Randomized, Single Oral Dose,Two Treatment,Four-period,Full-replicated,Cross-over Trial to Assess the BE of Orvical 200 mg/50 mg FT in Comparison With Kaletra 200 mg/50 mg FT in Healthy Male Subjects Under Fasting Conditions
Phase: PHASE1
Conditions: Bioequivalence
Sponsor: World Medicine ILAC SAN. ve TIC. A.S.

Study Code: NOV2020/01911   NCT04386876                                                    
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CLINICAL STUDY PROTOCOL 
“CONFIDENTIAL” 
 
 
 
Principal Investigator: 
Prof. Dr. Muradiye Nacak   
 
Clinical Center: 
 
Gaziantep Üniversitesi FARMAGEN GCP  Center, Gaziantep 
–Turkey 
 
 
Sponsor: 
 
World Medicine Ilaç San. ve Tic. A.Ş.   
 
 
İstanbul-Turkey 
 
Contract Research Organisation (CRO): ALPAN Farma Ltd.Şti. 
Kayseri- Turkey 
 
Contracted Analytical Laboratory: 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 World Medicine Ilaç San. ve Tic. A.Ş., Alpan 
Farma and Novagenix. Not divulged to unauthorised persons in any form, including publications and presentations, without written consent of World Medicine Ilaç San. 
ve Tic. A.Ş., Alpan Farma and Novagenix. 
 
OPEN-LABEL, RANDOMISED, SINGLE ORAL DOSE, TWO 
TREATMENT, FOUR-PERIOD, FULL-REPLICATED, 
CROSS-OVER TRIAL TO ASSESS THE BIOEQUIVALENCE 
OF ORVICAL 200 MG/50 MG FILM TABLET (TEST 
DRUG) IN COMPARISON WITH KALETRA 200 MG/50 
MG FILM KAPLI TABLET (REFERENCE DRUG) IN 
HEALTHY MALE SUBJECTS UNDER FASTING 
CONDITIONS 

Study Code: NOV2020/01911   NCT04386876                                                    
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STUDY SYNOPSIS 
 
Study Title: 
Open-label, randomised, single oral dose, two treatment, four-period,  
full-replicated, cross-over trial to assess the bioequivalence of Orvical 
200 mg/50 mg Film Tablet (Test Drug) in comparison with Kaletra 
200 mg/50 mg Film Kaplı Tablet (Reference Drug) in healthy male 
subjects under fasting conditions 
 
Study Code: 
NOV2020/01911 
 
Drugs: 
Test Drug*: “Orvical 200 mg/50 mg Film Tablet” containing 200 mg 
lopinavir and 50 mg ritonavir (World Medicine-Turkey).  
 
 *: This drug is manufactured by World Medicine Ilaç San. ve Tic. A.Ş., Turkey. 
 
  
Reference Drug**: “Kaletra 200 mg/50 mg Film Kaplı Tablet” 
containing 200 mg lopinavir and 50 mg ritonavir (AbbVie Tıbbi İlaçlar 
San. ve Tic. Ltd Şti-İstanbul, Turkey). 
 
**:This drug is manufactured by AbbVie Deutschland GmbH & Co. - 
Germany  
 
   
 
 
 
Dosage: 
A single dose of Reference product containing 200 mg lopinavir and 
50 mg ritonavir fixed dose combination and a single dose of Test 
product containing 200 mg lopinavir and 50 mg ritonavir fixed dose 
combination or vice versa; administered with 240 mL of water at room 
temperature, in each period. 
 
Indication: 
Bioequivalence study 
 
Study Design: 
Single-dose, open-label, randomised, two-treatment, four-period,  full-
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:                 
30 volunteers will be included. Drop-outs will not be replaced. 
  
  
 
 
Subjects: 
20 - 40 aged healthy male volunteers, normal weight according to the 
BMI 
 
Sponsor: 
World Medicine Ilaç San. ve Tic. A.Ş.-Turkey 
 

Study Code: NOV2020/01911   NCT04386876                                                    
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Phase: 
 
I (Bioequivalence study) 
 
Planned Initiation:  
2Q 2020 (inclusion of first subject) 
 
Planned Duration: 
13 days (approximately)  
 
Primary Endpoint:   
AUC0-tlast and Cmax of lopinavir and ritonavir  
 
  
 
Secondary Endpoint:  
AUC0-∞, t1/2, tmax of lopinavir and ritonavir 
  
  
Safety Endpoints: 
Adverse events, clinical and laboratory examinations. 
 
Principal Investigator:       Prof. Dr. Muradiye Nacak 
 
Co-investigators:  
İsmail Taner Ezgi, MD 
 
Erol Durucu, MD 
                                            Gaziantep Üniversitesi, FARMAGEN-GCP Center, Gaziantep- Turkey 
 
Analytics: 
     
Plasma concentrations of lopinavir and ritonavir will be analysed in 
LC system with appropriate detection system. 
 
GCP Statement: 
 
This study will be conducted to compliance with Good Clinical 
Practice (ICH-GCP), the Declaration of Helsinki (with amendments) 
and local legal and regulatory requirements. 
 
Blood Sampling:  
The samples will be drawn in the clinical study period: at pre-dose* 
and at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.33, 3.66, 4.00, 4.33, 4.66, 
5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 14.00, 24.00, 36.00 hours post-dose 
(1 x 5 mL each; totally 21 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 
lopinavir and ritonavir analysis [for details see section 13.7 (Blood 
Sampling for Drug Analysis)] 
 
 
Wash-out duration: 
   At least 48 hours. 
 
Acceptance Range: 
If intra-subject coefficient of variation of reference product (CVWR) is equal or 
less than 30%, acceptance range for Cmax and AUC0-tlast is 80.00-125.00%.  
 
If CVWR is more than 30% (the reference product exerts a highly variable drug 
product characteristic), the acceptance criteria for Cmax will be widened to a 
maximum of 69.84 -143.19% using scaled average bioequivalence (SABE) 
and for AUC0-tlast will be taken as 80.00-125.00% regardless of variability 

Study Code: NOV2020/01911   NCT04386876                                                    
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according to the EMA guideline (Guideline on the Investigation of 
Bioequivalence-CPMP/EWP/QWP/1401/98 Rev. 1/Corr, London 20 January 
2010).  
 
The other criteria for SABE: The geometric mean ratio should lie within the 
conventional acceptance range 80.00-125.00% for Cmax and AUC0-tlast. 
 

Study Code: NOV2020/01911   NCT04386876                                                    
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1.  THE PARTIES of PROJECT 
 
Study Code:                       
NOV2020/01911 
 
Study Title: 
Open-label, randomised, single oral dose, two-treatment, four-period, full-
replicated, cross-over trial to assess the bioequivalence of Orvical 200 mg/50 
mg Film Tablet (Test Drug) in comparison with Kaletra 200 mg/50 mg 
Film Kaplı Tablet (Reference Drug) in healthy male subjects under fasting 
conditions 
 
Sponsor: 
World Medicine Ilaç San. ve Tic. A.Ş. 
 
