.) 
 Standardised light breakfast will be served at approximately 21.30 pm. 
 Questioning for and registration of adverse events at hospitalisation day (Day 0), 
pre dose and 1.00, 4.00, 8.00, 14.00, 24.00 hours post-dose*.  
 Standardised breakfast and lunch will be served on day 4. 
 Discharge from the clinic (after final examinations) 
 
Final examination: 
 
The final examination will be carried out on the day of last blood sampling of the 2nd 
period. The following parameters will be documented: Interview (occurrence of adverse 
events) 
 
Clinical screening and examination (clinical state: body temperature, BP, PR, ECG, 
registration of pathological findings, if any, clinical chemistry, Covid-19 PCR test, 
haematology, urinalysis) 
 
Laboratory screening. The sampling for laboratory screening can be performed together 
with the last sampling for the kinetic profile in 24 hours post-dose. Abnormal laboratory 
findings which are judged by the investigator as adverse event at the final examination 
should be followed up until it will be resolved or is assessed as stable condition or a 
causality other than trial medication was found and whole data that collected during the 
entry examination, study period and final examination will be documented in the 
CRF.  
13.4. Restrictions 
The volunteers will be requested not to undertake vigorous exercise during the 2 days before 
the initial screening laboratory tests until after the final laboratory safety tests. 


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When confined to the clinical centre, the volunteers have to avoid from alcohol starting one 
week before hospitalization day until the last blood sampling of period. Smoking will not be 
permitted during the study of blood sampling during hospitalization of study. Chewing gum is 
not allowed. No foods and beverages containing caffeine or other methylxanthines (coffee, tea, 
coke, chocolate) and fruit-juice from 2 days prior to dosing until the last blood sampling of 
study will be allowed. No grapefruit containing products from 7 days prior to the dosing until 
the last sampling will be allowed. The volunteers will abstain from food and beverages from 
21:00 on the hospitalization evening until final examination.(Subjects will not be allowed to 
drink water between 1 h before to 1 h after administration, except while dosing).The total 
intake of water on the days of dosing during hospitalization will be maximum 1.5 L, beginning 
1 hour post-dosing. 
For the ambulatory phases of the study, volunteers will be requested to abstain from alcohol 
containing foods and beverages for the study starting 24 hours before the initiation  of the 
study until confinement to the clinic. Upon admission to the clinic for study, all volunteers will 
undergo an alcohol breath test and drug screening in the urine (see 13.1). Volunteers with a 
positive result of the test will be discontinued from the study. 
 
13.5. Drug Administration 
 
The following treatments will be administered: 
Test Drug; Favira 200 mg Film Kaplı Tablet (Novelfarma-Turkey) 
Reference Drug; Avigan 200 mg Film Tablet (Toyama  Chemical  Industry 
Co.Ltd./Japan)  
 
The precise instructions for drug administration are given in Ethical Committee (EC) 
and Ministry of Health (MoH) submission file. 
 
Immediately after pre-dose sampling, the volunteers will swallow 1 tablet of the test 
drug or 1 tablet of the reference drug (favipiravir each case) with 240 mL water. After 
the washout period; in Period II, the subjects will be administered by the other 
drug that they will not administered in the Period I.  
 
This will be followed by a mouth check. The investigator or the co-investigator will 
administer the study medication and this will be supervised by a second medical 
professional to ensure the correct drug administration.  
 
The subjects will be dosed in ascending numerical order according to the 
randomisation list whilst sitting position and they will be instructed to remain in 
sitting position in bed for 4 hours after drug administration without lying in bed for 
each period. In this interval (t0.17-t4.00); the blood samples will be performed in bed and 
lunch will be provided on bed. 
 
13.6. Dietary Regimen  
An evening meal (total caloric value of approximately 1200 kcal) will be served no 
later than 21:00 in the 1st hospitalization day (Day 0) in study.  
Period I and Period II: In treatment day (Day 1 and Day 3); 
A standard lunch (total caloric value is approximately 1200 kcal) will be provided 
4 hours after dosing in study.  


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A standard evening meal (total caloric value is approximately 1200 kcal) will be 
provided 10 hours after dosing in study.  
A standardised light breakfast will be served approximately 21:30 p.m. 
Also standard breakfast, standard lunch, standard evening meal and a standardised 
light breakfast will be served in Day 2. In 4th day of the study standard breakfast and 
lunch will be served.  
The same meal composition has to be served in all study of the trial. This will be 
documented in the CRF. 
 
13.7. Blood Sampling for Drug Analysis 
 
Venous blood will be drawn at the following times:  
Period 
Day 
Time (hour)* 
Tube No 
1-2 
1 
t0.00 
P01 
t0.17 
P02 
t0.25 
P03 
t0.50 
P04 
t0.75 
P05 
t1.00 
P06 
t1.33 
P07 
t1.66 
P08 
t2.00 
P09 
t2.50 
P10 
t3.00 
P11 
t3.50 
P12 
t4.00 
P13 
t5.00 
P14 
t6.00 
P15 
 
t8.00 
P16 
t10.00 
P17 
 
t14.00 
P18 
2 
t24.00 
P19 
 
* In the statistical analysis, if the deviation in the planned sampling time is 1 minute and within the 
range of ± 5%   deviation, the values will be used without any correction. 
8 mL blood samples will be drawn at predetermined sampling times during the clinical study 
to determine plasma favipiravir concentrations.  
Note: Only in Period I; at t0 the blood sample amount will be 20 mL and this sample will be 
divided into tubes and one of this tube will be used for the anti-coagulant validation purpose 
during the analytical validation process. This plasma sample will send to Novagenix with master 
and back-up samples. 
The blood samples will be taken by a short intravenous catheter. The blood samples 
will be collected into polypropylene tubes using K2 EDTA as anti-coagulating agent. 
The total amount of blood taken from each subject will be approximately 358 mL. 
[Including “The Heparinised Discarded Blood (approximately 10 mL during the 
study)”,“Blood for Entry/Final examinations Tests (*approximately 32 mL)”and “Other 
Repeat Clinical Laboratory Tests that may be deemed necessary during the study”]. 


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*At entry examination the blood sample amount will be 20 mL and 8 mL sample of 20 mL sample will 
be divided into tubes and one of this tube will be used for the anti-coagulant validation purpose during 
the analytical validation process. This plasma sample will send to Novagenix with master and back-up 
samples. At final examination the blood sample amount will be 12 mL and only will be used for clinical 
laboratory tests. 
After sampling the blood samples for pharmacokinetic analysis, the tubes will be immediately 
refrigerated at 2 - 8°C and will remain there for not more than 30 minutes. After centrifugation (3.000 
rpm, 4 - 6°C, 10 min), the separated plasma from each sample will be transferred into two 3 mL 
transparent, polypropylene tubes per sample (at least 1.5 mL per tube). All the aliquoted plasma 
samples will be flash freezing immediately. The flash frozen samples (aliquoted plasma samples) 
will be transferred to a deep-freezer and stored at -70°C.  
 
At the end of the study one aliquot will be shipped on dry ice (solid CO2) according to 
the sample transport SOP of FARMAGEN-Good Clinical Practice and Research 
Center by courier for the determination of plasma drug concentrations to the analytical 
laboratory: 
Novagenix Bioanalytical Drug R&D Centre  
Esenboğa Yolu 25. Km.  
Ankara-Turkey 
 
As precautionary measure, the other aliquot will at first be retained at the clinical unit 
in case that any adverse conditions, for example due to transport damage of the first 
shipment.Once the bioanalytical laboratory confirms receipt of the first shipment, the 
second set of aliquots will be sent. 
The samples will be packed on dry ice for transport, no interruption of the freeze chain 
is allowed and also data loggers will be included for temperature recording. 
All labels for blood and plasma samples will be provided by NOVAGENIX and will 
contain the following information: active ingredient name, study code, subject number, 
period, tube number and time (e.g. 2 h post-dosing). An example is given below: 
Favipiravir 
Study # :    NOV01923 
Subj #    1 
Period : 1 
Time: 0 h  P # : P1 
 
13.8. Endpoint(s) For The Study 
 
Primary Endpoint: AUC0-tlast and Cmax of favipiravir. 
 
Secondary Endpoint: AUC0-∞, t1/2, tmax of favipiravir. 
 
Safety Endpoints: Adverse events, clinical and laboratory examinations. 


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14. PREMATURE DISCONTINUATION 
The conditions for premature discontinuation of the trial in some particular volunteers 
or in general are summarized in this chapter. 
 
       14.1. Withdrawal of Volunteers 
Volunteers may be withdrawn for the following reasons: 
 at their own request with or without giving reasons, 
 at the discretion of the investigator for reasons of medical prudence. 
In either event, the Sponsor will be immediately notified and the date and reasons for 
the withdrawal will be clearly stated in the volunteer's CRF. 
      Volunteers must be withdrawn under the following circumstances: 
 if personal circumstances suggest that the visits required by the protocol cannot be 
guaranteed any longer, 
 if Covid-19 PCR test result is positive, the volunteer(s) will be dropped out from 
study. 
 if adverse events (including intercurrent illnesses) develop, which rule out 
continuation of the study medication, or, due to impaired validity of the results, make 
it appear inadvisable to further participate in the study , 
 if subjects who have intaked or administrated of any prescribed systemic or topical 
medication (including OTC medication) within 2 weeks of the start of the study 
(except singles doses of analgesics which have no drug interaction with study 
products) given in case of an adverse event (e.g. headache) during the study, 
 if circumstances defined as exclusion criteria are registered, 
 if administration of any drug is necessary, which is not permitted according to the 
exclusion criteria (see section 11.2), independently of its necessity due to the 
occurrence of adverse events (including intercurrent illnesses) or of its use due to other 
reasons, 
 if vomiting occurs at or before 2 times median tmax.  
 if diarrhea exists during screening and /or medication day. 
 
