Open-label, Randomized, Single Dose, 4period, Replicated, Cross-over Trial to Assess the Bioequivalence of Feniramidol HCl 400 mg Film Tablet in Comparison With Cabral 400 mg Film Tablet in Healthy Male Subjects Under Fed Conditions
Phase: PHASE1
Conditions: Bioequivalence
Sponsor: Humanis Saglık Anonim Sirketi

Study Code: NOV2019/01864       NCT04639869 
 
Date: 13.05.2019 
Clinical Study Protocol                                                                                                     Version: 1.0 
                                                
 
 
Page 1 of 60 
 
 
 
 
CLINICAL STUDY PROTOCOL 
“CONFIDENTIAL” 
 
 
 
Principal Investigator: 
Prof. Dr. Muradiye Nacak   
 
Clinical Center: 
 
Gaziantep 
University 
FARMAGEN 
GCP  
Center, Gaziantep –Turkey 
 
 
Sponsor: 
 
Pharmactive İlaç San.ve Tic. A.Ş. 
 
 
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  Pharmactive İlaç San.ve 
Tic. A.Ş. and Novagenix Bioanalytical Drug R&D Centre. Not divulged to unauthorised persons in any form, including publications and 
presentations, without written consent of Pharmactive İlaç San.ve Tic. A.Ş. and Novagenix Bioanalytical Drug R&D Centre.
 
OPEN-LABEL, RANDOMISED, SINGLE ORAL DOSE,  
FOUR-PERIOD, REPLICATED, CROSS-OVER TRIAL TO 
ASSESS THE BIOEQUIVALENCE OF FENIRAMIDOL HCl 
400 MG FILM TABLET (TEST DRUG) IN COMPARISON 
WITH CABRAL 400 MG FILM TABLET (REFERENCE 
DRUG) IN HEALTHY MALE SUBJECTS  
UNDER FED CONDITIONS 

Study Code: NOV2019/01864 
                                                   
 
 
 Date: 13.05.2019 
Clinical Study Protocol 
 
 
 
 
 
 
 
      Version: 1.0 
 
  
 
 
 
 
 
 
 
 
                      Page 2 of 60 
 
  
 
 
 
 
 
 
 
 
 
  STUDY SYNOPSIS 
 
Study Title: 
Open-label, randomised, single oral dose, four-period, replicated, cross-over 
trial to assess the bioequivalence of Feniramidol HCl 400 mg Film Tablet 
(Test Drug) in comparison with Cabral 400 mg Film Tablet (Reference 
Drug) in healthy male subjects under fed conditions 
 
Study Code: 
NOV2019/01864 
 
Drugs: 
Test Drug*: “Feniramidol HCl 400 mg Film Tablet” containing 400 mg 
phenyramidol HCl (Pharmactive -Turkey).  
 
 
 *: This drug is manufactured by Pharmactive İlaç San.ve Tic. A.Ş. -Turkey. 
 
  
 
 
Reference Drug**: “Cabral 400 mg Film Tablet” containing 400 mg 
phenyramidol HCl (Recordati-Turkey).  
 
   
 
 **: This drug is manufactured and licensed by Recordati İlaç San. ve Tic. A.Ş.-Turkey. 
 
Dosage: 
A single dose of the test drug and the reference drug or vice versa, 
administered with 240 mL of water at room temperature, in each period after 
a standardised high-fat and high-calorie breakfast. 
 
Indication: 
Bioequivalence study 
 
Study Design: 
Single-dose, open-label, randomised, four-period, replicated, 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:                 
44 (to be included) 
  
40-44 (completed subjects / per protocol population for pharmacokinetic 
evaluation) 
 
Subjects: 
18 - 55 aged healthy male volunteers, normal weight according to the BMI 
 
Sponsor: 
Pharmactive İlaç San.ve Tic. A.Ş.-Turkey 
 
Phase: 
 
I (Bioequivalence study) 
 
Planned Initiation:  
2Q 2019 (inclusion of first subject) 
 
Planned Duration: 
6 weeks (approximately) including the wash-out period of 7 days and the 
time between last blood sampling in the last period to the final examination 
tests. 
 
 
 

Study Code: NOV2019/01864 
                                                   
 
 
 Date: 13.05.2019 
Clinical Study Protocol 
 
 
 
 
 
 
 
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Primary Endpoint:   
AUC0-tlast and Cmax of phenyramidol 
 
Secondary Endpoint:  
AUC0-∞, t1/2, tmax of phenyramidol 
 
Safety Endpoints: 
Adverse events, clinical and laboratory examinations. 
 
Principal Investigator:       Prof. Dr. Muradiye Nacak 
 
Co-investigators:  
İsmail Taner Ezgi, MD 
 
Erol Durucu, MD 
                                            
Gaziantep University, FARMAGEN-GCP Center, Gaziantep- Turkey 
 
Analytics: 
     
Plasma concentrations of phenyramidol 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 each clinical study period: at pre-dose* and 
at 0.17, 0.33, 0.50, 0.66, 0.83, 1.00, 1.33, 1.66, 2.00, 2.33, 2.66, 3.00, 3.50, 
4.00, 6.00, 8.00, 10.00 hours post-dose (1 x 5 mL each; totally 18 blood 
sample points)  
 
 
 
 * Note:  
1. Only in Period I; at t0 the blood sample amount will be 12 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 
phenyramidol analysis [for details see section 13.7 (Blood Sampling for Drug 
Analysis)] 
 
Wash-out duration:  
   At least 7 days. 
 
Acceptance Range: 
If intra-subject coefficient of variation of reference product (CVR) is equal or 
less than 30%, acceptance range for Cmax and AUC0-tlast is 80-125%. If the 
reference product exerts a highly variable drug product characteristic (intra-
subject CVR > 30%), the acceptance criteria for only Cmax will be widened to a 
maximum of 69.84 -143.19% according to the EMA guideline (Guideline on 
the Investigation of Bioequivalence-CPMP/EWP/QWP/1401/98 Rev. 1/Corr, 
London 20 January 2010) using scaled-average-bioequivalence (SABE). The 
other criteria for SABE: The geometric mean ratio should lie within the 
conventional acceptance range 80-125%. 
 
 
If the results  do not met the criterias of SABE, reference-scaled average 
bioequivalence (RSABE) approach will be used defined in the Progesterone 
Capsule Guidance of FDA (Draft guidance for industry: bioequivalence 
recommendations for progesterone oral capsules. Silver Spring: Center for 
Drug Evaluation and Research (CDER), 2011) and given as additional 
information. 
 