15 Temmuz Mah. Cami Yolu Cad. No:50 WM Plaza, 34212  
                              
Güneşli,Bağcılar/İstanbul-Turkey 
 
Phone: +90 212 474 70 50 
 
Fax: +90 212 474 09 01 
 
CRO: 
Alpan Farma Ltd.Şti. 
 
Istanbul Branch 
 
Bomonti Business Center- No:4 Şişli/İstanbul-Turkey  
 
Phone: +90 536 216 27 21 
 
Contracted Analytical Laboratory: Novagenix Bioanalytical Drug R&D Centre 
 
Esenboğa Yolu 25. Km. 06970 Akyurt, Ankara-Turkey 
 
Phone: +90 312 398 10 81 
  
Fax: +90 312 398 07 18 
  
 
Clinical Facility: 
        Gaziantep Üniversitesi FARMAGEN GCP Center  
 
Gaziantep Üniversitesi Teknoloji Geliştirme Bölgesi (Teknopark),  
 
 Burç Yolu, Şahinbey 27260, Gaziantep-Turkey 
 
 Phone: +90 342 360 62 62 
 
 Fax: +90  342 360 64 57 
 
Monitor:                
Evrim Aksel 
World Medicine Ilac San.ve Tic. A.S.  
 
 
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, Alpan Farma and World Medicine Ilaç San. ve Tic. A.Ş., except to the 
extent necessary to obtain informed consent from potential subjects. 

Study Code: NOV2020/01911   NCT04386876                                                    
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2.  TABLE OF CONTENTS
1.  
THE PARTIES OF PROJECT 
5 
2.  
TABLE OF CONTENTS 
6 
3.  
RESPONSIBILITIES, SIGNATURES AND ADDRESSES 
8 
4.  
LIST OF ABBREVIATIONS AND TERMS 
12 
5.  
SUMMARY AND SCHEDULE FOR THE CLINICAL TRIAL 
13 
5.1. SUMMARY 
13 
5.2. SCHEDULE 
17 
6. 
STUDY FLOW CHART 
18 
7. INTRODUCTION 
20 
7.1. CHEMICAL AND PHARMACEUTICAL PROPERTIES 
20 
7.2. PHARMACOLOGICAL PROPERTIES 
20 
7.3. PHARMACOKINETICS 
20 
7.4. INDICATIONS 
22 
7.5. CONTRAINDICATIONS 
22 
7.6. ADVERSE REACTIONS 
24 
7.7. CAUTIONS AND PRECAUTIONS 
25 
8. OBJECTIVE OF THE TRIAL 
29 
9. BENEFIT-RISK EVALUATION 
29 
10. DESIGN 
29 
11.  
SELECTION OF VOLUNTEERS 
30 
11.1. INCLUSION CRITERIA 
30 
11.2. EXCLUSION CRITERIA 
31 
11.3. OTHER CONDITIONS 
32 
11.4. CODING SUBJECTS 
32 
12.  
MEDICATION 
33 
12.1. STUDY MEDICATION 
33 
12.1.1. Test Drug: 
34 
12.1.2. Reference Drug: 
34 
12.2. BLINDING 
34 
12.2.1. For Clinical Phase 
34 
12.2.2. For Analytical Phase 
34 
12.3. DOSAGE, DURATION OF TREATMENT 
34 
12.4. COMPLIANCE 
35 
12.5. HANDLING AND DRUG ACCOUNTABILITY 
35 
12.6. CONCOMITANT MEDICATION 
35 
12.7. RESCUE MEDICATION 
35 
12.8. STORAGE OF STUDY MEDICATION 
36 
13. STUDY PROCEDURE 
37 
13.1. GENERAL PROCEDURE 
37 
13.2. SPECIAL PROCEDURES 
39 
13.3. DAILY ACTIVITIES DURING THE TRIAL 
39 
13.4. RESTRICTIONS 
40 
13.5. DRUG ADMINISTRATION 
41 
13.6. DIETARY REGIMEN 
41 
13.7. BLOOD SAMPLING FOR DRUG ANALYSIS 
42 
13.8. ENDPOINT(S) FOR THE STUDY 
43 
14. PREMATURE DISCONTINUATION 
44 
14.1. WITHDRAWAL OF VOLUNTEERS 
44 
14.2. REPLACEMENT OF DROP-OUTS 
44 
14.3. EARLY TERMINATION OF THE STUDY 
45 

Study Code: NOV2020/01911   NCT04386876                                                    
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14.4. DROP-OUT SAMPLES 
45 
15.  
ADVERSE EVENTS 
46 
15.1. DEFINITION OF ADVERSE EVENT / SERIOUS ADVERSE EVENT / ADVERSE DRUG REACTION / UNEXPECTED 
ADVERSE DRUG REACTION 
46 
15.2. RELATIONSHIP TO THE STUDY MEDICATION 
46 
15.3. REPORTING AND DOCUMENTATION OF ADVERSE EVENT(S) 
48 
16.  
STUDY DOCUMENTATION 
49 
16.1. INVESTIGATOR'S FILE 
49 
16.2. CASE REPORT FORM (CRF) 
50 
17.  
ANALYTICAL EVALUATION 
51 
17.1. REANALYSIS OF STUDY SAMPLES 
51 
17.2. INCURRED SAMPLE REANALYSIS 
51 
18.  PHARMACOKINETIC EVALUATION 
52 
19. 
STATISTICAL PROCEDURES 
53 
19.1. TARGET VARIABLES 
53 
19.1.1. Primary Target Variables 
53 
19.1.2. Secondary Target Variables 
53 
19.1.3. Criteria for Bioequivalence 
53 
19.2. CALCULATION OF SAMPLE SIZE 
55 
19.3. STATISTICAL CODE AND RANDOMISATION 
55 
19.4. DOCUMENTATION OF THE DATA 
55 
19.5. INTERIM EVALUATION 
56 
20. 
ETHICAL CONSIDERATIONS 
57 
20.1. ETHICAL CONDUCT OF THE STUDY 
57 
20.2. ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
57 
20.3. VOLUNTEER INFORMATION AND INFORMED CONSENT 
58 
21. 
GOOD CLINICAL PRACTICE 
60 
21.1. LEGAL REQUIREMENTS 
60 
21.2. PREVENTIVE MEASURES TO REDUCE BIAS 
61 
21.3. INVESTIGATOR'S OBLIGATIONS 
61 
21.4. ADHERENCE TO THE PROTOCOL 
61 
21.5. DATA HANDLING PROCEDURES 
62 
21.6. MONITORING 
62 
21.7. AUDITING 
63 
21.8. CONFIDENTIALITY 
63 
21.9. INSURANCE 
63 
21.10. SUBJECT PAYMENT 
64 
21.11 QUALIFICATION OF THE INVESTIGATOR 
64 
22. 
PROTOCOL AMENDMENTS 
65 
22.1. PROTOCOL MODIFICATIONS 
65 
22.2. PROTOCOL VIOLATIONS 
65 
23. 
REPORTS 
67 
23.1. ARCHIVING 
67 
24. 
COMMUNICATION OF STUDY RESULTS 
68 
25.  CONTRACT AND COSTS 
68 
26. 
FINAL REGULATIONS 
69 
27. 
REFERENCES 
70 
28. 
LOCATION OF STUDY DOCUMENTATION 
72 
29. 
APPENDICES 
73 