14.2. Replacement of Drop-outs 
 
A total of 30 volunteers will be enrolled in the trial. If drop-out exists in isolation or in 
study period, then these dropouts WILL NOT BE replaced.  
For each volunteer being withdrawn from the study prior to regular termination of the 
individual study period, due to any reason, a complete final examination has to be 
performed on the day of drop-out, as far as possible with regard to the volunteer's 


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health conditions and as far as necessary with regard to safety aspects and the validity 
of study results. The reason for withdrawal has to be documented in the case report 
form and in the volunteer's medical records. 
 
14.3. Early Termination of the Study 
 
The Sponsor may discontinue the study at any time. 
If, in the opinion of the investigator, the clinical observations in the study suggest that 
it might not be justifiable for medical reasons to continue, she/he may terminate the 
study after consultation with the Sponsor or the Sponsor may terminate the trial for 
safety, administrative or other reasons. 
Reasons for discontinuation have to be documented appropriately and to be provided 
to the Sponsor and the Ethics Committee and MoH. In case of premature 
discontinuation of the study a complete final examination has to be performed for each 
volunteer as far as possible with regard to the volunteer's health conditions and as far 
as necessary with regard to safety aspects and the validity of study results. 
 
14.4. Drop-out Samples 
All drop-out samples which will be sent by the clinic will be analysed and results will 
be given in the Final Study Report. 
 


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15.  ADVERSE EVENTS 
 
15.1. Definition of Adverse Event / Serious Adverse Event / Adverse Drug 
Reaction / Unexpected Adverse Drug Reaction 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product which does not 
necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medical product, whether or not considered related to the medical product. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
results in death 
 
is life-threatening 
 
results in persistent or significant disabling/ incapacity 
 
requires inpatient hospitalization 
 
prolongs inpatient hospitalization 
 
is a congenital anomaly/birth defect 
An adverse event is defined as an Adverse Drug Reaction (ADR) if further analyses 
prove that the adverse event was caused or partially caused by the study medication: 
In the pre-approval clinical experience with a new medicinal product or its new usage 
all noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reaction. The phrase ''responses to a medicinal product'' 
means that a causal relationship between a medicinal product and an adverse event is 
at least a reasonable possibility, i.e. the relationship cannot be ruled out. 
Unexpected Adverse Drug Reaction (UADR) is an adverse reaction, the nature or 
severity of which is not consistent with applicable product information (e.g., 
Investigator's Brochure for an unapproved experimental medicinal product, summary 
of product characteristics for an approved product) or events previously unobserved or 
undocumented which are not on the basis of what might be anticipated from the 
pharmacological properties of a medicinal product. 
In the course of the study, the investigator will determine whether any adverse events 
have occurred and will grade their intensity as follows: 
- Mild:  
Awareness of symptoms but easily tolerated 
- Moderate:  Discomfort enough to cause interference with usual activity 
- Severe:  
Incapacitating with inability to work or to carry out usual activity. 
15.2. Relationship to the Study Medication 
The investigator will make judgement considering whether or not, in his opinion, the 
adverse event was related to the drug according to the following classification. 
However, even if the investigator feels that there is no relationship to the drug, the 
adverse event should be reported. 


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The likelihood of the relationship of adverse event to the study drug is to be recorded 
as follows. 
Causality assessment of suspected adverse reactions (criteria defined by members of 
WHO Drug Monitoring Programme): 
Certain:  A clinical event, including laboratory test abnormality, which occurs in a 
plausible time relationship to drug administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (de-challenge) should be clinically plausible. The 
event must be definitely pharmacological or phenomenological, using a 
satisfactory re-challenge procedure if necessary. 
Probable/likely: A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and on which a 
clinically reasonable response on withdrawal (de-challenge) follows. Re-
challenge information is not required to fulfil this definition. 
Possible: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information on 
drug withdrawal may be lacking or unclear. 
Unlikely: A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanation. 
Conditional/unclassified: A clinical event, including laboratory test abnormality, 
reported as an adverse reaction, about which more data is essential for a 
proper assessment or the additional data are under examination. 
Unassessable/unclassified: A report suggesting an adverse reaction which cannot be 
judged because information is insufficient or contradictory, and which cannot 
be supplemented or verified. 
 


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15.3. Reporting and Documentation of Adverse Event(s) 
AEs/ADR will be assessed by spontaneous, unsolicited reports of the volunteers, by 
observation and by routine open questionings of the volunteers. Questionings will be 
done by experienced staff of FARMAGEN-Good Clinical Practice and Research 
Center during admission to the clinical facility and at least at the following times of 
each study period: at Day 0, pre dose and t1.00, t4.00, t8.00, t14.00, t24.00 hours after the 
drug administration. If any adverse event occurs, it will be recorded on the Adverse 
Event Report page of the CRF. All findings will be recorded in English. The 
documentation includes type of AE/ADR, date and time of onset, treatment initiated (if 
applicable), outcome, intensity/severity code (mild, moderate, severe) and whether the 
event is serious. It is important that the investigator immediately reports any adverse 
event which by the definitions given above would be considered serious, even if the 
investigator does not consider the adverse event to be clinically significant or drug-
related.  
Occurrence of any serious adverse event has to be reported by the investigator 
immediately (within 24 hours), the latest on the next working day, by phone and e-
mail and/or by fax to Novelfarma İlaç San. ve Tic. Ltd. Şti. or to Novagenix 
Bioanalytical Drug R&D Centre as an initial report. 
As soon as new information about the SAE becomes known, the investigator has to 
forward it without any delay to Novelfarma İlaç San. ve Tic. Ltd. Şti. or to 
Novagenix Bioanalytical Drug R&D Centre. This applies to the follow-up and/or 
final SAE report and all medical records associated with it. 
A copy of the updated CRF-page for AE documentation will be forwarded to 
Novagenix Bioanalytical Drug R&D Centre or Novelfarma İlaç San. ve Tic. Ltd. 
Şti. as soon as possible. 
The responsible sites for the upper procedure are: 
Novelfarma İlaç San. ve Tic. Ltd. Şti. 
Sponsor Responsible  
Novagenix Bioanalytical Drug R&D Centre 
CRO Project Responsible 
Ecz. Yasin Alp 
Phone: +90 216 365 51 00 
Fax:+90 216 365 51 10 
GSM: +90 532 474 51 00 
E-mail: yasinalp@novefarma.com   
Onursal Sağlam 
Phone: +90 312 398 10 81/117 
Fax: +90 312 398 07 18 
GSM: +90 530 149 42 55 
E-mail: osaglam@novagenix.com 
Serious adverse events will be reported to sponsor and/or CRO by investigator 
immediately. After that, sponsor and/or CRO will report to the EC, MOH and to the 
regulatory authorities of the study site according to the local legal requirements in 7 
days. 
Serious Adverse Events which occurred within two weeks after termination of the 
clinical trial and which are considered to be related to the trial must also be reported. 
Any Adverse Event which is not resolved at the final visit should be followed-up until 
it will be resolved or assessed as a stable condition or causality other than the trial 
medication has been found. 
 
 


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           16.  STUDY DOCUMENTATION 
16.1. Investigator's File 
The investigator Trial File of the study will be included at least the following documents: 
1. Investigator and co-investigator's curriculum vitae  
2. Correspondence including relevant notes from telephone contacts 
3. List of monitoring visits/audit visits/inspections 
4. Signature sheet of clinical team 
5. Final volunteer information and informed consent form and volunteer identification 
    5.1 Signed informed consent forms 
    5.2 Sample Volunteer information and informed consent with any translation 
    5.3 Volunteer identification (screening log, identification list) 
6. Test and Reference Products 
    6.1 Drug accountability sheets (receipt, dispense, return) 
    6.2 Shipment, receipt, return, etc. 
6.3 Sample of labels attached to investigational product(s) containers  
7. Investigational products accountability at the site 
8. Trial Material (orders, deliveries, shipments, return and disposal if applicable) 
9. Study Protocol 
10. Special instructions concerning the conduct of the study, if available 
11. Sample CRF book 
12. Analytical Study Plan 
13.Hematology, 
Biochemistry 
and 
Serology 
tests’ 
normal 
ranges 
and 
certification/accreditation of Test's Laboratory 
14. Safety Documentation 
     14.1 Documentation of SAE reports 
      
14.2 Safety overviews: periodic reports sent to EC and MOH (country specific/whole 
study) 
      14.3 Erroneous SAE reports 
15. EC and MoH approval 
16. Insurance statement and conditions 
17. Subject screening and enrolment log 
18. Subject identification code list 
19. Regulatory Authority Approval/Notification (if applicable for the centre) 
20. GCP statement of investigator, personnel responsibilities signatures and CVs 
21. Financial arrangements and contracts with sponsor/investigator/CRO 
22. Product information (Investigator' Brochure or Summary of Product Characteristics) 
23. ICH-GCP Guidelines and local law (if applicable) 
24. CRFs of volunteers screened but not randomised (copies) 
25. CRFs of volunteers enrolled in the study in ascending order (copies), source  
Documents 
26. According to ICG GCP   a  copy of site initiation report should be added in Investigator’s 
site File 
 