Study Code: NOV2019/01864 
                                                   
 
 
 Date: 13.05.2019 
Clinical Study Protocol 
 
 
 
 
 
 
 
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                      Page 4 of 60 
 
  
 
 
 
 
 
 
 
 
 
1.  THE PARTIES of PROJECT 
 
Study Code:                       
NOV2019/01864 
 
Study Title: 
Open-label, randomised, single oral dose, four-period, replicated, cross-over 
trial to assess the bioequivalence of Feniramidol HCl 400 mg Film Tablet 
(Test Drug) in comparison with Cabral 400 mg Film Tablet (Reference 
Drug) in healthy male subjects under fed conditions 
 
Sponsor: 
Pharmactive İlaç San.ve Tic. A.Ş. 
 
Mahmutbey Mah. Dilmenler Cad. No:19/3 
 
Aslanoba Plaza MİA Bölgesi Bağcılar-İstanbul 
 
Phone: (+90) 212 444 72 92   
 
Fax: (+90) 212 445 11 85 
 
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 University FARMAGEN GCP Center  
 
Gaziantep University 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  Pharmactive İlaç San.ve Tic. A.Ş. , 
except to the extent necessary to obtain informed consent from potential volunteers. 

Study Code: NOV2019/01864 
                                                   
 
 
 Date: 13.05.2019 
Clinical Study Protocol 
 
 
 
 
 
 
 
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                      Page 5 of 60 
 
  
 
 
 
 
 
 
 
 
 
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 
16 
7.1. CHEMICAL AND PHARMACEUTICAL PROPERTIES 
16 
7.2. PHARMACOLOGICAL PROPERTIES 
16 
7.3. PHARMACOKİNETİCS 
16 
7.4. INDICATIONS 
16 
7.5. CONTRAINDICATIONS 
16 
7.6. ADVERSE REACTIONS 
17 
7.7. CAUTIONS AND PRECAUTIONS 
17 
7.8. INTERACTIONS 
17 
8.     OBJECTIVE OF THE TRIAL 
18 
9. BENEFIT-RISK EVALUATION 
18 
10.  
DESIGN 
18 
11.  
SELECTION OF VOLUNTEERS 
19 
11.1. INCLUSION CRITERIA 
19 
11.2. EXCLUSION CRITERIA 
20 
11.3. OTHER CONDITIONS 
21 
11.4. CODING SUBJECTS 
21 
12.  
MEDICATION 
22 
12.1. STUDY MEDICATION 
22 
12.1.1. Test Drug: 
23 
12.1.2. Reference Drug: 
23 
12.2. BLINDING 
24 
12.2.1. For Clinical Phase 
24 
12.2.2. For Analytical Phase 
24 
12.3. DOSAGE, DURATION OF TREATMENT 
24 
12.4. COMPLIANCE 
24 
12.5. HANDLING AND DRUG ACCOUNTABILITY 
24 
12.6. CONCOMITANT MEDICATION 
25 
12.7. RESCUE MEDICATION 
25 
12.8. STORAGE OF STUDY MEDICATION 
25 
13. STUDY PROCEDURE 
26 
13.1. GENERAL PROCEDURE 
26 
13.2. SPECIAL PROCEDURES 
27 
13.3. DAILY ACTIVITIES DURING THE TRIAL 
28 
13.4. RESTRICTIONS 
29 
13.5. DRUG ADMINISTRATION 
29 
13.6. DIETARY REGIMEN 
30 
13.7. BLOOD SAMPLING FOR DRUG ANALYSIS 
31 
13.8. ENDPOINT(S) FOR THE STUDY 
32 
14. PREMATURE DISCONTINUATION 
33 
14.1. WITHDRAWAL OF VOLUNTEERS 
33 
14.2. REPLACEMENT OF DROP-OUTS 
33 

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14.3. EARLY TERMINATION OF THE STUDY 
34 
14.4. DROP-OUT SAMPLES 
34 
15.  
ADVERSE EVENTS 
35 
15.1. DEFINITION OF ADVERSE EVENT / SERIOUS ADVERSE EVENT / ADVERSE DRUG REACTION / UNEXPECTED 
ADVERSE DRUG REACTION 
35 
15.2. RELATIONSHIP TO THE STUDY MEDICATION 
35 
15.3. REPORTING AND DOCUMENTATION OF ADVERSE EVENT(S) 
37 
16.  
STUDY DOCUMENTATION 
38 
16.1. INVESTIGATOR'S FILE 
38 
16.2. CASE REPORT FORM (CRF) 
39 
17.  
ANALYTICAL EVALUATION 
40 
17.1. REANALYSIS OF STUDY SAMPLES 
40 
17.2. INCURRED SAMPLE REANALYSIS 
40 
18.  PHARMACOKINETIC EVALUATION 
41 
19. 
STATISTICAL PROCEDURES 
42 
19.1. TARGET VARIABLES 
42 
19.1.1. Primary Target Variables 
42 
19.1.2. Secondary Target Variables 
42 
19.1.3. Criteria for Bioequivalence 
42 
19.2. CALCULATION OF SAMPLE SIZE 
44 
19.3. STATISTICAL CODE AND RANDOMISATION 
44 
19.4. DOCUMENTATION OF THE DATA 
44 
19.5. INTERIM EVALUATION 
45 
20. ETHICAL CONSIDERATIONS 
46 
20.1. ETHICAL CONDUCT OF THE STUDY 
46 
20.2. ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
46 
20.3. VOLUNTEER INFORMATION AND INFORMED CONSENT 
47 
21. 
GOOD CLINICAL PRACTICE 
49 
21.1. LEGAL REQUIREMENTS 
49 
21.2. PREVENTIVE MEASURES TO REDUCE BIAS 
50 
21.3. INVESTIGATOR'S OBLIGATIONS 
50 
21.4. ADHERENCE TO THE PROTOCOL 
50 
21.5. DATA HANDLING PROCEDURES 
51 
21.6. MONITORING 
51 
21.7. AUDITING 
52 
21.8. CONFIDENTIALITY 
52 
21.9. INSURANCE 
53 
21.10. SUBJECT PAYMENT 
53 
21.11 QUALIFICATION OF THE INVESTIGATOR 
53 
22. 
PROTOCOL AMENDMENTS 
54 
22.1. PROTOCOL MODIFICATIONS 
54 
22.2. PROTOCOL VIOLATIONS 
54 
23. 
REPORTS 
55 
23.1. ARCHIVING 
55 
24. 
COMMUNICATION OF STUDY RESULTS 
56 
25.  CONTRACT AND COSTS 
56 
26. 
FINAL REGULATIONS 
56 
27. 
REFERENCES 
58 
28. 
LOCATION OF STUDY DOCUMENTATION 
59 
29. 
APPENDICES 
60 