Study Code: NOV2020/01911   NCT04386876                                                    
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3.  RESPONSIBILITIES, SIGNATURES AND ADDRESSES 
We, herewith, confirm that the study protocol, CRFs and appendices contains all the information and rules necessary to 
conduct the study according to GCP regulations and that the study will be carried out and documented in complete 
compliance with this study protocol. The legal regulations and described agreements will be observed. The study 
medication will be used only for the purpose of the clinical trial. The clinical investigator will be informed about the 
pharmacological/toxicological tests and all new knowledge about the drug as well as about any newly occurring, hitherto 
unknown adverse events of test and reference drug. 
 
Principal lnvestigator: 
Prof. Dr. Muradiye Nacak 
FARMAGEN GCP Center                                                      
Phone: +90 342 360 62 62 
                                                                 
Fax: +90 342 360 64 57 
 
E-mail: m.nacak@farmagenarge.com 
 
Date and Signature:  
 
 
 
 
_________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Code: NOV2020/01911   NCT04386876                                                    
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CRO Representative  
 (Project Manager):  
  
Prof. Dr. Aydın Erenmemişoğlu 
                                                                 
 
                                                                 
Phone: +90 536 216 27 21 
                                                                 
E-mail: erenmemis@gmail.com 
 
  
Date and signature: 
 
 
 
 
 
  
_________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Code: NOV2020/01911   NCT04386876                                                    
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Sponsor Representative:  
  
Evrim Aksel  
                                                                                 World Medicine Ilaç San. ve Tic. A.Ş.  
 
  
Addresses: 15 Temmuz Mah. Cami Yolu Cad. 
No:50 WM Plaza, 34212 Güneşli, 
Bağcılar/İstanbul-Turkey 
                                                                                 Phone: +90 212 474 70 50 
                                                                            
Fax: +90 212 474 09 01 
 
  
E-mail: evrim.aksel@worldmedicine.com.tr  
 
  
Date and Signature:  
 
 
 
 
 
 
_________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Code: NOV2020/01911   NCT04386876                                                    
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Contracted Analytical Laboratory  
Bioanalytical Laboratory Manager: 
 
Berrak Güney 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                 
Phone: +90 312 398 10 81/138 
                                                                
Fax: +90 312 398 07 18 
 
Date and Signature:  
 
 
 
_________________________________________ 
 
 
 
 
 
Data Management Responsible:                
  Erkin Alkan 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                 
Phone: +90 312 398 10 81/126 
                                                                
Fax: +90 312 398 07 18 
 
Date and Signature:  
 
 
 
_________________________________________ 
 
 
 
 
 
 
 
Statistical Calculation Responsible:                             Emel Doğan Kurtoğlu, PhD. 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                 
Phone: +90 312 398 10 81/127 
                                                                
Fax: +90 312 398 07 18 
 
Date and Signature:  
 
 
 
_________________________________________ 
 
 
 
 
 
 
Quality Assurance Manager:                
Çiğdem Özer 
                                                                 
Novagenix Bioanalytical Drug R&D Centre 
                                                                
Phone: +90 312 398 10 81/125 
                                                                 
Fax: +90 312 398 07 18 
 
Date and Signature:  
 
 
 
 
________________________________________ 

Study Code: NOV2020/01911   NCT04386876                                                    
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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 
Estimated Glomerular Filtration Rate 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration  
GCP  
Good Clinical Practice 
GGT  
Gamma-Glutamyl transferase 
GLP  
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HBsAg  
Hepatitis B Surface Antigen 
HBV                             
Hepatitis B Virus 
HCV                            
Hepatitis C Virus 
HCV-Ab 
Antibodies against Hepatitis C Virus 
HIV                              
Human Immunodeficiency Virus 
HIV-Ab  
Antibodies against Human Immunodeficiency Virus 
HR                             
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITF  
Investigator's Trial File 
LC 
Liquid Chromatography 
log  
Logarithmic 
MAOI 
Monoamine oxidase inhibitor 
MoH 
Ministry of Health 
MRT  
Mean Residence Time 
n  
Number (observations; volunteers; sampling points; etc.) 
NA 
Not Applicable 
PR  
Pulse rate 
PTH 
Parathyroid hormone 
SAE 
Serious Adverse Event 
SBP                             
Systolic Blood Pressure  
SD  
Standard Deviation 
SGOT                         
Serum Glutamic Oxaloacetic Transaminase 
SGPT                        
Serum Glutamic Pyruvic Transaminase  
SOP 
Standard Operating Procedures 
t1/2  
Terminal elimination half-life 
 tmax  
Time to reach maximum concentration 
 UADR 
Unexpected Adverse Drug Reaction  
 λz 
Terminal rate constant 

Study Code: NOV2020/01911   NCT04386876                                                    
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5.  SUMMARY AND SCHEDULE FOR THE CLINICAL TRIAL 
5.1. Summary 
 
Title: 
Open-label, randomised, single oral dose, two treatment, four-period, 
full-replicated, cross-over trial to assess the bioequivalence of Orvical 
200 mg/50 mg Film Tablet (Test Drug) in comparison with Kaletra 
200 mg/50 mg Film Kaplı Tablet (Reference Drug) in healthy male 
subjects under fasting conditions 
 
 
Study objective: 
The aim of this study is to evaluate the pharmacokinetic profiles and 
the relative bioavailability of lopinavir and ritonavir from the test 
product (Orvical 200 mg/50 mg Film Tablet, World Medicine-
Turkey) in comparison with the reference product (Kaletra 200 mg/50 
mg Film Kaplı Tablet, AbbVie Tıbbi İlaçlar Sanayi ve Ticaret 
Limited Şirketi-İstanbul, Turkey) under fasting conditions. The 
primary objective is to demonstrate the bioequivalence of test and 
reference products.  
 
  
Test Drug*:  
“Orvical 200 mg/50 mg Film Tablet” containing 200 mg lopinavir 
and 50 mg ritonavir  (World Medicine-Turkey). 
 
 
 *: This drug is manufactured by World Medicine Ilaç San. ve Tic., 
Turkey. 
    
 
  
Reference Drug**:  
“Kaletra 200 mg/50 mg Film Kaplı Tablet” containing 200 mg 
lopinavir and 50 mg ritonavir (AbbVie Tıbbi İlaçlar Sanayi ve Ticaret 
Limited Şirketi-İstanbul, Turkey). 
 