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16.2. Case Report Form (CRF) 
NOVAGENIX will design the Case Report Form in close co-operation with the 
Sponsor. Standardized CRFs will be used as source document regarding volunteers' 
raw data during the course of the study. The investigator will assure that all data are 
entered promptly, legibly, completely, accurately and in accordance with other source 
documents (e.g. ECGs, laboratory results, diet and fluid intake records). This 
procedure will be applied to the data of both volunteers who met the inclusion 
criterion and will be included into the study and the volunteers that will not be 
included into the study because of a valid reason.  
To ensure legibility, the CRFs should be filled out only with a blue ball-point. 
Any corrections to the CRFs must be carried out by the investigator or his designate. A 
single stroke must be drawn through the original entry. The reason for the correction 
has to be given and it has to be dated and initialled. Incorrect entries must not be 
covered with correcting fluid, or obliterated, or made illegible in any way. 
Even if there are no changes from a previous examination, in the interests of 
completeness of data acquisition, the questions which are repeated in each section of 
the CRFs should be answered in full text. A reasonable explanation must be given by 
the investigator for all missing data. 
The CRFs will be completed immediately after termination of the individual treatment 
and observation periods and the final examination. After being signed by the 
investigator, they will be sent to NOVAGENIX for data validation. Thereafter, CRFs 
will be returned to NOVAGENIX and eventually forwarded to the Investigator for 
final corrections, if applicable. CRFs can not be sent by post but only be personally 
submitted to the NOVAGENIX monitor during a visit or sent by courier. Any other 
way of transport is to be previously discussed with the NOVAGENIX. NOVAGENIX 
will send the original CRFs to Sponsor with the final report of the study. 
NOVAGENIX will store the copy of all CRFs. 
All medical records upon which the CRFs are based must be kept for at least 14 years 
after completion of the study. At this time NOVAGENIX will discuss with the Sponsor 
whether or not storage is required for a longer period. Image carriers or other data 
carriers can be used for the purpose of storage. 
 


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17.  ANALYTICAL EVALUATION  
Plasma concentrations of favipiravir will be determined by means of a validated LC 
method, according to Novagenix’s SOP NOV-ENG-08-TEC1.  
Detailed characteristics of the analytical method applied will be described in the 
“Analytical Study Plan” (see Appendix III: Analytical Study Plan). All assay 
validations will be performed in consideration of the Guideline on Bioanalytical Method 
Validation,EMA,21 July 2011 and  US FDA Guidance for Industry, Bionalytical Method 
Validation May 2018 or current guidance on method validation date. 
Volunteer’s all samples will be measured in a single analytical run in order to 
eliminate the influence of the inter-assay variance on the assessment. The analyst has 
to provide a final analytical report with tables for all samples that were analysed. 
Already measured samples will be stored at <-20°C for at least 6 months (storage 
period can be prolonged in exceptional cases, e.g. upon special request of authorities) 
after termination of bio-analysis. At that point a further decision by the Sponsor will 
be taken. 
20% of the chromatograms are to be included in printed Final Study Report. But 100 
% of chromatograms will be given also as electronically. 
 
17.1. Reanalysis of study samples 
The reasons for reanalysis of study samples are presented in Appendix III: Analytical 
Study Plan. 
 
17.2. Incurred Sample Reanalysis 
Incurred Sample Reanalysis (ISR) will be performed at any time after starting subject 
analysis by choosing two sampling points near or at Cmax and two sampling points in 
the elimination phase per period (total 8 sampling points per subject). These ISR 
points will be selected according to the literatures and/or  in the very first batches of 
subject analysis. The subjects will be randomly selected and the number of subjects 
that defined as ISR points will be equal or more than 10% of samples for the first 1000 
study samples and an additional 5% of samples for study samples in excess of 1000. 
The difference between the study samples’ and incurred samples’ values obtained 
should be within 20% of the mean for at least 67% of the repeats according to 
EMEA/CHMP/EWP/192217/2009 Rev.1 Corr.2. Guideline on  Bioanalytical Method 
Validation. London, 21 July 2011, p.13-14;  Novagenix's SOP-NOV-ENG-08-CQU4 
and documented in the Final Study Report. 


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18.  PHARMACOKINETIC EVALUATION 
Pharmacokinetic parameters of favipiravir will be determined using non-
compartmental methods from measured plasma concentrations. 
For each treatment (Test Drug or Reference Drug) and each volunteer participating 
completely in this single-dose, two period, cross-over study the following 
pharmacokinetic parameters will be calculated:  
Primary pharmacokinetic parameters: 
Cmax: Maximum observed plasma concentration 
AUC0-tlast: Area under the plasma concentration-time curve from zero to the last 
measurable concentration, calculated by the linear log trapezoidal rule. 
Secondary pharmacokinetic parameters: 
AUC0-∞: Area under the plasma concentration-time curve, calculated by extrapolation 
to infinity. 
tmax: Time to maximum observed plasma concentration 
t1/2 :  Terminal half-life 
Additional pharmacokinetic parameters: 
MRT:  Mean residence time 
λz: Terminal rate constant. 
For pharmacokinetic calculations, the program package Phoenix WinNonlin (Version 
8.1, Certara L.P.) or above will be employed. Phoenix WinNonlin will also be used to 
generate concentration/time plots. 
 
 


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19. STATISTICAL PROCEDURES 
The statistical analysis of the pharmacokinetic data described in this section 
corresponds with provisions according to the EMA guideline for bioequivalence (Doc. 
Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **)- 2010. 
Statistical analysis will be performed as a valid case analysis including all volunteers 
in which no major protocol deviations occurred and all primary target variables are 
available for measurement.  
If a volunteer is to be excluded from evaluation, this decision has to be justified in the 
Final Study Report. Statistical analysis will be performed by means of the program 
Phoenix WinNonlin (Version 8.1, Certara L.P.) or above. 
 
 
19.1. Target Variables 
19.1.1. Primary Target Variables 
Cmax and AUC0-tlast are declared to be primary target variables.  
 
19.1.2. Secondary Target Variables 
AUC0-, tmax and t1/2 are declared to be secondary target variables. MRT and z   will 
be determined also. 
In order to achieve a better approximation to a normal distribution Cmax and AUCs data 
will be logarithmically transformed (base e) before analysis. The sources of variation 
will be treatments, periods, sequence and subjects (nested within sequence) in 
Analysis of variance (ANOVA). Evaluation of treatment, period, sequence and subject 
(nested within sequence) effects at 5% level of significance will be performed. From 
the result of this procedure, the two one-sided hypothesis at the 5% level of 
significance will be tested by constructing the 90% confidence interval for the 
geometric mean ratios test/reference products. The confidence interval is calculated by 
retransformation of the shortest confidence interval for the difference of the ln-
transformed mean values. Differences in tmax will be evaluated non-parametrically. 
Bioequivalence will be concluded if the 90% confidence intervals for the geometric 
mean ratios of the products (test/reference) are fully contained within the limits of 
acceptance of  80% - 125% for Cmax and AUC0-tlast. For the secondary target variables, 
the 90% confidence intervals will be investigated for exploratory purposes. 
Evaluating excluding values from statistical calculations, the criteria which are given 
in “Novagenix SOP-NOV-ENG-08-CQU5” will be applied. 
These criteria are; 
 If a suspicious case about safety of blood samples such as in the absence of label,  label is not read 
exactly or any confusion of sample, these samples are documented on “Protocol For Handing Over 
Receipt of Samples” form. These samples are analysed but not included in statistics. 
 
 After completing study analysis, reanalysis is done due to analytical reason according to SOP-NOV-
ENG-08-TEC1 and SOP-NOV-ENG-08-CQU4. If the reanalysed data is still invalid for the analytical 
reason and there is insufficient plasma sample for reanalysis, that data should be excluded from 
statistical analyses. Any exclusion should be properly reported on final study report. 
 


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 A subject with lack of any measurable concentrations or only very low plasma concentrations for 
reference medicinal product. A subject is considered to have very low plasma concentrations if its AUC 
is less than 5% of reference medicinal product geometric mean AUC (which should be calculated 
without inclusion of data from the outlying subject). That subject will be evaluated and may be 
excluded. Accordingly the two results are reported in final study report. 
 
 Subjects with non-zero baseline concentrations > 5% of Cmax. Such subject should be excluded from 
statistical calculation. 
 
 Total number of subject should not be under 12 in the statistical calculation, whether not this study 
would be repeated from the clinic part. 
19.1.3. Safety Evaluation 
The assessment of safety will be based mainly on the frequency of AEs and on the 
number of  laboratory values that fall outside of pre-determined ranges. Other safety 
data (e.g. electrocardiogram, vital signs and special tests) will be considered as 
appropriate. 
19.2. Calculation of Sample Size 
The intra-individual variability of Cmax is estimated as 17% according to only one 
literature. Since there is insufficient information for intra-individual variability, sample 
size has been choosen as 30 subjects in order to demonstrate bioequivalence for a 2x2 
crossover design. 
19.3. Randomisation 
The randomisation table will be provided by Novagenix. 30 subjects, who will be 
included in the study, will be determined to receive either Test or Reference Product 
[In each study period, subjects will take different products (one dose of Test Drug or 
one dose of Reference Drug)] by a randomisation table. 
30 subjects, who will be included in the study, will be determined to receive either 
Treatment A or Treatment B in Period I and Period II by a randomisation table 
generated by a computer programme. Which one of the Test or Reference 
administration will be Treatment A or Treatment B is randomised by the Investigator. 
All the analytical analyses are done without the knowledge of the Test and the 
Reference product. These products will be named and known as Treatment A or 
Treatment B by CRO. Then the form defining Treatment-Period relationship will be 
enveloped, sealed and sent to CRO by the Investigator. CRO will open the sealed 
envelope in the “Project Evaluation Meeting” which will be held after the laboratory 
analyses are completed. Once the seal is opened, no new reanalyse or no data 
change/exclusion will be allowed. 
 