Study Code: NOV2019/01864 
                                                   
 
 
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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: NOV2019/01864 
                                                   
 
 
 Date: 13.05.2019 
Clinical Study Protocol 
 
 
 
 
 
 
 
      Version: 1.0 
 
  
 
 
 
 
 
 
 
 
                      Page 8 of 60 
 
  
 
 
 
 
 
 
 
 
 
 
Sponsor Representative:  
  
 Başak Acar Karaköy   
 
                                                                   
Pharmactive İlaç San.ve Tic. A.Ş.  
                                                                   
Phone: (+90) 282 735 60 00 
                                                                   
Fax: (+90) 282 758 35 25  
 
  
E-mail: BasakAcar.karakoy@pharmactive.com.tr 
 
  
Date and Signature:  
 
 
 
 
 
 
_________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Code: NOV2019/01864 
                                                   
 
 
 Date: 13.05.2019 
Clinical Study Protocol 
 
 
 
 
 
 
 
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                      Page 9 of 60 
 
  
 
 
 
 
 
 
 
 
 
Project Manager:  
Peri Aytaç, PhD. 
          
Novagenix Bioanalytical Drug R&D Centre  
 
 
 
Phone: +90 312 398 10 81/119 
 
 
 
Fax: +90 312 398 07 18 
 
 
 
E-mail: paytac@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: NOV2019/01864 
                                                   
 
 
 Date: 13.05.2019 
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 
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 
Epidermal growth factor receptor 
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 
RSABE 
Reference-Scaled-Average Bioequivalence 
SAE 
Serious Adverse Event 
SABE 
Scaled-Average Bioequivalence 
SBP                             
Systolic Blood Pressure  
SD  
Standard Deviation 
SGOT                         
Serum Glutamic Oxaloacetic Transminase 
SGPT                        
Serum Glutamic Pyruvic Transminase  
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: NOV2019/01864 
                                                   
 
 
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Clinical Study Protocol 
 
 
 
 
 
 
 
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5.  SUMMARY AND SCHEDULE FOR THE CLINICAL TRIAL 
5.1. Summary 
 
Title: 
Open-label, randomised, single oral dose, four-period, replicated, 
cross-over trial to assess the bioequivalence of Feniramidol HCl 400 
mg Film Tablet (Test Drug) in comparison with Cabral 400 mg Film 
Tablet (Reference Drug) in healthy male subjects under fed 
conditions 
 
Study objective: 
The aim of this study is to evaluate the pharmacokinetic profiles of 
phenyramidol and the relative bioavailability of the test product 
(Feniramidol HCl 400 mg Film Tablet, Pharmactive -Turkey) in 
comparison with the reference product (Cabral 400 mg Film Tablet,  
Recordati-Turkey) under fed conditions. The primary objective is to 
demonstrate the bioequivalence of test and reference products. 
 
  
Test Drug*:  
“Feniramidol HCl 400 mg Film Tablet” containing 400 mg 
phenyramidol HCl (Pharmactive-Turkey).  
 
 
 *: This drug is manufactured by Pharmactive İlaç San.ve Tic. A.Ş. -Turkey. 
 
  
Reference Drug**:  
 “Cabral 400 mg Film Tablet” containing 400 mg phenyramidol HCl 
(Recordati-Turkey).  
 
 
 
 
 
 **: This drug is manufactured and licensed by Recordati İlaç San. ve Tic. A.Ş.-Turkey. 
 
Dosage: 
Once daily 400 mg phenyramidol HCl in a period. 
 
Indication: 
Bioequivalence study 
 
Study design: 
Single dose, open-label, randomised, four-period, replicated, 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: 
44 (to be included) 
  
40-44 
(completed 
subjects 
/ 
per 
protocol 
population 
for 
pharmacokinetic evaluation) 
 
 
Subject selection criterion:  18 - 55 aged healthy male volunteers. Normal weight according to the 
BMI. 
 
Blood sampling:  
 
The samples will be drawn in each clinical study period: at pre-
dose* and at 0.17, 0.33, 0.50, 0.66, 0.83, 1.00, 1.33, 1.66, 2.00, 2.33, 
2.66, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00 hours post-dose (1 x 5 mL 
each; totally 18 blood sample points)  
                                       
   *Note:  
1. Only in Period I; at t0 the blood sample amount will be 12 mL. 

Study Code: NOV2019/01864 
                                                   
 
 
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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 phenyramidol analysis 
[for details see section 13.7 (Blood Sampling for Drug Analysis)] 
Route of   
Administration: 
 
Oral 
 
Duration of Treatment:  
6 weeks (approximately) including the wash out period of 7 days and 
the time between last blood sampling in the last period to the final 
examination tests. 
 
Duration of Wash-out:  
At least 7 days. 
 
Procedure:  
In the 1st period, each volunteer will receive in random order one single 
oral dose of pheyramidol HCl product (either 1 tablet of the test drug 
or 1 tablet of the reference drug) under fed conditions (the volunteers 
will be fast at least 10 hours until the high-fat and high-calorie 
breakfast). Blood samples will be drawn immediately before the 
dosing and at 0.17, 0.33, 0.50, 0.66, 0.83, 1.00, 1.33, 1.66, 2.00, 2.33, 
2.66, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00 hours after the dosing. In the 
2nd, 3rd and 4th periods there will be the same procedure.  
 
Analysis of phenyramidol: Plasma concentrations of phenyramidol 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: 
If intra-subject coefficient of variation of reference product (CVR) is 
equal or less than 30%, acceptance range for Cmax and AUC0-tlast is  
80-125%. If the reference product exerts a highly variable drug product 
characteristic (intra-subject CVR > 30%), the acceptance criteria for 
only Cmax will be widened to a maximum of 69.84 -143.19% according 
to the EMA guideline using SABE. The other criteria for SABE: The 
geometric mean ratio should lie within the conventional acceptance 
range 80-125%. 
 