 
 
 
 
 **: This drug is manufactured by AbbVie Deutschland GmbH & Co. -
Germany  
 
Dosage: 
A single dose of Reference product containing 200 mg lopinavir 
and 50 mg ritonavir fixed dose combination and a single dose 
of Test product containing 200 mg lopinavir and 50 mg 
ritonavir fixed dose combination or vice versa; administered 
with 240 mL of water at room temperature, in each period 
 
Indication: 
Bioequivalence study 
 
Study design: 
Single-dose, open-label, randomised, two-treatment, four-period, full-
replicated, cross-over, study. 
 
Variables: 
 Pharmacokinetics: 
 Primary variables: AUC0-tlast and Cmax of lopinavir and ritonavir  
 Secondary variables: AUC0-, tmax, t1/2 of lopinavir and ritonavir  
 Safety and Tolerability: Adverse events, clinical laboratory, medical        
examinations 
  
Sample size: 
30 volunteers will be included. Drop-outs will not be replaced. 
  
 

Study Code: NOV2020/01911   NCT04386876                                                    
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Subject selection criterion:  20 - 40 aged healthy male volunteers. Normal weight according to the 
BMI. 
 
 
Blood sampling:  
The samples will be drawn in the clinical study period: at pre-dose* 
and at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.33, 3.66, 4.00, 4.33, 4.66, 
5.00, 5.50, 6.00, 7.00, 8.00, 10.00, 14.00, 24.00, 36.00 hours post-dose 
(1 x 5 mL each; totally 21 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 lopinavir and ritonavir 
analysis [for details see section 13.7 (Blood Sampling for Drug 
Analysis)] 
 
Route of   
Administration: 
 
Oral 
 
Duration of Treatment:  
13 days (approximately)  
 
Duration of Wash-out:  
At least 48 hours. 
 
 
Procedure:  
In the 1st period, each volunteer will receive after an overnight fasting 
in random order one single oral dose of 200 mg lopinavir and 50 mg 
ritonavir product [either one tablet of the test drug or one tablet of the 
reference drug according to the randomisation table]. Blood samples 
will be drawn immediately before the dosing and at 0.50, 1.00, 1.50, 
2.00, 2.50, 3.00, 3.33, 3.66, 4.00, 4.33, 4.66, 5.00, 5.50, 6.00, 7.00, 
8.00, 10.00, 14.00, 24.00, 36.00 hours after the dosing. In the 2nd, 3rd 
and 4th period there will be the same procedure. 
 
Analysis of Lopinavir and Ritonavir : Plasma concentrations of lopinavir and ritonavir 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 (CVWR) is 
equal or less than 30%, acceptance range for Cmax and AUC0-tlast is 
80.00-125.00%.  
 
If CVWR is more than 30% (the reference product exerts a highly 
variable drug product characteristic), the acceptance criteria for Cmax 
will be widened to a maximum of 69.84 -143.19% using scaled-
average-bioequivalence (SABE) and for AUC0-tlast will be taken as 
80.00-125.00% regardless of variability according to the EMA 
guideline (Guideline on the Investigation of Bioequivalence-
CPMP/EWP/QWP/1401/98 Rev. 1/Corr, London 20 January 2010).  

Study Code: NOV2020/01911   NCT04386876                                                    
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The other criteria for SABE: The geometric mean ratio should lie within 
the conventional acceptance range 80.00-125.00% for Cmax and AUC0-
tlast. 
 
Evaluation of 
bioequivalence: 
In order to investigate the bioequivalence of all products, the 90% 
confidence intervals will be calculated for the geometric mean ratios of 
test and reference for Cmax and AUC0-tlast of lopinavir and ritonavir. 
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 lopinavir and ritonavir will be 
logarithmically transformed (base e) before analysis. The sources of 
variation will be treatments, periods, sequences and subjects within the 
sequence. Evaluation of treatment, period, sequence and subject 
(nested within sequence) effects at 5% level of significance will be 
performed. From the result, the two one-sided hypothesis at the 5% 
level of significance will be tested by constructing the 90% confidence 
interval for the 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: 
 World Medicine Ilaç San. ve Tic. A.Ş. 
   Representative: Evrim Aksel 
Protocol code: 
NOV2020/01911 
 
Phase: 
I (Bioequivalence study) 
 
Planned initiation: 
2Q 2020 (inclusion of first subject) 
 
Planned duration: 
13 days (approximately)  
 
Primary Endpoint:          AUC0-tlast and Cmax of lopinavir and ritonavir  
 
Secondary Endpoint:   
AUC0-∞, t1/2, tmax of lopinavir and ritonavir  
 
Safety Endpoints: 
Adverse events, clinical and laboratory examinations. 
 
Principal Investigator: 
Prof. Dr. Muradiye Nacak 
 
Co-investigators:              İsmail Taner Ezgi, MD 
                                        
  Erol Durucu, MD 
                                              Gaziantep Üniversitesi, FARMAGEN-GCP Center, Gaziantep- Turkey 
 
Project Manager 
Prof. Dr. Aydın Erenmemişoğlu 
  
Alpan Farma Ltd.Şti. Kayseri - 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 

Study Code: NOV2020/01911   NCT04386876                                                    
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(ICH-GCP), the Declaration of Helsinki (with amendments) and local 
legal and regulatory requirements. 

Study Code: NOV2020/01911   NCT04386876                                                    
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5.2. Schedule 
Estimated time frame for each step is given below: 
X -Contract signed 
Y -Ethics Committee and the Ministry of Health (MoH) approvals 
W -End of clinical part of trial 
Q -End of Analytical Analysis 
Z -End of Statistical Analysis 
 
Approvals:  
X + 1-1½ month 
 
Enrollment of volunteers:  
Y + ½ month 
 
Clinical trial, monitoring:  
Y + ½ month 
 
Evaluation of plasma samples:  
W + 2-3 months 
 
Data input, statistical evaluation  Q + ¼ month 
 
Final Report (Draft)  
 
Z + ½ month  
 

Study Code: NOV2020/01911   NCT04386876                                                    
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6. 
STUDY FLOW CHART 
 
SCREENING AND 
ISOLATION 
PERIOD I 
PERIOD II 
PERIOD III 
PERIOD IV 
*Final 
examination 
Study Days: 
1st 
DAY 
screeni
ng   
2nd  
DAY 
(isolati
on) 
3rd  
DAY 
(isolati
on) 
4th 
DAY 
(isolati
on) 
5th DAY 
Hospitali
zation 
day 
(Day 0) 
6th DAY 
1st  
dosing 
day and 
blood 
sampling 
(Day 1) 
7th DAY 
blood 
sampling 
(t24.00 and 
t36.00) 
Wash-
out day  
(Day 2) 
8th DAY 
2nd   
dosing 
day and 
blood 
sampling 
(Day 3) 
 