19.4. Documentation of the Data 
Measured plasma concentrations will be listed per treatment for each volunteer and 
each sampling point. In addition, mean values, standard deviations and the standard 
error of the mean will be given per sampling point of each treatment. 


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For all pharmacokinetic parameters determined, the individual values per treatment 
will be tabulated with descriptive statistics (i.e. calculation of arithmetic means, 
standard deviation and standard error of the mean, geometric means, minimum, 
maximum, median and the number of evaluated values). 
To display the time course of the plasma concentrations, individual concentration time 
curves as well as mean curves for each formulation will be plotted both in the linear 
and loglinear scale, using Phoenix WinNonlin (Version 8.1, Certara L.P.)  or above. 
All results will be summarized in tables and plots and will be reported and discussed in 
the Final Study Report. 
Descriptive analysis of demographic and safety data reported in the CRFs will be 
included in the Clinical Raw Data. 
19.5. Interim Evaluation 
No interim evaluation is planned in the present trial. 


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20. ETHICAL CONSIDERATIONS 
20.1. Ethical Conduct of the Study 
The study will be performed in accordance with the relevant articles of the Declaration 
of Helsinki (1964) as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), 
Somerset West, RSA (1996), Edinburgh (2000), Washington (2002), Tokyo (2004) and 
Seoul (2008) and Fortaleza (2013). 
20.2. Ethical, Legal and Administrative Aspects 
Prior to the initiation of the study, the protocol, the volunteer information leaflet, the 
informed consent and other related documents will be submitted to the Ethics 
Committee (EC) and Ministry of Health (MoH) by NOVAGENIX for review and 
approval. The CRO project responsible and the Investigator must inform each other in 
writing that all ethical and/or legal requirements have been met before the first 
volunteer is enrolled into the study. In case of both two approvals, the study can be 
started immediately after the copies of approvals have been sent to the Sponsor. If 
protocol changes require the preparation of an amendment, this amendment has to be 
submitted to the EC and MoH for approval or only for notification provided that the 
amendment does not concern the safety and the well-being of the volunteers. 
The study will only be performed when full approval of the study protocol has been 
obtained from the EC and MoH and copy of the certification has been received. A list 
of the members of the Ethics Committee will be attached, too. 
 
Ethics Committee 
Erciyes University 
School of Medicine  
        38039 Kayseri, Turkey 
 
Ministry of Health, Turkish Medicines and Medical Devices Agency 
Söğütözü Mah. 2176 Sok. No:5 
Çankaya, Ankara-Turkey 
 
 
 
 


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20.3. Volunteer Information and Informed Consent 
Before being admitted to the clinical study, the volunteer must consent to participate in 
the study by signing the informed consent form between time period of before 14 days 
to before 1 day of dosing day in response to a complete written and verbal explanation 
of the nature, scope and possible consequences of the clinical study explained in an 
understandable way for him by the physician.  
The volunteers must be able to understand the full implications of their decision. 
The Volunteer Informed Consent Forms will be prepared by NOVAGENIX and is 
given as attachment to this study protocol (see Appendix IV). It will explain the 
nature of the study, its objectives and potential risks and benefits. In addition, the 
following points must also be covered: 
 a description of the aims of the study and how it will be organized 
 the type of treatment and the way in which the volunteers will be allocated to 
treatment (e.g. by randomisation) 
 the positive effects which can be expected of the study treatments 
 any negative effects possibly attributable to the study treatments 
 the freedom to ask for further information at any time 
 the volunteer's right to withdraw from the clinical study at any time without giving 
reasons and without jeopardizing the further course of treatment 
 the existence of volunteer insurance cover 
 the right of the monitor and an independent authorized person to look into personal 
data. 
 Personal information will be treated as strictly confidential and not be publicly 
available. 
The Volunteer Informed Consent Forms (see Appendix IV) will be supplied by 
NOVAGENIX and will be also translated into Turkish. The translated forms will be 
used for confirmation of the volunteer's consent by the signature of the investigator 
and the volunteer. If necessary, the Volunteer Informed Consent Form will be signed 
by witness(es). 
The volunteers will be informed about this study by verbal and by reading the 
Volunteer Informed Consent Form from an authorized medical doctor who is in 
the clinical study team. 
Each volunteer will give in writing his authorization that the study data may be given 
for review to the responsible Local and National Authorities. 


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The volunteer information and informed consent form will be provided in duplicate 
[one signed version (original 1) will be left at the investigator; the other signed 
version (original 2) will be forwarded to the volunteer].  
To ensure medical confidentiality and data protection, the signed informed consent 
forms remain with the investigator and must be kept there for at least 14 years after 
the study has been completed. The investigator will allow these documents to be 
inspected on request and will affirm - by signing and dating - in the case report forms 
that informed consent has been obtained. The investigator will not undertake any 
investigations specifically required only for the clinical study until valid consent is 
obtained.  
 


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21. GOOD CLINICAL PRACTICE 
21.1. Legal Requirements 
This study will be conducted in accordance with the following: 
 
The Guidance for GCP, published by the Ministry of Health of Turkey. Circular, 13.11.2015. 
 
The Guidance on Safety Declaration of Clinical Trials , published by the Ministry of Health of Turkey,  
 
13.11.2015. 
 
Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. Official  
Journal, No: 29474; 13.09.2015. 
 
Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. Official  
 
Journal, No: 29041; 25.06.2014. 
 
Regulation on Clinical Trials of Drugs and Biological Products. Official Journal, No: 28617;  
 
13.04.2013. 
 
Regulation on the Principles of Good Laboratory Practice, Harmonisation of the Test Units,  
 
Supervision of Good Laboratory Practices and the Studies. Official Journal, No: 27516, 09.03.2010. 
 
Regulations on Evaluation of Bioequivalence and Bioavailability of Pharmaceutical Preparations.  
 
Official Journal, No: 21942; 27.05.1994.  
 
Guideline on Bioanalytical Method Validation, EMEA/CHMP/EWP/192217/2009 Rev.1 Corr.2,  
 
London, 21 July 2011. 
 
Guideline on The Investigation of Bioequivalence. CPMP/EWP/QWP/1401/98 Rev.1/Corr., London,  
 
EMA, 20 January 2010. 
 
Bioanalytical Part, Pharmacokinetic and Statistical Analyses of Bioequivalence Trials:  
 
EMEA/INS/GCP/97987/2008, London, 28.05.2008. 
 
Guidance for Industry. Bioavailability and bioequivalence studies for orally administered drug  
 
products- General Considerations. FDA, CDER, March 2003. 
 
Guidance for Industry. Statistical approaches to establishing bioequivalence. FDA, CDER, January  
 
2001. 
 
ICH Topic E 9. Statistical Principles for Clinical Trials. September 1998 (CPMP/ICH/363/96). 
 
Guideline for good clinical practice E6(R2)-2017. EMA/CHMP/ICH/135/1995. 
 
Guidance for Industry. Bioanalytical Method Validation. FDA, CDER, May 2018. 
 
ICH Topic E3. Note for Guidance on Structure and Content of Clinical Study Reports. Step 4.  
 
Consensus Guideline from 30.11.1995 (CPMP/ICH/137/95). 
 
GLP Principles of Good Laboratory Practice as specified by international (OECD- Paris 1998.;  
 
Directive 2004/10/EC of the European Parliament and of the council of 11 February 2004) 
 
ICH Topic E2A. Guidance on Clinical Safety Data Management: Definitions and Standards for  
 
Expedited Reporting, November 1994 (CPMP/ICH/377/95). 
 
Declaration of Helsinki, Fortaleza, 2013. 
 


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21.2. Preventive Measures to Reduce Bias 
The following measures are incorporated into the study in order to minimize bias: 
 Volunteers are sequentially assigned to randomly ordered treatments, 
 Volunteer enrollment is dependent on satisfactory fulfilment of the given list of 
inclusion criteria, 
 The circumstances when individual volunteers withdraw prior to planned 
completion of the study are specified. 
21.3. Investigator's Obligations 
Prior to initiation of this study, the investigator will approve this protocol by signing 
the signature page. This signature confirms that the study will be performed in 
compliance with the protocol. The investigator must ensure that the Sponsor or the 
NOVAGENIX provides adequate documents (i.e. Product Information) giving 
information about the pharmacological and toxicological properties of the test product. 
The investigator or his medically educated representative will review the CRFs for 
completeness and accuracy. The investigator will sign and date the CRFs and any 
changes in the CRF. 
The signatures serve to attest that the information contained in the CRFs is true and 
has not been falsified. In case of a correction, the reason for it shall also be given. It is 
the investigator's responsibility to assure completion of entries and to review and 
approve all CRFs. At all times the investigator has the final responsibility for the 
accuracy and authenticity of all clinical and laboratory data entered in the CRFs 
(section 16.2). 
21.4. Adherence to the Protocol 
Protocol violations are any deviations from the procedures outlined in this document, 
missing evaluations, incorrect timing of evaluations, non-compliance with study 
procedures and intake of prohibited medications. 
After a volunteer has been enrolled, it is the investigator's responsibility to make a 
reasonable effort to avoid any protocol violations and to keep the subject in the study.  
All protocol violations will be reported immediately to the Sponsor during the course 
of the study. The nature of these violations will be defined in written form. All 
protocol deviations will be listed and will be discussed with the Sponsor prior to the 
statistical analysis. 
The investigator undertakes all reasonable measures to record data in adherence with 
the protocol. Under practical working conditions, however, some minor variations may 
occur due to circumstances beyond the control of the investigator. All such deviations 
will be documented on the project records, together with the reason for their 
occurrence, and where appropriate, detailed in the study report. 
 