 
If the results  do not met the criterias of SABE, RSABE approach will 
be used defined in the Progesterone Capsule Guidance of FDA and 
given as additional information.  
Evaluation of 
bioequivalence: 
In order to investigate the bioequivalence of Test Drug and Reference 
Drug, the 90% confidence intervals will be calculated for the geometric 
mean ratios of test and reference for Cmax and AUC0-tlast of 
phenyramidol. 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 phenyramidol will be logarithmically 

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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 
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: 
 Pharmactive İlaç San.ve Tic. A.Ş. 
   Representative: Başak Acar Karaköy 
 
 
Protocol code: 
NOV2019/01864 
 
Phase: 
I (Bioequivalence study) 
 
Planned initiation: 
2Q 2019 (inclusion of first subject) 
 
Planned duration: 
6 weeks (approximately) including a wash out period of 7 days followed 
by final examination tests. 
 
Primary Endpoint:   
AUC0-tlast and Cmax of phenyramidol 
 
Secondary Endpoint:  
AUC0-∞, t1/2 and tmax of phenyramidol 
 
Safety Endpoints: 
Adverse events, clinical and laboratory examinations. 
 
Principal Investigator: 
Prof. Dr. Muradiye Nacak 
 
Co-investigators:             İsmail Taner Ezgi, MD 
                                         Erol Durucu, MD 
                                              Gaziantep University, 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 + 2 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 
 
 
*  The final examination will be carried out on the day of last blood sampling in the last period or not more than 7 days 
thereafter. 
 
**  For amphetamines, cannabinoids, benzodiazepines, cocaine, opioids, and barbiturates.  
 
   ***Blood sampling points (for each period): at pre-dose (12 mL only in Period I)  and at 0.17, 0.33, 0.50, 0.66, 
0.83, 1.00, 1.33, 1.66, 2.00, 2.33, 2.66, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00  
hours post-dose (1 x 5 mL each; totally 18 blood sample points) 
Note:  
1. 
Only in Period I; at t0 the blood sample amount will be 12 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 phenyramidol analysis. [for details see section 13.7 (Blood Sampling 
for Drug Analysis)] 
 
****Adverse event questioning (in each period): at hospitalisation/randomization day (Day 0), pre-dose, 1.00, 4.00, 10.00 
hours post-dose.  
Note: The subjects will give the information about any adverse events occurring in out-patient period (including wash-out period). Also, in 
the first day (medication day) of Periods II-IV, investigator will ask the subjects about any adverse events during wash-out period. 
 
Screening 
PERIOD 
I 
 
 
PERIOD 
II 
 
PERIOD 
 III 
 
PERIOD  
IV 
 
*Final 
examination 
Wash-out period  
(at least 7 days) 
 
 
Wash-out  
 
Wash-out  
 
Wash-out  
 
 
Study Day: 
-14 ... -1 
0 
1 
2….6 
0 
1 
2....6 
0 
1 
2…6 
0 
1 
2..9 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
(Birth date, ethnic 
group, gender, height, 
weight, BMI) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical 
● 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, anti-HCV, HIV 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical examination 
(Physical examination,  
ECG) 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
Clinical chemistry, 
haematology, urinalysis 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
Blood pressure, pulse 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
● 
Drug abuse screening** 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
Alcohol breath test 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
Body temperature 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
● 
Check of restrictions, 
 
● 
● 
 
● 
● 
 
● 
● 
 
● 
● 
 
Exclusion criteria and 
withdrawal of 
volunteers 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Hospitalisation day 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
Randomisation day 
 
● 
 
 
 
 
 
 
 
 
 
 
 
Drug administration 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
Blood sampling*** 
(0-10 h) 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
Adverse event 
questioning**** 
 
● 
● 
 
● 
● 
 
● 
● 
 
● 
● 
 

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7. INTRODUCTION 
7.1. Chemical and Pharmaceutical Properties 
 
Phenyramidol is a skeletal muscle relaxant agent and an aminopyridine derivative  
chemically described as (1S)-1-phenyl-2-(pyridin-2-ylamino)ethanol with an empirical 
formula of C13H14N2O and a molecular weight of 214.27 g/mol. 
Phenyramidol is a white, crystalline, water soluble salt that forms slightly acid aqueous 
solutions. It is quite stable either in the pure state or in solution under a variety of 
temperature or PH conditions. 
 
Figure 1. Chemical structure of Phenyramidol 
 
N
N
H
OH
 
 
      7.2. Pharmacological Properties 
 
Phenyramidol shows its muscle relaxant activity by interneuronal blockage without 
disrupting neuromuscular function. Thus, it relieves muscle spasm, and breaks pain-
spasm chain by blocking polisynaptic reflexes in the brain and medulla spinalis. It does 
not affect monosynaptic reflexes.  
Phenyramidol has a very high analgesic effect than aspirin and close to codeine. It used 
in the treatment of acute and chronic human musculoskeletal system pains as muscle 
relaxant and analgesic. 
 
7.3. Pharmacokinetics  
 
Phenyramidol reaches maximum plasma concentration in an hour (0.25-1) after 
absorption from gastrointestinal tract. It is widely distributed in skeletal muscles and 
involved in circulatory system very slowly.  
Studies have shown that cytochrome P450 enzymes are effective in phenyramidol 
metabolism. It is conjugated with glucuronic acid in the liver and it is excreted as 
glucuronide conjugates from the urinary tract. The drug is eliminated from the bile and 
the bacterial glucuronidase enzymes make the glucuronide conjugate of phenyramidol 
free. The drug enters enterohepatic circulation and is excreted by faeces. Its elimination 
half-life is 1-2 hours.  
7.4. Indications 
Phenyramidol is indicated in the symptomatic treatment of acute painful muscle spasms 
associated with musculoskeletal system. 
7.5. Contraindications 
Phenyramidol is contraindicated in who have hypersensitivity to the active substance or 
to any of the other excipients. 
 

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7.6. Adverse Reactions 
The adverse events, considered to be at least possibly related to treatment, are listed 
below by body system, organ class, and absolute frequency. Frequencies are defined as 
very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), 
rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).  
 