9th DAY 
blood 
sampling 
(t24.00 and 
t36.00) 
Wash-
out day  
(Day 4) 
10th DAY 
3rd    
dosing 
day and 
blood 
sampling 
(Day 5) 
11th DAY 
blood 
sampling 
(t24.00 and 
t36.00) 
Wash-
out day 
(Day 6) 
12th DAY 
4th     
dosing day 
and blood 
sampling 
(Day 7) 
13th   
DAY 
24th  and 
36th 
hours 
blood 
(Day 8) 
13th DAY Final 
examination 
Informed 
consent 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Covid-19 
Rapid Test 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Covid-19 PCR 
Test 
● 
 
 
 
● 
 
 
 
 
 
 
 
 
● 
Inclusion 
it i
● 
 
 
 
● 
 
 
 
 
 
 
 
 
 
Demography 
(Birth date, 
ethnic group, 
gender, height, 
weight, BMI) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“Medical/Surgi
cal history 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, anti-
HCV, HIV 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
● 
 
 
 
 
 
 
 
 
 
 
 
 
● 
Clinical 
examination 
(Physical 
examination) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
Clinical 
chemistry, 
haematology, 
urinalysis 
● 
 
 
 
 
 
 
 
 
 
 
 
 
● 
Blood 
pressure, pulse 
rate 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
 
● 
Body 
temperature 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Drug abuse 
screening** 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath 
test 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check of 
restrictions, 
diet 
 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Exclusion 
criteria and 
Withdrawal of 
volunteers 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Hospitalization 
day 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 
Randomisation 
● 
 
 
 
 
 
 
 
 
 
 
 
Drug 
administration 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
 
Blood 
sampling*** 
(0-36.00 h) 
 
 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Adverse event 
questioning***
* 
 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 

Study Code: NOV2020/01911   NCT04386876                                                    
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*  The final examination will be carried out on the day of last blood sampling . 
° Body temperature monitoring will be performed at the following times: at “screening/isolation days”,  
  “hospitalisation day, during “study period” and “final  examination”.  
**  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 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.33, 3.66, 4.00, 4.33, 4.66, 5.00, 
5.50, 6.00, 7.00, 8.00, 10.00, 14.00, 24.00, 36.00 hours post-dose (1 x 5 mL each; totally 21 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 
lopinavir and ritonavir analysis. [for   details see section 13.7 (Blood Sampling for Drug Analysis)] 
****Adverse event questioning (in each period): at hospitalisation day, pre dose and 1.00, 4.00, 10.00, 24.00, 36.00 hours post-dose.  
 

Study Code: NOV2020/01911   NCT04386876                                                    
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7. INTRODUCTION 
7.1. Chemical and Pharmaceutical Properties 
 
Lopinavir 
Lopinavir is an antiviral agent chemically designated as [1S-[1R*,(R*),3R*,4R*]]-N-[4-
[[(2,6­dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl] 
tetrahydro-alpha­(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide. 
Its 
molecular 
formula is C37H48N4O5, and its molecular weight is 628.80 g/mol.  
 
Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, 
soluble in isopropanol and practically insoluble in water.  
 
Ritonavir 
Ritonavir acts as a booster in this combination. It is chemically designated as 10-
hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1­methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-
bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-
(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular 
weight is 720.95 g/mol.  
 
Ritonavir is a white to light tan powder. It is freely soluble in methanol and ethanol, 
soluble in isopropanol and practically insoluble in water.       
 
  
 
7.2. Pharmacological Properties 
 
Lopinavir is an inhibitor of the HIV-1 and HIV-2 protease. Inhibition of HIV protease 
prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, 
non-infectious virus. Lopinavir provides the antiviral activity of lopinavir/ritonavir 
combination. When lopinavir, an antiviral drug, is co-formulated with ritonavir, 
ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing 
increased plasma levels of lopinavir. 
 
7.3. Pharmacokinetics 
 
7.3.1.Absorption 
 
Lopinavir 
In a bioequivalence study, it is reported that the Cmax and tmax of reference lopinavir 
product is 3.68±1.35 ng/mL and 4.3±0.9 h respectively, following single dose of 200 
mg/50 mg of lopinavir/ritonavir tablets. According to the WHO’s bioequivalence 
guidance for lopinavir/ritonavir combination, tmax of lopinavir was observed between 3 
and 4 hours after a single dose.  Multiple dosing with 400/100 mg lopinavir/ritonavir 
twice daily for 2 weeks and without meal restriction produced a mean ± SD lopinavir 
peak plasma concentration (Cmax) of 12.3 ± 5.4 μg/ml, occurring approximately 4 hours 
after administration. The mean steady-state trough concentration prior to the morning 
dose was 8.1 ± 5.7 μg/ml. Lopinavir AUC over a 12 hour dosing interval averaged 
113.2 ± 60.5 μg•h/ml. The absolute bioavailability of lopinavir co-formulated with 
ritonavir in humans has not been established. 
 

Study Code: NOV2020/01911   NCT04386876                                                    
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Ritonavir  
In a bioequivalence study, it is reported that the Cmax and tmax of reference ritonavir 
product is 173±82 and 4.3±0.9 h respectively, following single dose of 200 mg/50 mg 
of lopinavir/ritonavir tablets. According to the WHO’s bioequivalence guidance for 
lopinavir/ritonavir combination, ritonavir peak plasma concentrations are observed after 
approximately 3-4 hours after oral administration.  
 
7.3.2.Distribution 
 
Lopinavir 
At steady state, lopinavir is approximately 98 − 99% bound to serum proteins.  
 
Ritonavir 
The apparent volume of distribution (VB/F) of ritonavir is approximately 20-40 L after 
a single 600 mg dose. The protein binding of ritonavir in human plasma is 
approximately 98 - 99%.  
 
7.3.3.Biotransformation  
 
Lopinavir 
Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost 
exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits 
the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-
lopinavir study in humans showed that 89% of the plasma radioactivity after a single 
400/100 mg lopinavir/ritonavir dose was due to parent active substance. 
 
Ritonavir  
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 
system, primarily by the CYP3A isozyme family and to a lesser extent by the CYP2D6 
isoform.  
 
7.3.4.Elimination  
 
Lopinavir 
After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4±2.3% and 
82.6±2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and 
faeces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% 
of the administered dose in urine and faeces, respectively. According to the WHO’s 
bioequivalence guidance for lopinavir/ritonavir combination, the half-life was of 4-6 
hours approximately, after a single dose administration. In a bioequivalence study, it is 
reported that t1/2 of lopinavir is 4.3±0.9 h. 
 
Ritonavir 
Human studies with radiolabelled ritonavir demonstrated that the elimination of 
ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel 
was recovered from stool, part of which is expected to be unabsorbed ritonavir. 
According to the WHO’s bioequivalence guidance for lopinavir/ritonavir combination, 
ritonavir half-life when administered with lopinavir has been reported to be 5-6 hours. 
In a bioequivalence study, it is reported that t1/2 of ritonavir is 6.3±1.6 h. 