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21.5. Data Handling Procedures 
The results from screening and data collected during the study will be recorded in the 
volunteer's Case Report Form (CRF) which will be designed and printed by 
NOVAGENIX. Each volunteer receives a code number. His personal identification 
remains in a separate confidential file that can be used only together with the 
investigator. Each CRF will be signed and dated by the investigator. All corrections in 
the CRFs are to be made legibly and signed by the investigator. 
NOVAGENIX is responsible for the first step of data validation, receiving the results 
from the investigator. The investigator is responsible for the transfer of CRF and other 
required documents to NOVAGENIX by cargo together with the samples. All CRFs 
are thereafter delivered to NOVAGENIX. Copies thereof will be made by 
NOVAGENIX for Final Study Report writing and data quality assurance.  
In order to maintain volunteer confidentiality, all data recorded during the course of 
the study will only be identified by volunteer initials and volunteer study number. 
However, the investigator agrees to record the complete volunteer identification on the 
volunteer identification list. This list will be treated with strict adherence to 
confidentiality and will be filed in the Investigator's File. 
21.6. Monitoring 
It is the responsibility of the investigator to assure that the study is conducted in 
accordance with the protocol and that valid data are entered into the CRF. 
Monitoring and auditing of this study will be performed by Standard Operating 
Procedures “SOP-NOV-ENG-07-MON1” developed by the NOVAGENIX and the 
Sponsor in order to check the adherence to the protocol in compliance with Good 
Clinical Practice guidelines and to ensure international acceptability of the study data. 
In support of these measures, the investigator will make the records available to 
NOVAGENIX or to the Sponsor upon request at reasonable times. Case report forms 
will be checked for completeness and clarity. 
Data verification is legally required and will be done by direct comparison with source 
documents in case of volunteer's respective consent with data on CRFs or by cross-
checking with source documents in the presence of the investigator - always giving 
due consideration to data protection and medical confidentiality. In this respect the 
investigator assures NOVAGENIX of support at all times. 
The investigator will permit a representative of NOVAGENIX or the Sponsor to 
monitor the study as frequently as necessary to determine that data recording and 
protocol adherence are satisfactory. The CRFs and related documents will be reviewed 
in detail in accordance with the SOPs of NOVAGENIX and the Sponsor and Good 
Clinical Practice regulations. 
Visits may be conducted also by a representative of the NOVAGENIX or the Sponsor 
at suitable intervals throughout the study. These visits will be for the purpose of 
verifying adherence to the protocol and the completeness and exactness of the data 
entered on the Case Report Forms. The Sponsor is allowed to get any information 
about the state of the study. Case Report Forms will be transported from the 
investigator via NOVAGENIX to the Sponsor after completion of the trial. 


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In fulfilment of their obligation to the Sponsor to verify compliance with the protocol, 
NOVAGENIX will require that the investigator permits the NOVAGENIX's monitor to 
review those portions of the volunteer's primary medical records which directly 
concern this study. 
It is the investigator's obligation to assure documentation of all relevant data in the 
volunteer's file, such as medical history / concomitant diseases, date of study 
enrollment, visit dates, results of examinations, administrations of medication and 
adverse events. 
The investigator will affirm and uphold the principle of the subject's right to protection 
against the invasion of privacy. Throughout the study, all data will only be identified 
by volunteer number and volunteer initials. The data will be blinded correspondingly 
in all data analyses. 
All obtained data will be checked for plausibility and completeness by the Project 
Responsible in-house and by the Quality Assurance Unit of NOVAGENIX. Further 
plausibility checks will be performed by means of special computer programs. Study 
protocol and final report will be additionally examined by the Sponsor. 
After completion of the study, all unused study medication and empty blisters will be 
returned to the Sponsor by clinical center. 
21.7. Auditing 
In order to guarantee that the performance of the study is in accordance with the GCP 
provisions, in-house and, if needed, on-site audits may be carried out. The auditor will 
be independent from the staff involved in the proceedings of this clinical study. 
The investigator agrees to give the auditor access to all relevant documents for review. 
The same applies in case of an inspection of local or national authorities. In  case of 
any inspection of FARMAGEN-Good Clinical Practice and Research Center by an 
outside authority, the Sponsor will be consulted before the Inspectors are permitted 
access to any of the project records. 
After every on-site audit the investigator will receive an audit confirmation by the 
auditor. This has to be filed together with the study documentation and be made 
available to the local authorities in case of inspection. At the end of the study, an audit 
certificate will be included in the final report. 
The NOVAGENIX Quality Assurance Unit (QAU) may conduct an inspection of the 
study procedures. The findings will be reported to the CRO Project Responsible. 
21.8. Confidentiality 
Volunteers will be informed that all study findings will be stored on computer and 
handled strictly confidential. Volunteers will be identified throughout documentation 
and evaluation by the individual volunteer number only, whereas all volunteer names 
will be kept secret by the investigator. 
All information concerning study medication, all study materials and study drugs shall 
remain the property of the Sponsor. NOVAGENIX and the investigator are obliged to 
keep all data and information of the study confidential and to use those data only after 


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permission of the Sponsor. It is understood that no study material or information 
developed in this trial in connection with Favira 200 mg Film Kaplı Tablet by the 
Sponsor shall be made available to third parties, except for official representatives 
such as Regulatory Authorities.  
21.9. Insurance 
The volunteers will be insured by  in accordance with the requirements and regulations 
for participants in a clinical trial. This insurance is taken out with Mapfre Sigorta 
A.Ş.  
A copy of the Insurance Certificate for this study is included in Appendix V of this 
protocol. 
 
21.10. Subject Payment 
 
It will be paid to the volunteers who will participate the clinical phase of the study for  
the loss of their working days and their expenditure during and for the trial (e.g. 
transportation, communication, meal, accommodation, etc.). The amount is being 
determined in the Budget Form in the EC and MOH submission files. 
21.11 Qualification of the Investigator 
By his signature of the study protocol, the investigator certifies that she/he has more 
than 5 years experience in the conduction of clinical trials. A signed and dated CV of 
the investigator containing this information will be submitted in Appendix VI of this 
study protocol. 


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22. PROTOCOL AMENDMENTS 
22.1. Protocol Modifications 
In order to ensure most comparable conditions during all phases of the trial and in the 
interests of valid statistical analysis neither the investigator nor NOVAGENIX or the 
Sponsor will alter the study conditions agreed upon and set out in this protocol. 
Amendments should be made only in exceptional cases and by mutual agreement 
between the investigator, NOVAGENIX and the Sponsor. Any amendment must be set 
out in writing, at the same time giving the reasons, and signed by all parties concerned. 
The amendment then becomes part of the study protocol. 
Amendments which might have an impact on the safety and well-being of the subject 
such as the use of additional invasive examination methods require a new vote by the 
EC and MoH and a further Informed Consent Form that is to be signed by all subjects 
enrolled in the trial who are affected by the amendment. Other changes will only be 
submitted to the EC and MoH in a written form. 
The investigator may implement a deviation from, or a change of the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior EC and MoH approval 
opinion. As soon as possible, the implemented deviation or change, the reason for it, 
and if appropriate, the proposed protocol amendment(s) should be submitted: 
(a)  
to the EC and MoH  for review and approval opinion, 
(b)  
to the Sponsor for agreement and if required, 
(c)  
to the regulatory authority(ies). 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval opinion 
from EC and MoH of an amendment, except where necessary to eliminate an 
immediate hazard(s) to volunteers, or when the change(s) involves only logistical or 
administrative aspects of the trial (e.g., change in monitor(s), change of telephone 
number(s)). 
If the approval by an EC and MoH is required for amendments, this must also be 
sought. 
22.2. Protocol Violations 
Protocol violations are major deviations from the procedures outlined in this document 
like missing evaluations, incorrect timing of evaluations, non-compliance with study 
medication and intake of prohibited medications. After a subject has been enrolled, it 
is the investigator's responsibility to make a reasonable effort to correct any protocol 
violations and to keep the subject in the study.  


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Protocol violations will be reported to the CRO Project Responsible during the course 
of the study in Monitoring Reports. All protocol violations with a possible influence 
on the aim of the trial will be listed and the evaluability of the subject concerned will 
be discussed in a blinded meeting with the CRO Project Responsible prior to the 
statistical analysis. 
23. REPORTS 
Prior to issuing the Final Study Report, NOVAGENIX will prepare a draft report 
according to the ICH guideline for approval by sponsor. The draft report will be 
submitted for a Quality Assurance audit and any findings or notifications will be 
appropriately considered in the final version. NOVAGENIX will prepare one Final 
Study Report with original signatures and send to sponsor both in paper and as CDs. 
 
23.1. Archiving 
NOVAGENIX will store all essential documents (i.e. copy of original CRFs, Clinical 
Study  Protocol, audit certificates, all written statements concerning the study etc.) and 
the Final Study Report at least 14 years. 
The investigator will keep the volunteer files and original data as long as possible and 
according to the local methods and facilities. The investigator should maintain the trial 
documents as specified in the ICH-GCP guideline (essential documents). The 
investigator must take measures to prevent accidental or premature destruction of these 
documents. Essential documents should be retained for at least 14 years after the 
completion of study. The subject identification codes list and subject's signed informed 
consent will be archived for at least 14 years. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the investigator when there is no further need 
to retain these documents.  
Documents of a terminated study have to be archived accordingly at least 14 years 
after termination of the study. 
In case of any change concerning the archiving procedures the investigator/institution 
has to inform the Sponsor immediately. 
 