Undesirable effects in patients receiving phenyramidol are: 
 
System Organ Class 
Immune system disorders 
Hypersensitivity, pruritus, skin rash, exanthem 
rare 
Nervous system disorders 
Sleep disorders, sedation, dizziness, drowsiness 
rare 
Gastrointestinal disorders 
Nausea, vomiting, abdominal fullness 
rare 
General disorders and administration site conditions 
Tongue burn 
rare 
 
7.7. Cautions and Precautions 
Phenyramidol strengthens the effects of antigoagulants, certain oral antidiabetics and 
anticonvulsant drugs. For this reason, caution should be exercised when using these 
drugs together. 
Phenyramidol may cause central effects such as sedation and widespread depression, 
especially at higher doses. It should be used with caution in people which have low 
blood pressure. 
Caution should be exercised in liver insufficiency or in combination with drugs known 
to be harmful to the liver. 
 
7.8. Interactions 
Phenyramidol inhibits the metabolism of anticoagulants such as coumarin derivatives 
(eg bishydroxycoumarin, warfarin or fenindione) via P450 enzymes, when used in 
combination with these drugs. For this reason, the duration of action of anticoagulants 
and therefore prothrombin time may be prolonged. Phenyramidol should not be used 
simultaneously with these drugs. 
Phenyramidol 
inhibits 
the 
metabolism 
of 
anticonvulsant 
drugs 
such 
as 
diphenylhydantoin. 
Since anticonvulsant plasma levels may cause nystagmus, ataxia and mental changes 
due to increased plasma levels, concomitant use of such drugs with phenyramidol 
should be avoided. 
Phenyamidol inhibits tolbutamide metabolism and may lead to the observation of 
prolonged hypoglycaemia. Therefore, caution should be exercised when used in 
combination with tolbutamide. 

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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 phenyramidol of the Test Drug (Feniramidol HCl 400 mg Film Tablet, 
Pharmactive-Turkey) in comparison with Reference Drug (Cabral 400 mg Film Tablet, 
Recordati- Turkey) under fed conditions.  
 
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, four-period, replicated, cross-over study, 44 
healthy male subjects (intention to treat population) will receive one single oral dose of 
phenyramidol HCl (one film tablet of the test drug or one film tablet of the reference 
drug) after a standardised high-fat and high-calorie breakfast according to a sequence 
determined by randomisation.  
 
A total of 44 volunteers will be enrolled in the trial and treated accordingly with the aim 
to have at least 40 volunteers (completed subjects / per protocol population for 
pharmacokinetic evaluation) who completed the study in accordance with the study 
protocol. Any subject withdrawn/drop-out from the study due to any reason after 
inrandomization (on day 0) and before dosing of Period-1 (on Day 1), he/they will be 
replaced (completed) with additional enrolled subjects for ensuring dosing of 44 subjects.  If 
any volunteer(s) is dropped out after dosing (on Day 1), he/they will not be replaced until 
total number of subjects fall below 40. 
 
Test Drug: “Feniramidol HCl 400 mg Film Tablet” is manufactured by Pharmactive İlaç 
San.ve Tic. A.Ş., Turkey; will be licensed and will be marketed by Pharmactive İlaç San.ve 
Tic. A.Ş., Turkey. 
 
Reference Drug: “Cabral 400 mg Film Tablet” is manufactured and marketed by Recordati 
İlaç San. ve Tic. A.Ş.-Turkey.   
 
In each of the four study periods, the subjects will be admitted to the FARMAGEN 
Clinical Unit in the evening (18:00) prior to morning of the administration of medication. 
Volunteers will be confined to the clinical unit and dosing will occur under conditions of 
hospitalization. The subjects will be fast at least 10 hours, until the high-fat breakfast (the 
composition of the meal corresponds approximately to 150 kcal from protein, 250 kcal from 
carbonhydrate and 500-600 kcal from fat with a total caloric content of approximately 800-
1000 kcal) in the morning. They will have a breakfast at least 30 minutes before dosing and 
the breakfast will be completed at least 5 minutes before the administration of the drug, at the 
same time in each periods. Medications will be administered between 08:00-09:00 a.m. after a 
standardised high-fat breakfast. The lunch will be 4 hours post dosing and the dinner will be 
10 hours post dosing.. Blood sampling for the determination of phenyramidol plasma 
concentrations will be drawn at specified time points. After taking the last blood sample and 
carried out the post-study examination, the subjects will be allowed to leave the clinic. 

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The standardised high-fat and high calorie breakfast consists of: 
 
2 boiled eggs, 100 g of sausage, 2 slices of toast with 10g butter, 113g of hash brown potatoes 
with 10 g butter, 240 ml of whole milk. 
An overview of the study procedures is given in the Study Flow Chart provided in section 6. 
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 18 and 55 years, 
2. Non smokers or smoking maximum 5 cigarettes a day, those who won’t smoke or drink 
coffee during each study period, 
3. Negative alcohol breath test results, 
4. Normal physical examination at screening visit, 
5. 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, 
6. Ability to communicate adequately with the investigator himself or his/her representatives, 
7. Ability and agreement to comply with the study requirements, 
8. 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, 
9. Normal/ acceptable 12-lead electrocardiographic results at least after 5 minutes of rest, 
10. 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), 
11. Understanding of the study and agreement to give a written informed consent according to 
section 20.3. 
 

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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 and/or known allergy for phenyramidol HCl or any other 
ingredients of the products. 
2. 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. 
3. 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). 
4. Presence or history of malabsorption or any gastrointestinal surgery except appendectomy or except 
herniotomy. 
5. 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. 
6. 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. 
7. 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). 
8. Use of any vitamins or herbal products within 7 days prior to the initial dose of the study 
medication. 
9. History of allergic response to heparin. 
10. Subjects who have any chronic disease which might interfere with absorption, distribution, 
metabolism or excretion of the drug. 
11. 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. 
12. Subjects who has taken any grapefruit or grapefruit juice during 7 days prior to drug administration, 
during the study, or during the washout periods. 
13. History of drug abuse. 
14. 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). 
15. Positive blood test for HBV, HCV and HIV. 
16. Who have relationship to the investigator. 
17. Who are not suitable to any of inclusion criteria. 
18. History of difficulty of swallowing. 
19. Intake of depot injectable solutions (including study medications) within 6 months before start of 
the study. 