Study Code: NOV2020/01911   NCT04386876                                                    
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Some pharmacokinetics parameters of lopinavir are shown in the following table: 
 
tmax 
(h) 
Cmax 
(ng/mL) 
 Protein binding(%) 
t½ 
(h) 
Excretion and 
metabolism 
3-4.3  
3.68±1.35  (200 mg single 
dose) 
98-99 
4-6 
mainly faeces 
 
Some pharmacokinetics parameters of ritonavir are shown in the following table: 
 
tmax 
(h) 
Cmax 
(ng/mL) 
Volume of 
distribution 
(L) 
t½ 
(h) 
Excretion and 
metabolism 
4.3 
173±82(50 mg single 
dose) 
20-40 (after a single 
600 mg dose). 
5-6.3 
~mainly faeces 
 
This combination can be taken with or without food.  
 
7.4. Indications 
Lopinavir/Ritonavir combination is indicated in combination with other antiretroviral 
agents for the treatment of HIV1 infection in adults and pediatric patients. 
 
7.5. Contraindications 
 Hypersensitivity to the active substances or to any of the excipients in both products. 
Severe hepatic insufficiency. 
 Lopinavir/Ritonavir tablets both of which are  inhibitors of the P450 isoform 
CYP3A. Lopinavir/ritonavir should not be co-administered with medicinal products 
that are highly dependent on CYP3A for clearance and for which elevated plasma 
concentrations are associated with serious and/or life threatening events. These 
medicinal products include: 
Medicinal product class 
Medicinal products 
within class 
Rationale 
Concomitant medicinal product levels increased 
Alpha1-adrenoreceptor 
antagonist 
Alfuzosin 
Increased 
plasma 
concentrations 
of 
alfuzosin which may lead to severe 
hypotension.  
Antianginal 
Ranolazine 
Increased 
plasma 
concentrations 
of 
ranolazine which may increase the 
potential 
for 
serious 
and/or 
life-
threatening reactions  
Antiarrhythmics 
Amiodarone, 
dronedarone 
Increased 
plasma 
concentrations 
of 
amiodarone and dronedarone. Thereby, 
increasing the risk of arrhythmias or 
other serious adverse reactions 
Antibiotic 
Fusidic Acid 
Increased 
plasma 
concentrations 
of 
fusidic 
acid. 
The 
concomitant 
administration 
with 
fusidic 
acid 
is 
contraindicated 
in 
dermatological 
infections 

Study Code: NOV2020/01911   NCT04386876                                                    
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Anticancer 
Venetoclax 
Increased 
plasma 
concentrations 
of 
venetoclax. Increased risk of tumor lysis 
syndrome at the dose initiation and 
during the ramp-up phase 
Anti-gout 
Colchicine 
Increased 
plasma 
concentrations 
of 
colchicine. Potential for serious and/or 
lifethreatening reactions in patients with 
renal and/or hepatic impairment 
Antihistamines 
Astemizole, 
terfenadine 
Increased 
plasma 
concentrations 
of 
astemizole and terfenadine. Thereby, 
increasing the risk of serious arrhythmias 
from these agents 
 
Antipsychotics/ 
Neuroleptics 
Lurasidone 
Increased 
plasma 
concentrations 
of 
lurasidone which may increase the 
potential 
for 
serious 
and/or 
life 
threatening reactions  
Pimozide 
Increased 
plasma 
concentrations 
of 
pimozide. Thereby, increasing the risk of 
serious haematologic abnormalities, or 
other serious adverse effects from this 
agent  
Quetiapine 
Increased 
plasma 
concentrations 
of 
quetiapine which may lead to coma. The 
concomitant 
administration 
with 
quetiapine is contraindicated 
Ergot alkaloids 
Dihydroergotamine
, 
ergonovine, 
ergotamine, 
methylergonovine 
Increased plasma concentrations of ergot 
derivatives leading to acute ergot toxicity, 
including vasospasm and ischaemia 
GI motility agent 
Cisapride 
Increased 
plasma 
concentrations 
of 
cisapride. Thereby, increasing the risk of 
serious arrhythmias from this agent 
Hepatitis C virus direct 
acting antivirals 
Elbasvir/grazoprevi
r 
Increased risk of alanine transaminase 
(ALT) elevations 
Ombitasvir/paritapr
evir/ritonavir with 
or 
without 
dasabuvir 
Increased 
plasma 
concentrations 
of 
paritaprevir; thereby, increasing the risk 
of alanine transaminase (ALT) elevations  
HMG 
Co-A 
Reductase 
Inhibitors 
Lovastatin, 
simvastatin 
Increased 
plasma 
concentrations 
of 
lovastatin 
and 
simvastatin; 
thereby, 
increasing the risk of myopathy including 
rhabdomyolysis 
Phosphodiesterase (PDE5) 
inhibitors 
Avanafil 
Increased 
plasma 
concentrations 
of 
avanafil  
Sildenafil 
Contraindicated when used for the 
treatment 
of 
pulmonary 
arterial 
hypertension 
(PAH) 
only. 
Increased 
plasma 
concentrations 
of 
sildenafil. 
Thereby, increasing the potential for 
sildenafilassociated 
adverse 
events 

Study Code: NOV2020/01911   NCT04386876                                                    
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(which 
include 
hypotension 
and 
syncope). 
Vardenafil 
Increased 
plasma 
concentrations 
of 
vardenafil 
Sedatives/hypnotics 
Oral 
midazolam, 
triazolam 
Increased plasma concentrations of oral 
midazolam 
and 
triazolam. 
Thereby, 
increasing the risk of extreme sedation 
and respiratory depression from these 
agents.  
Lopinavir/ritonavir medicinal product level decreased 
Herbal products 
St. John’s wort 
Herbal preparations containing St John’s 
wort (Hypericum perforatum) due to the 
risk of decreased plasma concentrations 
and reduced clinical effects of lopinavir 
and ritonavir 
 
7.6. Adverse Reactions 
The adverse effects are classified below by system organ class according to the 
following convention: Very common (≥1/10), Common (≥1/100 to < 1/1.000), 
Uncommon (≥1/1.000 to < 1/1.000), Rare (≥1/10,000 to < 1/1,000), Very rare, including 
isolated reports (<1/10.000), Not known (cannot be estimated from the available data). 
System organ class  
Frequency 
Adverse reaction 
Infections and infestations  
Very common  
Upper respiratory tract infection 
Common  
Lower 
respiratory 
tract 
infection, 
skin 
infections including cellulitis, folliculitis and 
furuncle 
Blood 
and 
lymphatic 
system disorders  
Common  
Anaemia, 
leucopenia, 
neutropenia, 
lymphadenopathy 
Immune system disorders  
Common  
Hypersensitivity 
including 
urticaria 
and 
angioedema 
Uncommon  
Immune 
reconstitution 
inflammatory 
syndrome 
Endocrine disorders  
Uncommon  
Hypogonadism 
Metabolism and nutrition 
disorders  
Common 
Blood glucose disorders including diabetes 
mellitus, 
hypertriglyceridaemia, 
hypercholesterolemia, 
weight 
decreased, 
decreased appetite 
Uncommon  
Weight increased, increased appetite 
Psychiatric disorders  
 