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24. COMMUNICATION OF STUDY RESULTS 
Any publication requires the consent of the Sponsor. 
By signing the protocol the investigator gives his/her consent that the trial results may be 
used for authorization purposes, for the compilation of information material and the 
publication. Results deriving from the present study can only be published by 
NOVAGENIX if both the Investigator and the Sponsor give their consent. 
      25.  CONTRACT AND COSTS 
NOVAGENIX and the Investigator conclude an agreement on fees. This agreement 
considers the number of volunteers that are to be included and the costs differentiated by 
the visits performed for each volunteer, hospitalization and for laboratory analyses. 
The expenditures of volunteers who are terminated their participation at an earlier point 
are paid according to the actual number of visits conducted, according to the provisions of 
the contract signed. 
NOVAGENIX and Sponsor conclude an agreement on payments. This agreement covers 
the costs of clinic, analysis, biometrics and reporting. 
Agreements on the amount and the methods of payment will be signed separately between 
the NOVAGENIX and the Investigator and Sponsor as well as between NOVAGENIX and 
Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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26. FINAL REGULATIONS 
NOVAGENIX certifies that the information in this protocol is consistent with the 
current benefit-risk evaluation of the study medication, and the moral, ethical and 
scientific principles governing clinical research as set out in the Declaration of 
Helsinki (last revision). 
Current versions of the SOPs will be used during the study. 
The Sponsor will supply the Investigator and NOVAGENIX with details of any 
significant or new findings, including adverse events, relating to treatment with the 
study medication. 
By signing the protocol the Investigator certifies that he/she has received the following 
documents: 
 Product information 
 Text of the Declaration of Helsinki (1964) as revised in Tokyo (1975), Venice (1983), 
Hong Kong (1989), Somerset West, RSA (1996), Edinburgh (2000), Washington 
(2002), Tokyo (2004) and Seoul (2008) and Fortaleza, 2013. 
 Text of the ICH Guideline for Good Clinical Practice (2017) 
 A sufficient number of volunteer information sheets, informed consent forms, CRFs 
and forms for reporting serious adverse events (''Serious adverse event in clinical 
study'') to start the study 
Furthermore, by signing this protocol the investigator affirms that 
 He/she has been adequately informed on the study drug and agrees that the study 
protocol contains all information required to perform the study as set out in the 
protocol. 
 The first volunteer will not be included in the study until receipt of approval by the 
EC and MoH and/or until all legal requirements have been fulfilled. 
 The study will be conducted in accordance with the moral, ethical and scientific 
principles governing clinical research as set out in the Declaration of Helsinki (last 
revision), with ICH Guideline for Good Clinical Practice (2017) and the Turkish 
Drug Regulations. 
 Informed consent to participate for all volunteers enrolled in the study will be 
obtained according to section 20.3 of this protocol, and that the consent forms as 
well all source data will be kept for 14 years. 
 He/she will submit to the NOVAGENIX an up-to-date Curriculum Vitae. 


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27. 
REFERENCES 
 Report on the Deliberation Results of Avigan Tablet 200 mg (Favipiravir), 
Pharmaceuticals and Medical Devices Agency (PMDA), 04.03.2014 
https://www.pmda.go.jp/files/000210319.pdf 
 Prescribing information of  Avigan Tablets 200 mg, revised date 11.2017 
https://health.tainan.gov.tw/warehouse/%7BEF3588B5-E673-41F4-88D8-
B4CF30E9C27F%7D/%E5%85%AC%E8%B2%BB%EF%A7%8A%E6%84%9F%E6%8A
%97%E7%97%85%E6%AF%92%E8%97%A5%E5%8A%91Avigan%E4%BD%BF%E7%
94%A8%E6%96%B9%E6%A1%88.pdf 
 EMA, CHMP Assessment Report, Medicinal Products under Development for the 
Treatment of Ebola, 03.02.2016 
https://www.ema.europa.eu/en/documents/referral/assessment-report-article-53-
procedure-medicinal-products-under-development-treatment-ebola_en.pdf 
 EMA, Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic, Version.3 28.04.2020 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
 MHRA, Advice for Management of Clinical trials in relation to Coronavirus, 
12.03.2020 https://mhrainspectorate.blog.gov.uk/2020/03/12/advice-for-management-of-
clinical-trials-in-relation-to-coronavirus/ 
 FDA, FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Pandemic, updated :02.04.2020 https://www.fda.gov/media/136238/download 
 The Guidance for GCP, published by the Ministry of Health of Turkey. Circular, 13.11.2015. 
 The Guidance on Safety Declaration of Clinical Trials , published by the Ministry of Health 
of Turkey, 13.11.2015.  
 Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. 
Official Journal, No: 29474; 13.09.2015. 
 Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. 
Official Journal, No: 29041; 25.06.2014. 
 Regulation on Clinical Trials of Drugs and Biological Products. Official Journal, No: 28617; 
13.04.2013. 
 Regulation on the Principles of Good Laboratory Practice, Harmonisation of the Test Units, 
Supervision of Good Laboratory Practices and the Studies. Official Journal, No: 27516, 
09.03.2010. 
 Regulations on Evaluation of Bioequivalence and Bioavailability of Pharmaceutical 
Preparations. Official Journal, No: 21942; 27.05.1994.  
 Guideline on Bioanalytical Method Validation, EMEA/CHMP/EWP/192217/2009 Rev.1 
Corr.2, London, 21 July 2011. 
 Guideline on The Investigation of Bioequivalence. CPMP/EWP/QWP/1401/98 Rev.1/Corr., 
London, EMA, 20 January 2010. 


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 Bioanalytical Part, Pharmacokinetic and Statistical Analyses of Bioequivalence Trials: 
EMEA/INS/GCP/97987/2008, London, 28.05.2008. 
 Guidance for Industry. Bioavailability and bioequivalence studies for orally administered 
drug products- General Considerations. FDA, CDER, March 2003. 
 Guidance for Industry. Statistical approaches to establishing bioequivalence. FDA, CDER, 
January 2001. 
 ICH Topic E 9. Statistical Principles for Clinical Trials. September 1998 
(CPMP/ICH/363/96). 
 Guideline for good clinical practice E6(R2)-2017. EMA/CHMP/ICH/135/1995. 
 Guidance for Industry. Bioanalytical Method Validation. FDA, CDER, May 2018. 
 ICH Topic E3. Note for Guidance on Structure and Content of Clinical Study Reports. Step 
4. Consensus Guideline from 30.11.1995 (CPMP/ICH/137/95). 
 GLP Principles of Good Laboratory Practice as specified by international (OECD- Paris 
1998.; Directive 2004/10/EC of the European Parliament and of the council of 11 February 
2004) 
 ICH Topic E2A. Guidance on Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, November 1994 (CPMP/ICH/377/95). 
 Declaration of Helsinki, Fortaleza, 2013. 


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28. 
LOCATION OF STUDY DOCUMENTATION 
The following documents are kept in the Project File at the NOVAGENIX and 
FARMAGEN with coded NOV2020/01923 as printout and/or electronically in server: 
1. The Approved and Originally Signed Protocol and Its Amendments, as well as 
Other Relevant Signature Documents * 
2. Announcement of The Trial to The Central Authorities * 
3. Announcement of The Trial to The Local Authorities * 
4. Agreement(s) with The Investigator(s) 
5. The Ethics Committee Approval Notice **,  
6. The Ministry of Health Approval Notice ** 
7. The Correspondence with The Sponsor, Investigator, Ethics Committee, 
Ministry of Health and Personnel Involved in The Study 
8. Curricula Vitae for Key CRO and Clinical Personnel *** 
9. Copy of The Sample Volunteer Information Document and Informed Consent 
Form 
10. Copy of the CRF and Additional Related Documents (Form for SAE) 
11. Personnel Assignment List with Signatures ** 
12. Randomisation List 
13. Trial Medication Documents (Record of The Receipt **, Dispensing and 
Disposal of Drug Supplies **, Analytical Certificates, Copy of The Labelling of 
Trial Medication) 
14. Laboratory Reference Ranges and Laboratory Certificate ** 
15. Audit Certificates (if available) ** 
16. Volunteer's Insurance 
17. Screening-log, Identification***- and/or Enrolment-log of Volunteers 
18. Monitoring Reports ** 
19. Documentation of Data Handling, Plausibility Checks, Data Base Codes and 
Closure 
20. CRFs of all Volunteers Including Query Forms * 
21. Reports on Serious and/or Unexpected Adverse Events (Adverse Drug 
Reactions) * 
22. Publications 
23. Records of any Deviation From Planned Procedures 
 
*  original; 
  **  copy will be sent to the Sponsor 
*** only in clinical center 
 
 


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29. APPENDICES 
Appendix 1: Table of Body Mass Index 
Appendix 2: Case Report Form 
Appendix 3: Analytical Study Plan 
Appendix 4: Volunteer Informed Consent Form 
Appendix 5: Copy of Insurance Certificate 
Appendix 6: Curriculum Vitae for key CRO and Clinical Personnel 
Appendix 7: Isolation procedure due to Covid-19 pandemic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
Study Code: NOV2020/01923                    NCT04400682                                              
  
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Subject’s paraph 
 
                                                   CONFIDENTIAL                                                               Page 1/5 
Subject Screening Number: ............................. 
 