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20. Intake of enzyme-inducing, organotoxic or long half-life drugs within 4 weeks before start of the 
study. 
21. 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.  
The replacement volunteers will receive the treatment sequence of the drop-outs and 
will be assigned the same number as the volunteers they are replacing, however with 
an "R" suffix will be add to their volunteer code within the study. For instance, if 
volunteer code 03 is a drop-out, the additionally enrolled volunteer receives the code 
03R. 
If the replaced volunteers will be drop-out, likewise the previous one, replaced 
volunteers will receive the treatment sequence of the drop-outs and will be assigned 
the same number as the volunteers they are replacing. For instance, if volunteer code 
03R is a drop-out, the additionally enrolled volunteer receives the code 03RR. 

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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, Pharmactive İlaç San.ve Tic. 
A.Ş.-Turkey. The packaging and labelling will be done according to the GMP and 
GCP requirements.  
The reference drugs marketing authorisation holder is Recordati İlaç San. ve Tic. 
A.Ş.-Turkey. 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 University 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:  
Phenyramidol HCl 
Formulation: 
 
Film Tablets for oral administration 
Strength: 
 
400 mg  
Manufacturer:                   
Pharmactive İlaç San.ve Tic. A.Ş. - Turkey 
 
Marketing Authorisation Holder:  
Pharmactive İlaç San.ve Tic. A.Ş. - Turkey 
       Trade name: 
Feniramidol HCl 400 mg Film Tablet 
 
Storage requirements:      
Store below 25°C at room temperature. 
  
Certificate of analysis: 
To be provided by the Sponsor together with medication 
 
    12.1.2. Reference Drug: 
 
Active substance:  
Phenyramidol HCl 
Formulation: 
 
Film Tablets for oral administration 
Strength: 
 
400 mg 
Manufactured:                   
Recordati İlaç San. ve Tic. A.Ş. -Turkey 
Marketing Authorisation Holder:  
Recordati İlaç San. ve Tic. A.Ş.-Turkey 
Trade name: 
 
 Cabral 400 mg Film Tablet 
 
Storage requirements:      
Store below 25°C at room temperature. 
Certificate of analysis: 
 
To be provided by the Sponsor together with medication 
 
 
 
   

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         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 1 film tablet of the test drug or 1 film 
tablet of the reference drug or vice versa in each period. 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.  
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) which have not been used have to be returned to 
sponsor after completion of the study. It is not allowed to use the study medication for 
any other purpose. 

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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 (e.g. paracetamol) 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 (“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 safety / tolerability profiles of the administered drug substance are 
well known. 
12.8. Storage of Study Medication 
The investigator will be responsible for proper storage of the investigational products. 
All drug supplies must be stored below 25°C 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 between time period of before 14 days to before 1 day 
of dosing day 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 not more than 14 days before the beginning 
of the trial (first study period). 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. 
Clinical laboratory tests will be performed using the auto analyser at a contracted and         
certified laboratory (GAMA Tıp Merkezi-G.Antep). 
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. The volunteers will also be 
checked for presence of HBsAg, HCV-Ab and HIV-Ab in serum. 
*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 entry visit and hospitalization/randomization days of Period I-IV the 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. 
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: 

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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. 
The test and reference products will be administered under fed conditions each in a 
randomised manner in four-period with at least 7 days wash-out period. Volunteers 
will be treated under hospitalization conditions on Day 1 of either period and will be 
hospitalised at the Clinical Facility (FARMAGEN-Good Clinical Practice and 
Research Center)  from the evening of  Day 0 (hospitalization/randomization day) 
normally until the 18.00 (t10.00) in Day 1 to ensure subjects’ safety as well as 
standardised trial conditions during profiling days (e.g. in view of food and fluid 
intake, diet, fed 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 at approximately 18:00 on the day before the 
treatment (Day 0) of each period and will remain there for 26 hours. A measurement 
of body temperature will be performed in the evening before each in-house period.  
The subjects will be fast at least 10 hours until the breakfast. 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 examination and laboratory 
tests on the day of  last sampling in last (fourth) period or not more than 7 days 
thereafter.  
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. 
13.2. Special Procedures 
Study drugs will be administered on the Days 1. The subjects will be fasted overnight 
(at least 10 hours) and will take standardised high-fast breakfast (2 boiled eggs, 100 g 
of sausage, 2 slices of toast with 10 g butter, 113 g of hash brown potatoes with 10 g 
butter, 240 mL of whole milk) in the morning. The breakfast will be served at least 30 
minutes before dosing on the days of dosing and will be completed at least 5 minutes 
before drug administration. Administrations will take place in the morning between 
08:00-09:00 a.m. and the exact time will be recorded on CRFs. The lunch time will be 
4 hours post dosing and the dinner will be 10 hours post dosing. 
Subjects are not allowed to drink water from 1 h before until 1 h after administration, 
except that while dosing.  

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Subjects will be dosed in sitting position and during the next 2 hours they will either 
sit or stand without lying in bed for each period.   
 
13.3. Daily Activities during the Trial 
Entry examination: 
The entry examination will be carried out not more than 14 days before the beginning 
of the trial. 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, 
haematology, HBsAg, HIV-Ab, HCV-Ab, drug screening, alcohol breath test,  
urinalysis). 
 
PERIOD I-IV: 
 
 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 with separation of plasma. 
 Standardised high-fat breakfast will be served before dosing on day 1 (The breakfast  
will be served at least 30 minutes before dosing and completed at least 5 minutes 
before taking the drug). 
 Treatments will be given according to randomised administration (single dose of the 
Test Drug or Reference Drugs) with compliance check (approximately 08:00-09:00 
a.m.)  
  Blood sampling (0.17-10.00 hours) will be done after drug administration with 
separation of plasma 
 Standardised lunch will be served at 4 hours after the dosing.   
 Standardised dinner will be served at 10 hours after the dosing.  
 Questioning for and registration of adverse events at hospitalization/randomization 
day (Day 0), pre dose, 1.00, 4.00, 10.00 hours post-dose*.  
 Discharge from the clinic (after t10.00) 
 
*: The subjects will be given the information about any adverse events occurring in out-patient period (including 
wash-out period). Also, in the first day (medication day) of Periods II-IV, investigator will ask the subjects about 
any adverse events during wash out period. 
 