Common  
Anxiety 
Uncommon  
Abnormal dreams, libido decreased 
Nervous system disorders  
Common  
Headache (including migraine), neuropathy 
(including peripheral neuropathy), dizziness, 
insomnia 
Uncommon  
Cerebrovascular 
accident, 
convulsion, 
dysgeusia, ageusia, tremor 
Eye disorders 
Uncommon 
Visual impairment 
Uncommon 
Tinnitus, vertigo 
Cardiac disorders  
Uncommon  
Atherosclerosis such as myocardial infarction, 
atrioventricular 
block, 
tricuspid 
valve 

Study Code: NOV2020/01911   NCT04386876                                                    
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incompetence  
Vascular disorders  
Common  
Hypertension  
Uncommon  
Deep vein thrombosis  
Gastrointestinal disorders  
Very common  
Diarrhoea, nausea  
Common  
Pancreatitis, 
vomiting, 
gastrooesophageal 
reflux disease, gastroenteritis and colitis, 
abdominal pain (upper and lower), abdominal 
distension, 
dyspepsia, 
haemorrhoids, 
flatulence  
Uncommon  
Gastrointestinal 
haemorrhage 
including 
gastrointestinal ulcer, duodenitis, gastritis and 
rectal haemorrhage, stomatitis and oral ulcers, 
faecal incontinence, constipation, dry mouth  
Hepatobiliary disorders  
Common  
Hepatitis including AST, ALT and GGT increases  
Uncommon  
Hepatic steatosis, hepatomegaly, cholangitis, 
hyperbilirubinemia  
Not known  
Jaundice  
Skin 
and 
subcutaneous 
tissue disorders  
Common  
Rash 
including 
maculopapular 
rash, 
dermatitis/rash 
including 
eczema 
and 
seborrheic dermatitis, night sweats, pruritus  
Uncommon  
Alopecia, capillaritis, vasculitis  
Not known  
Stevens-Johnson 
syndrome, 
erythema 
multiforme  
Musculoskeletal 
and 
connective 
tissue disorders 
 
Common  
Myalgia, 
musculoskeletal 
pain 
including 
arthralgia 
and back pain, muscle disorders such as 
weakness 
and spasms 
 
Uncommon  
Rhabdomyolysis, osteonecrosis 
Renal and urinary disorders  Uncommon  
Creatinine clearance decreased, nephritis, 
haematuria 
Reproductive system and 
breast 
disorders 
 
Common  
Erectile dysfunction, menstrual disorders - 
amenorrhoea, menorrhagia 
 
7.7. Cautions and precautions 
 
Risk of Serious Adverse Reactions Due to Drug Interactions 
Initiation of lopinavir/ritonavir, a CYP3A inhibitor, in patients receiving medications 
metabolized byCYP3A or initiation of medications metabolized by CYP3A in patients 
already receiving lopinavir/ritonavir, may increase plasma concentrations of 
medications metabolized by CYP3A. 
Initiation of medications that inhibit or induce CYP3A may increase or decrease 
concentrations of lopinavir/ritonavir, respectively. These interactions may lead to: 
• Clinically significant adverse reactions, potentially leading to severe, life-threatening, 
or fatal events from greater exposures of concomitant medications. 
• Clinically significant adverse reactions from greater exposures of lopinavir/ritonavir. 
• Loss of therapeutic effect of lopinavir/ritonavir and possible development of 

Study Code: NOV2020/01911   NCT04386876                                                    
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resistance. 
Consider the potential for drug interactions prior to and during lopinavir/ritonavir 
therapy; review concomitant medications during lopinavir/ritonavir therapy, and 
monitor for the adverse reactions associated with the concomitant medications. 
 
Pancreatitis 
Pancreatitis has been observed in patients receiving lopinavir/ritonavir therapy, 
including those who developed marked triglyceride elevations. In some cases, fatalities 
have been observed. Although a causal relationship to lopinavir/ritonavir has not been 
established, marked triglyceride elevations are a risk factor for development of 
pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, 
abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or 
amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or 
symptoms should be evaluated and lopinavir/ritonavir and/or other antiretroviral therapy 
should be suspended as clinically appropriate. 
 
Hepatotoxicity 
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to 
treatment may be at increased risk for developing or worsening of transaminase 
elevations or hepatic decompensation with use of lopinavir/ritonavir. 
Elevated transaminases with or without elevated bilirubin levels have been reported in 
HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of 
lopinavir/ritonavir in conjunction with other antiretroviral agents.  
Appropriate laboratory testing should be conducted prior to initiating therapy with 
lopinavir/ritonavir and patients should be monitored closely during treatment. Increased 
AST/ALT monitoring should be considered in the patients with underlying chronic 
hepatitis or cirrhosis. 
 
QT Interval Prolongation 
Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and 
with other drugs that prolong the QT interval. 
 
PR Interval Prolongation 
Lopinavir/ritonavir prolongs the PR interval in some patients. Lopinavir/ritonavir 
should be used with caution in patients with underlying structural heart disease, pre-
existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, 
as these patients may be at increased risk for developing cardiac conduction 
abnormalities. 
The impact on the PR interval of co-administration of lopinavir/ritonavir with other 
drugs that prolong the PR interval has not been evaluated. As a result, co-administration 
of lopinavir/ritonavir with these drugs should be undertaken with caution, particularly 
with those drugs metabolized by CYP3A. 
 
Diabetes Mellitus/Hyperglycemia 
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and 
hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected 
patients receiving protease inhibitor therapy. Consider monitoring for hyperglycemia, 
new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated 
with lopinavir/ritonavir. 

Study Code: NOV2020/01911   NCT04386876                                                    
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Immune Reconstitution Syndrome 
During the initial phase of combination antiretroviral treatment, patients whose immune 
system responds may develop an inflammatory response to indolent or residual 
opportunistic infections which may necessitate further evaluation and treatment. 
Autoimmune disorders have also been reported to occur in the setting of immune 
reconstitution, however, the time to onset is more variable, and can occur many months 
after initiation of treatment. 
 
Lipid Elevations 
Treatment with lopinavir/ritonavir has resulted in large increases in the concentration of 
total cholesterol and triglycerides. Triglyceride and cholesterol testing should be 
performed prior to initiating lopinavir/ritonavir therapy and at periodic intervals during 
therapy. Lipid disorders should be managed as clinically appropriate, taking into 
account any potential drug-drug interactions with lopinavir/ritonavir and HMG-CoA 
reductase inhibitors. 
 
Fat Redistribution 
Redistribution/accumulation of body fat including central obesity, dorsocervical fat 
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and 
"cushingoid appearance" have been observed in patients receiving antiretroviral therapy. 
The mechanism and long-term consequences of these events are currently unknown. A 
causal relationship has not been established. 
 