INFORMED CONSENT FORM 
 
Principal Investigator: Prof. Dr. Muradiye Nacak 
Gaziantep Üniversitesi FARMAGEN GCP Center 
Gaziantep Üniversitesi Teknoloji Geliştirme Bölgesi (Teknopark) 
Burç Yolu, Şahinbey 27260, Gaziantep-Turkey 
Telephone : +90 342 360 62 62 
GSM: +90 505 252 54 69 
  
“Open-label, randomised, single oral dose, two-period, cross-over trial  to assess to bioequivalence of Favira 200 mg Film 
Kaplı Tablet(Test Drug) in comparison with Avigan 200 mg Film Tablet (Reference Drug) in healthy male subjects under 
fasting conditions”  
                            
 
  
Dear Volunteer, 
 
The drugs tested in this trial is Favira 200 mg Film Kaplı Tablet (Test Drug) containing 200 mg favipiravir of Novelfarma İlaç San. ve 
Tic. Ltd. Şti. It is a medication used orally and it could be valuable in the treatment of the diseases caused by highly pathogenic influenza 
viruses 
 
The purpose of the present research study is to investigate the bioequivalence of orally administered test drug Favira 200 mg Film Kaplı 
Tablet containing 200 mg favipiravir (Test drug) and on the other orally administered reference drug containing 200 mg favipiravir  
(Avigan 200 mg Film Tablet). The reference drug is already registered and commercially available for years in Japan as Avigan 200 mg 
Film Tablet. The company responsible for placing the reference product on the market is Toyama Chemical Industry Co Ltd.-Japan . The 
efficacy and safety of this reference drug has been proven through the clinical studies that were carried out in order to obtain the license for 
the drugs. Therefore, this drug will be used as reference and will establish the basis of comparison to be used for the test drug. (test drug is 
manufactured by Pharma Plant İlaç San. ve Tic. A.Ş. in Turkey.) The comparison will be based on the measurement of the concentrations of 
the active ingredient of the drugs in blood. In addition, the safety of the test product will be compared to the safety of the reference products 
based on the evaluation of adverse events. 
 
After the “Covid-19 PCR Test*” to be applied to you, your screening examinations will be carried out at the FARMAGEN GCP Center 
based on your negative test result. Screening tests will be done before the beginning of the study and will include standard clinical and 
laboratory research. Standard clinical research includes your medical history, a complete clinical examination, drug abuse screening, alcohol 
breath test, Covid-19 PCR test*, standard ECG, and measurement of your height, weight, body temperature, blood pressure, and heart rate 
after five minutes of rest in the supine position. Depending on the suitability of your clinical examination and laboratory results, you will be 
transferred to Gaziantep University Hotel where you will be during the isolation period for clinical study. Your isolation period will be 
provided for 4 nights in single rooms reserved for you at Gaziantep University Hotel. During this time, breakfast, lunch, dinner and snacks 
will be served to your room. In addition, fever, blood pressure and heart rate will be measured in every morning.  
It will be important that the volunteers participating in the study do not come into contact with each other during the isolation and that the 
rules of isolation are followed. On Day 5 Covid-19 PCR test* will be applied. You will be transferred to FARMAGEN GCP Center for 
clinical study in suitable isolation conditions according to your test result and general condition.  
 
Under fasting condition in this 2 period trial, each of 30 subjects who enrolled into trial will be given a single dose of Test Drug (200 mg 
favipiravir) in one period and a single dose of Reference Drug (200 mg favipiravir) in one period and there will be a wash-out of at least 
48 hours. You will take a total of 2 drugs [(Test Drug) / (Reference Drug)] during the trial (total 400 mg favipiravir). The drugs will be 
assigned randomly. Therefore, you will have an equal chance of receiving either drug. The total duration of the trial including isolation 
period will be approximately 9 days. 
 
The final examination will be carried out on the day of last blood sampling in the last period and will include standard clinical and laboratory 
research. Standard clinical research includes a complete clinical examination, standard ECG, body temperature, blood pressure, and heart rate 
after five minutes of rest in the supine position. Also, Covid-19 PCR* test will be applied in the final examination. 
 
* Covid-19 PCR screening tests will be made by taking a swab from your throat and nose. Volunteers who have positive results in Covid-19 
screening tests will be taken to Gaziantep University Research Hospital Emergency Department under appropriate conditions. 
 
Approximately 32 mL blood sample (20 mL# for entry examination and 12 mL for final examination) is going to be collected for the standard 
laboratory tests on entry and final examination with HIV (AIDS) and hepatitis tests at only entry examination. The blood samples collected 
for laboratory (entry and final examination) tests will be sent to GAMA Medical Laboratories (GAMA Tıp Laboratuvarları) which is located 
in 
Gaziantep-Turkey, 
and 
will 
be 
used 
exclusively 
for 
this 
research, 
specifically 
for 
it’s 
purpose.  
Covid-19 PCR test analyzes will be carried out at FARMAGEN GCP Center. An amount of blood sample will be needed if any Clinical 
Laboratory Tests occur which need to be repeated. 
# 8 mL of 20 mL of entry examination blood sample will be used for analytical studies of this project. 
 
 
Approximately 30 mL urine sample is going to be collected for the standard laboratory tests on entry and final examination with drug abuse 
tests. 
 
You will come to the clinic the day before study period around 18:00 and will stay in the clinic for 90 hours. But according to your health 
situation, the investigator and/or co-investigator will be decided whether you can leave the clinic at that time or not. Your body 


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temperature will be measured in the mornings during study period.  Final examination and laboratory tests will be done on the day of last 
blood sampling in the 2. period 
 
You should not consume alcohol and cigarette during the trial. You will not be allowed to chewing gum on the day of drug administration.  
You will not be allowed to consume food or drink (coffee, tea, cola, hot chocolate, etc.) and fruit juices that contain caffeine or other 
methylxanthines starting two days before  administration and lasting until the last blood sample for that period is drawn. Grapefruit 
products should not be consumed starting seven days before the first dose is administered and lasting until the last blood sample is drawn. 
No food and beverages will be consumed starting the evening before the drug is administered, i.e. 22:00 in the evening and lasting until the 
lunchtime (approximately 4 hours after drug administration) in each study period. Not allowed to drink water between 1 h before to 1 h after 
administration, except while dosing in each period. No vigorous physical activity is allowed starting with the initial screening tests and 
lasting until the last laboratory test in the final check up is performed.  
 
Dinner on the day before drug application will be served no later than 21:00. A typical lunch will be served approximately 4 hours after the 
drug is administered and a typical dinner will be served approximately 10 hours after the drug is administered. Light breakfast will be served 
at around 21.30 in the evening. The total amount of water to be consumed on the day of drug administration is maximum 1.5 litters and water 
consumption will begin 1 hour after the administration of the drug. 
 
The following day of drug administration, a standard breakfast, lunch, dinner and a light breakfast (at around 21.30 in the evening )will be 
served. From 22.00 in the evening, no food or drink other than water will be consumed until 4 hours after the 2nd Period drug application. 
Standard lunch will be given approximately 4 hours after the medication and standard dinner will be given approximately 10 hours after the 
drug. A light breakfast will be served at around 21.30 in the evening. In the 2nd period drug application, after the last blood sample is taken 
(t24.00), final examination and laboratory tests will be performed. 
 
A test drug or reference drug will be taken with 240 mL of water -as a whole in sitting position and this will be followed by mouth 
check. You should sit without lying in your bed during 4 hours after the drug administration. In this interval (t0.17-t4.00); the blood 
collections will be performed in bed; lunch will be provided on bed. The drug will be administered approximately at 08:00 a.m. 
 
Blood samples for drug analysis (8 mL at most each time, only in Period I; at pre-dose (t0) the blood sample amount will be 20 mL) will be 
drawn at the following times in each study period: before the drug is administered, and then 10, 15, 30, 45.minutes and 1.00, 1.33, 1.66, 
2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 14.00, 24.00 hours after the drug is administered. Blood samples will be drawn using a 
catheter during the time period passed at the Clinic. The total volume of blood to be drawn during the entire study is expected to be 
approximately 358 mL, including blood samples for initial and the heparinised discarded blood at determined blood sampling points each of 
approximately 0.5 mL and final laboratory controls. An amount of blood loss could provoke; dizziness, faintness, sweating, thirst, weak 
and rapid pulse, rapid respiration, orthostatic hypotension and eventual decrease in some laboratory parameters such as hemoglobin 
and hematocrit. Having in mind that the blood loss in the present trial will take place over a period of several weeks, the risk for the 
volunteers to experience one of the upper side effects is relatively low.  
 
The collected blood samples will be transferred to NOVAGENIX Bioanalytical Drug R&D Centre in Ankara- Turkey to determine 
the level of drug in blood. These samples will be used to only for this study and in accordance with study objectives and any 
remaining material will be destroyed.  
You can decide at any time whether your samples can be used for the analysis of determine the level of drug in blood or should be 
destroyed. If you decide that your blood samples shall not be subjected to analysis, you will have to inform the investigator about 
your decision in a written form. 
However, the samples can be stored for monitoring, inspection and audit activities of the relevant health authorities for the aim of 
verifying the information on clinical studies. 
Samples can not be used as a source of commercial gain in any way. However, intellectual property and patent rights are exempted 
from this condition.  
 
To monitor your compliance with the study, all the rooms and the corridors are being observed continuously by video cameras during the 
time in the clinic. All the records will be deleted after the study. 
 
On admission to the clinic (hospitalization day in study) the luggage of all volunteers will be checked for not allowed items (food, beverages, 
cigarettes, chewing-gum, and any drugs). A security service personnel or clinical personnel will perform a security check on your body and 
on your luggage by a hand on admission to the clinic and before the start of hospitalization. 
 
To monitor your compliance with the study, all the rooms and the corridors are being observed continuously by video cameras during the 
time in the clinic. All the records will be kept for 2 months after completion of the clinical period, and all records will be deleted at the end of 
this period. 
 


Study Code: NOV2020/01923                    NCT04400682                                              
  
      Date: 11.05.2020 
 
 
 
 
 
   
 
 
 
                      Version: 1.0 
Subject’s paraph 
 
                                                   CONFIDENTIAL                                                               Page 3/5 
Side effects: 
The main adverse events of favipiravir seen during the development of the product for influenza include mild to moderate diarrhoea, 
abdominal pain, headache and asymptomatic elevations of blood uric acid, decrease of neutrophil count, increase of AST (GOT), 
increase of ALT (GPT). 
 