 

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Final examination: 
The final examination will be carried out on the day of last blood sampling of the last 
(fourth) period or not more than 7 days thereafter. 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, haematology, urinalysis) 
 
Laboratory screening. The sampling for laboratory screening can be performed together 
with the last sampling for the kinetic profile in 12 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 periods 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. 
When confined to the clinical centre, the volunteers have to avoid from alcohol starting one 
week before hospitalization/randomization day until the last blood sampling of either 
period. Smoking will not be permitted during the periods of blood sampling during 
hospitalization of either period. 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 either period will be allowed. No 
grapefruit containing products from 7 days prior to the first dosing until the last sampling will 
be allowed. The volunteers will abstain from food and beverages from 21:00 on the 
hospitalization evening until breakfast.(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 period starting 24 hours before the initiation  of the 
study until confinement to the clinic. Upon admission to the clinic for each treatment period, 
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; Feniramidol HCl 400 mg Film Tablet  
Reference Drug; Cabral 400 mg Film Tablet  
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 products (Phenyramidol HCl each case) 
will be administered. After the washout period; in Period II-IV, the subjects will be 
administered by the other drug that they will not administered in the Period I-III. 
 
 

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The investigator or the co-investigator will administer the study medications 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 during the next 2 hours they will 
either sit or stand without lying down in bed. 
 
The drugs will be administered approximately at 08:00-09:00 a.m.for each period. 
 
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/randomization day (Day 0) in each period.  
In treatment day (Day 1), a standardised high-fat breakfast (total caloric value is 
approximately 800- 1000 kcal) will be started at least 30 minutes before dosing in each 
period. 
A standard lunch (total caloric value is approximately 1200 kcal) will be provided 
4 hours after dosing in each period.  
A standard evening meal (total caloric value is approximately 1200 kcal) will be 
provided 10 hours after dosing in each period.  
The same meal composition has to be served in all periods of the trial. This will be 
documented in the CRF. 

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13.7. Blood Sampling for Drug Analysis 
 
Venous blood will be drawn at the following times:  
Period 
Day 
Time (hour)* 
Tube No 
 
1-4 
1 
 
t0.00 
P01 
t0.17 
P02 
t0.33 
P03 
t0.50 
P04 
t0.66 
P05 
t0.83 
P06 
t1.00 
P07 
t1.33 
P08 
t1.66 
P09 
t2.00 
P10 
t2.33 
P11 
t2.66 
P12 
t3.00 
P13 
t3.50 
P14 
t4.00 
P15 
t6.00 
P16 
t8.00 
P17 
t10.00 
P18 
* 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. 
5 mL blood samples will be drawn at predetermined sampling times during the clinical 
study to determine plasma phenyramidol concentrations.  
Note:  
1. Only in Period I; at t0 the blood sample amount will be 12 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. 
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 phenyramidol analysis. 
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 419 mL. 
[Including “The Heparinised Discarded Blood (approximately 20 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”]. 
*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 approximately 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 

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plasma from each sample will be transferred into two 3 mL transparent, polypropylene 
tubes per sample (at least 1.5 mL per tube), The tubes will be capped, wrapped in  
aluminium foil (for light protecting) and transferred to a deep-freezer and stored at   
-70°C. Protection from light as far as possible is strongly recommended because of 
the light sensitivity of the compound phenyramidol. Blood samples will be withdrawn 
in dark (under sodium vapour lamp).  
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: 
 
Phenyramidol 
Study # :    NOV01864 
Subj #    1 
Period : 1 
Time: 0 h  P # : P1 
 
 
13.8. Endpoint(s) For The Study 
 
Primary Endpoint: AUC0-tlast and Cmax of phenyramidol. 
 
Secondary Endpoint: AUC0-∞, t1/2, tmax of phenyramidol. 
 
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 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 44 volunteers will be enrolled in the trial and treated accordingly with the aim to 
have at least 40 volunteers (completed subjects / per protocol population for pharmacokinetic 
evaluation) who completed the study in accordance with the study protocol. Any subject 
withdrawn/drop-out from the study due to any reason after randomization (on day 0), and 
before dosing of Period-1 (on Day 1), he/they will be replaced (completed) with additional 
enrolled subjects for ensuring dosing of 44 subjects.  If any volunteer(s) is dropped out after 
dosing (on Day 1), he/they will not be replaced until total number of subjects fall below 40. 
 

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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, 1.00, 4.00, 10.00 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 Pharmactive İlaç San.ve Tic. A.Ş. 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 Pharmactive İlaç San.ve Tic. A.Ş. 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 Pharmactive İlaç San.ve Tic. A.Ş. 
as soon as possible. 
The responsible sites for the upper procedure are: 
Pharmactive İlaç San.ve Tic. A.Ş. 
Sponsor Responsible  
Novagenix Bioanalytical Drug R&D Centre 
CRO Project Responsible 
Başak Acar Karaköy 
Phone: (+90) 282 735 60 00    
Fax: (+90) 282 758 35 25 
GSM: +90531 101 15 80 
E-mail: BasakAcar.karakoy@pharmactive.com.tr 
Peri Aytaç, PhD. 
Phone: +90 312 398 10 81/119 
Fax: +90 312 398 07 18 
GSM: +90 532 790 34 83 
E-mail: paytac@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 phenyramidol 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, May 2001 or current 
guidance on method validation date. (Note: Due to the sensitivity of phenyramidol to the 
light, sample preparation should be carried out in the dark under sodium vapour 
lamp. All samples and solutions should be kept in amber glass containers or 
protected from light by wrapping containers and tubes with aluminum foil.) 
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 16 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 phenyramidol 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, four-period, replicated, cross-over study (n = 44 
volunteers will be included), the following primary, secondary and additional 
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 given by the CPMP guideline CPMP/EWP/QWP/1401/98 
Rev. 1 dated 20 January 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 (n = 44 volunteers will be included).  
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. 
19.1.3. Criteria for Bioequivalence 
Bioequivalence of  Test Drug in comparison with Reference Drug will be evaluated 
(T vs R) and concluded if the 90% confidence intervals for the geometric mean ratios 
of the treatments are fully contained within the limits of acceptance of 80 - 125 % for 
Cmax and AUC0-tlast. But, after completion of pharmacokinetic/statistical analysis of 
this replicated study’ data 
 If the intra-subject coefficient of variation of Reference Drug (CVR) for 
pharmacokinetic parameter Cmax is greater than 30%: 
Bioequivalence of Test product will be determined using SABE according to: [U, 
L] = exp [±k· swr], where U is the upper limit of the acceptance range, L is the 
lower limit of the acceptance range, k is the regulatory constant set to 0.760, and swr 
is the intra-subject standard deviation of the log-transformed values of Cmax of the 
Reference product.  swr will be obtained from Linear Mixed Effects model 
including only data for the Reference product with the subject effect (nested within 
sequence), the period at which it is given, the sequence in which each product is 
received as fixed effects.  
Before CVR calculation for Cmax, to show the calculated intra-subject variability is a 
reliable estimate and that it is not the result of outliers, outlier analysis using 
studentized intrasubject residual will be applied to reference product data. 
The table below gives examples of how different levels of variability lead to 
different acceptance limits using this methodology; 

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The other criteria for SABE: The geometric mean ratio should lie within the 
conventional acceptance range 80- 125%. 
 