Adverse reactions observed in Japanese clinical studies and the global phase III clinical study (studies conducted with dose levels 
lower than the approval dosage) are shown in the table below with frequency. 
 
 
≥ 1%  
%0.5 - < 1 
< 0.5% 
Hypersensitivity 
 
Rash 
eczama, pruritus 
Hepatic 
AST (GOT) 
increased,ALT (GPT) 
increased, 
γ-GTP 
increased 
 
Blood ALP 
increased, blood 
bilirubin 
increased 
Gastrointestinal 
Diarrhoea 
(4.79%) 
Nausea, 
vomiting, 
abdominal 
pain 
Abdominal 
discomfort, 
duodenal ulcer, 
haematochezia, 
gastritis 
Hematologic 
Neutrophil 
count 
decreased, 
white blood 
cell count 
decreased 
 
White blood cell 
count increased, 
reticulocyte count 
decreased, 
monocyte 
increased 
Metabolic 
disorders 
Blood uric 
acid increased 
(4.79%), 
blood 
triglycerides 
increased 
Glucose urine 
Present 
Blood potassium 
decreased 
Respiratory 
 
 
Asthma, 
oropharyngeal 
pain, rhinitis, 
nasopharyngitis 
Others 
 
 
Blood CK (CPK) 
increased, blood 
urine present, 
tonsil polyp, 
pigmentation, 
dysgeusia, bruise, 
vision blurred, 
eye pain, vertigo, 
supraventricular 
extrasystoles 
 
Clinically significant adverse reactions such as, shock, anaphylaxis, pneumonia, hepatitis fulminant, hepatic dysfunction, jaundice, 
toxic epidermal necrolysis (TEN), oculomucocutaneous syndrome (Stevens-Johnson syndrome), acute kidney injury decrease of white 
blood cell, neutrophil count and platelet count, neurological and psychiatric symptoms (consciousness disturbed, abnormal behavior, 
deliria, hallucination, delusion, convulsion, etc.) haemorrhagic colitis have been reported with other anti-influenza virus agents. 
 
 (Also, a verbal explanation will be made about the unexpected side effects by the investigator.) 
 
You and your partner need to practice adequate contraception for 7  days after the study. 
 
Please ask the informing physician about any terms you do not understand. If any side effect will occur, report to the study 
investigator immediately. You can ask additional questions any time during the trial about additional information not provided in this form. 
Investigator and authorised personnel have to be reachable 7/24 during the entire clinical study (see the phone number given in the 
first page). 
 
As with all prescription drugs, other unpredictable side effects or life-threatening events can occur in addition to the above mentioned side 
effects.  Do not drive or operate machine on medication day. 
 
Your participation of this study will be finished after the last blood sampling at 24. hours for pharmacokinetic purpose in the last 
period and the following post-study examination and laboratory tests and /or in the cases of the drop-out or occurring a serious 
adverse event. 
 
Because of participating the clinical phase of the study, a payment will be done to you with a receipt/voucher or a signed minute for the loss 
of your working days and the some private expenditures (e.g. transportation, communication, meal, accommodation etc.). Except these, you 
will not have any payment for the use of blood samples obtained from clinical study or other purposes. If you violate the procedures of the 
study or of your own health protection, you may be withdrawn from the study before its completion or the amount of the money which 
will be paid to you may reduced.   
 


Study Code: NOV2020/01923                    NCT04400682                                              
  
      Date: 11.05.2020 
 
 
 
 
 
   
 
 
 
                      Version: 1.0 
Subject’s paraph 
 
                                                   CONFIDENTIAL                                                               Page 4/5 
 
Data Protection: 
 
Only the birth dates and initial letters of subject names will be used as identity markers in study records. Your identity will be kept 
confidential. Study records will only be used for scientific purposes and will be delivered to the sponsor of this study. To ensure a fair study 
in accordance with the rules, the authorized study monitors of the drug firm (Novelfarma İlaç San. ve Tic. Ltd. Şti.) or the Contract 
Research Organisation (Novagenix), inspectors, ethics committees, and legal authorities are permitted to access your medical records. 
Individuals working with the study have been specially trained in this area and must adhere to occupational guidelines. They can only be 
given access to your personal data not including your name.  
 
The privacy of your records will always be respected. The data protection law will be followed.  
 
You can withdraw from the study without explanation and without risking clinical treatment that might be needed in the future. 
Your signature under the informed consent form does not entitle you to complete the study. 
 
All subjects participating in this study are insured. By mutual agreement between the clinical study sponsor (Novelfarma İlaç San. ve Tic. 
Ltd. Şti) and the principal investigator, NOVAGENIX insured all participants for the cases of study-related loss of function or cases, 
where hospitalization or surgical intervention is required, death, or permanent disability due to this study. In case of your request a 
copy of the insurance policy will be given to you by investigator.  
 
The insurer is responsible for health-related problems that may occur only under the following conditions: 
1. 
Health-related issues that occur due to the treatment and/or administration of drugs with the decision and approval of the 
conducting physician during the research, 
 
2. 
Any problem that may occur regarding your health due to the clinical study is immediately reported to your investigating 
physician and insurer by you or your relatives.  
 
 
 
  


Study Code: NOV2020/01923                    NCT04400682                                              
  
      Date: 11.05.2020 
 
 
 
 
 
   
 
 
 
                      Version: 1.0 
Subject’s paraph 
 
                                                   CONFIDENTIAL                                                               Page 5/5 
Screening Number: …………………………….. 
 
Test Drug: Favira 200 mg Film Kaplı Tablet (Novelfarma -Turkey)  
Reference Drug: Avigan 200 mg Film Tablet (Toyama Chemical Industry Co Ltd.-Japan) 
 
II, ……….., agree to take part voluntarily in the above research conducted by Novagenix (Contract Research Organisation) on behalf of 
Novelfarma İlaç San. ve Tic. Ltd. Şti (Sponsor) of my own free will. I have been informed about the structure of the study, its possible 
duration, risks and about my responsibilities by the physician whose name is given below. I have read and understood the above 
explanations. Physician who is responsible for informed have advised me about possible disorders and side effects. I have also read the 
informing document about all aspects and details of the study. Finally, I have understood and accepted all the information, explanations, and 
recommendations provided.  
 
I have reported my previous and current illnesses along with the treatments and drugs I received in the last three months and all the 
information about any consultations with a doctor in the last six months and the drug treatments I am planning to take.  
 
I promise to report any deterioration of my well being or my health, as well as the occurrence of any unexpected/unusual symptoms to the 
researchers immediately, to work in collaboration with the researchers, and to follow the instructions provided during the study and 
isolation period. If I violate the rules, my participation to the clinical trial will be ended by the investigator(s). I have given explicit 
information about the previous studies in which I participated. I have been told that this research is reviewed and approved by an ethics 
committee. I was also told that I can ask any further questions I might have to those individuals.  
 
I understand that I am free to withdraw from the study anytime, without giving any explanation.  
 
I am aware that although this study can contribute to the development of medical knowledge, it will not be of direct help to my health and I 
might even harm myself by participating in this study if I am not honest with the information I provide or if I do not follow the instructions 
given to me.  
 
I promise not to behave in any way that is likely to affect the results of the study. I also understand that I will be notified immediately in case 
any information that might affect my participation is discovered during the course of the study.  
 
I am not stipulating any restrictions for the use of study results. I accept that the results will be given to authorized people and corporations.  I 
accept that the data recorded during the study will be delivered to the sponsor firm and later to health authorities.  I understand and consent 
that study results will be evaluated by computer, keeping the identities of participants confidential. 
 
I understand that all the subjects participating in this study are insured. The sponsor drug firm approves that the compensation fee will be 
paid by insurance in case I suffer from any important disorder in my health or wellbeing due to my participation in this study.  
 
I accept that any damage that occurs to my health at my own fault and/or for disobeying the instructions of the researcher will not be covered 
by insurance. I have understood and accepted that damages will not be covered by insurance in case my health deteriorates due to any drugs 
or treatments I receive outside of the researcher’s permission or knowledge. I have understood and accepted that the insurer can cover the 
damages that may occur due to drugs used during and for the purposes of the study, the applied procedures, or another medical treatment 
administration carried out by the consent of the conducting physician.  
 
The maximum compensation fee to be paid in such a situation is up to the amount mentioned in the insurance policy in case the liability is 
accepted.  
 
I know that some private insurance companies accept participating in medical studies as an issue to be reported in insurance claim demands 
and I will check if my participation in the study will affect current policies in case of such an insurance claim demand or application for 
renewal.  
 
I or my relatives will notify the insurer and the study doctors in case any deterioration occurs in my health. I have been informed about 
content, structure, aim and risks of this clinical study by verbal and by Volunteer Informed Consent Form document from an 
authorized medical doctor who is in the clinical study team. Also, I have read and understood this informed subject consent and study-
related subject information form and accepted with my own free will, signed, and received one copy of it.  
 
Subject’s:  
 
 
 
 
 
 
 
 
NAME …………………………. 
 
DATE OF BIRTH ……………..  
SIGNATURE…………………  
 
 
 
 
 
DATE …………………………  
 
 
 
As the responsible physician, I am convinced that the subject understood all the written and verbal explanations provided, read and 
understood the given information, and agreed to participate in the study of his/her own free will.  
 
Doctor Who Is Responsible For Informed: 
 
 
 
 
                                                                                                                                                   
NAME……………………………. 
 
 
SIGNATURE…………………….. 
 
 
DATE……………………………. 
                                                      
 
 
 
This Informed Consent Form includes 5 pages.