If intra-subject coefficient of variation of Reference Drug (CVR) is equal or 
less than 30%: 
Assessment of bioequivalence will be determined using average bioequivalence 
methods. For the assessment of bioequivalence, 90% CIs for the ratio of mean 
values of Cmax and AUC0-tlast which are indicatives of the rate and extent of 
absorption, respectively, were calculated using ln-transformed data and the 
acceptance limits for bioequivalence criteria, 80-125%, are applied. 
For both conditions, in order to achieve a better approximation to a normal 
distribution Cmax and AUCs data will be logarithmically transformed (base e) before 
analysis. The terms to be used in Analysis of Variance (ANOVA)  model are 
sequence, subject within sequence, period and treatment. 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 intervals for the ratios test versus 
reference preparation. The confidence intervals are calculated by retransformation 
of the shortest confidence intervals for the difference of the ln-transformed mean 
values.  
If the results do not met the criterias of SABE, RSABE approach will be used 
defined in the Progesterone Capsule Guidance of FDA and given as additional 
information. 
Differences in tmax will be evaluated non-parametrically. 
AUC0-tlast should cover at least 80% of AUC(0-∞) [(AUC0-tlast/AUC0-≥. 
Subjects should not be excluded from the statistical analysis if AUC(0-tlast) covers 
less than 80% of AUC(0-∞), but if the percentage is less than 80% in more than 20% 
of the observations then the validity of the study may need to be discussed. 
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. 
 
  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 

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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-subject coefficient of variation (CV) of Cmax is estimated to be about 60% 
according to the in-house studies. In order to demonstrate bioequivalence with a power 
of 80%, a test/reference parameter ratio 0.90 and scaled bioequivalence limits 
according to CV of Reference product, then 40 completed cases (per protocol for 
pharmacokinetic evaluation) have been estimated to be necessary for a full-replicated 
cross-over study. Considering potential dropouts and/or withdrawals, 44 subjects will 
be enrolled into the study. 
19.3. Statistical Code and Randomisation 
The randomisation table will be provided by Novagenix. 44 subjects, who will be 
included in the study, will be determined to receive either Test(s) or Reference 
Product(s) [In each study period, subjects will take different products (one dose of Test 
Drug or one dose of Reference Drug)] by a randomisation table. 
44 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 or Period III and Period IV 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 and standard deviations 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 an original 
signed version for the investigator and a copy of the signed form for 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 Feniramidol HCl 400 mg Film 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. 
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 (2016) 

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 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 (2016) 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 
1. O’Dell, TB. Pharmacology of phenyramidol (IN511) with emphasis on analgesic and muscle-
relaxant effects. Annals New York Academy of Sciences. 86(1), 191-202, 1960. 
2. Ergün, H., Polat, O., Demirkan, NA., Günalp, M., Gürler, S. The efficacy, safety, and 
pharmacokinetics of intramuscular and oral phenyramidol in patients with low back pain in an 
emergency department. Turkish Journal of Medical Sciences. 40(1): 71-76, 2010. 
3. Feniramidol Kısa Ürün Bilgisi. http://www.recordati.com.tr/Urunler/116-cabral%C2%AE-400-mg-
film-tablet-ila%C3%A7-prospekt%C3%BCs/68/. Erişim tarihi 26.03.2018. 
4. The Guidance for GCP, published by the Ministry of Health of Turkey. Circular, 13.11.2015. 
5. The Guidance on Safety Declaration of Clinical Trials , published by the Ministry of Health of Turkey, 
13.11.2015. 
6. Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. Official Journal, 
No: 29474; 13.09.2015. 
7. Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. Official Journal, 
No: 29041; 25.06.2014. 
8. Regulation on Clinical Trials of Drugs and Biological Products. Official Journal, No: 28617; 13.04.2013. 
9. 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. 
10. Regulations on Evaluation of Bioequivalence and Bioavailability of Pharmaceutical Preparations. Official 
Journal, No: 21942; 27.05.1994.  
11. Guideline on Bioanalytical Method Validation, EMEA/CHMP/EWP/192217/2009 Rev.1 Corr.2, London, 
21 July 2011. 
12. Guideline on The Investigation of Bioequivalence. CPMP/EWP/QWP/1401/98 Rev.1/Corr., London, 
EMA, 20 January 2010. 
13. Bioanalytical 
Part, 
Pharmacokinetic 
and 
Statistical 
Analyses 
of 
Bioequivalence 
Trials: 
EMEA/INS/GCP/97987/2008, London, 28.05.2008. 
14. Guidance for Industry. Bioavailability and bioequivalence studies for orally administered drug products- 
General Considerations. FDA, CDER, March 2003. 
15. Guidance for Industry. Statistical approaches to establishing bioequivalence. FDA, CDER, January 2001. 
16. ICH Topic E 9. Statistical Principles for Clinical Trials. September 1998 (CPMP/ICH/363/96). 
17. Guideline for good clinical practice E6(R2)-2017. EMA/CHMP/ICH/135/1995. 
18. Guidance for Industry. Bioanalytical Method Validation. FDA, CDER, May 2018. 
19. 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). 
20. 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) 
21. ICH Topic E2A. Guidance on Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, November 1994 (CPMP/ICH/377/95). 
22. Declaration of Helsinki, Fortaleza, 2013. 
23. FDA, Draft guidance for industry: bioequivalence recommendations for progesterone oral capsules.Silver 
Spring: Center for Drug Evaluation and Research (CDER), 2011. 

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28. 
LOCATION OF STUDY DOCUMENTATION 
The following documents are kept in the Project File at the NOVAGENIX with coded 
NOV2019/01864 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 
 
 

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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