Patients with Hemophilia 
Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been 
reported in patients with hemophilia type A and B treated with protease inhibitors. A 
causal relationship between protease inhibitor therapy and these events has not been 
established. 
 
Resistance/Cross-resistance 
Because the potential for HIV cross-resistance among protease inhibitors has not been 
fully explored in lopinavir/ritonavir-treated patients, it is unknown what effect therapy 
with lopinavir/ritonavir will have on the activity of subsequently administered protease 
inhibitors. 
7.8. Interactions 
Potential for Lopinavir/ritonavir to Affect Other Drugs 
Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of 
agents 
that 
are 
primarily 
metabolized 
by 
CYP3A. 
co-administration 
of 
lopinavir/ritonavir with drugs highly dependent on CYP3A for clearance and for which 
elevated plasma concentrations are associated with serious and/or life-threatening 
events is contraindicated. Co-administration with other CYP3A substrates may require a 
dose adjustment or additional monitoring. Additionally, lopinavir/ritonavir induces 
glucuronidation. Published data suggest that lopinavir is an inhibitor of OATP1B1. 
 
Potential for Other Drugs to Affect Lopinavir 
Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may 
decrease lopinavir plasma concentrations and reduce therapeutic effect of 
lopinavir/ritonavir. Although not observed in the lopinavir/ritonavir /ketoconazole drug 

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interaction study, co-administration of lopinavir/ritonavir and other drugs that inhibit 
CYP3A may increase lopinavir plasma concentrations. 
 
Established and Other Potentially Significant Drug Interactions  
Some members of the following pharmacological groups provide an established or 
potentially clinically significant drug interactions. Alteration in dose or regimen may be 
recommended concomitant use of lopinavir/ritonavir with the member of these groups.   
 HIV-1 Protease Inhibitors 
 HIV CCR5 Antagonists 
 Non-nucleoside Reverse Transcriptase Inhibitors 
 Nucleoside Reverse Transcriptase Inhibitors 
 Antiarrhytmics 
 Anticancer agents 
 Anticoagulants 
 Anticonvulsants 
 Antidepressants 
 Antiinfectives 
 Antifungals 
 Antigouts 
 Antimycobacterials 
 Antiparasitics 
 Antipsychotics 
 Sedative/hypnotics 
 Contraceptives 
 Corticosteroids 
 Dihydropyridine Calcium Channel Blockers 
 Endothelin Receptor Antagonists 
 Hepatitis C direct acting Antivirals 
 HMG-CoA Reductase Inhibitors 
 Immunosuppressants  
 Inhaled or Intranasal Steroids 
 Long-acting beta-adrenoceptor Agonists 
 Narcotic Analgesics 
 PDE5 inhibitors 
      

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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 lopinavir and ritonavir from the Test Drug (Orvical 200 mg/50 mg Film 
Tablet, World Medicine-Turkey) in comparison with Reference Drug (Kaletra 200 mg/50 
mg Film Kaplı Tablet, AbbVie Tıbbi İlaçlar San. ve Tic. Ltd Şti-İstanbul, Turkey) under 
fasting conditions. The primary objective is to demonstrate the bioequivalence of both 
products. 
 
9. BENEFIT-RISK EVALUATION 
For the approval of any product, its efficacy and safety has to be proved. There are two 
possibilities to do this for a new generic product: either by proving therapeutic equivalence or 
by proving bioequivalence with a marketed reference on the basis of comparison of relative 
bioavailability. The first option requires huge numbers of patients and a long period of 
administration of either the test or the reference product. A bioequivalence trial on the basis of 
bioavailability is therefore generally accepted as the better alternative. This trial is conducted 
with the aim to investigate whether any differences concerning the rate and extent of 
absorption exist between the test and the reference products.  
 
10. DESIGN 
In this open-label, randomised, single-dose, two-sequence, two treatment, four-period, full-
replicated, cross-over study, 30 healthy male subjects (intention to treat population) will 
receive one single oral dose of 200 mg lopinavir and 50 mg ritonavir [either one tablet of 
the test drug or one tablet of the reference drug according to the randomisation table] under 
fasting conditions, according to a sequence determined by randomisation [in Period II and 
Period IV, the subjects will be administered by the other drug that they will not administered in 
the Period I and Period III].  
Data of the subjects who have completed the study according to the Clinical Study Protocol 
will be used for analytical, pharmacokinetic and statistical evaluation.  
Test Drug: “Orvical 200 mg/50 mg Film Tablet” is manufactured by World Medicine Ilaç 
San. ve Tic. A.Ş., Turkey and is will be licensed by World Medicine Ilaç San. ve Tic. A.Ş., 
Turkey. 
 
Reference Drug: “Kaletra 200 mg/50 mg Film Kaplı Tablet” is manufactured by AbbVie 
Deutschland GmbH & Co. Germany and is licensed by AbbVie Tıbbi İlaçlar Sanayi ve Ticaret 
Limited Şirketi-İstanbul, Turkey 
 
In study period, the subjects will be admitted to the FARMAGEN Clinical Unit in the evening 
(18:00) prior to morning of the administration of medication after screening and isolation 
period as described in Appendix 7. 
 
Volunteers will be confined to the clinical unit and dosing will occur under conditions of 
hospitalization. Medications will be orally administered at approximately at 8:00 (t=0) after an 
overnight fasting (at least 10 hours in fasting). The lunch will be 4 hours post dosing and the 
dinner will be 10 hours post dosing. Blood sampling for the determination of lopinavir and 
ritonavir 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. 
An overview of the study procedures is given in the Study Flow Chart provided in 
section 6. 

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11.  SELECTION OF VOLUNTEERS 
11.1. Inclusion Criteria 
Only volunteers fulfilling all of the following criteria should be enrolled in the present 
trial: 
1. Healthy Caucasian male subjects aged between 20 and 40 years, 
2. Non smokers or smoking maximum 5 cigarettes a day, those who won’t smoke or 
drink coffee during the study period, 
3. Negative Covid-19 Rapid Test results and two Negative Covid-19 PCR test 
results, 
4. Negative alcohol breath test results, 
5. Normal physical examination at screening visit, 
6. Having the Body Mass Index ranged between 18.5-30 kg/m2 (see Appendix I)  
which is in the desirable range according to the age, 
7. Ability to communicate adequately with the investigator himself or his 
representatives, 
8. Ability and agreement to comply with the study requirements, 
9. Normal blood pressure and heart rate measured under stabilised conditions at the 
screening visit after at least 5 minutes of rest under supine position: SBP within 
100 to 140 mmHg, DBP within 60 to 90 mmHg and HR within 50 to 90 bpm, 
10. Normal/ acceptable 12-lead electrocardiographic results at least after 5 minutes of 
rest, 
11. Laboratory results within normal range or clinically non-significant (CBC, glucose, 
urea, uric acid, creatinine, estimated GFR (eGFR), total bilirubin, sodium, potassium, 
calcium, chloride, SGOT (AST), SGPT (ALT), GGT, alkaline phosphatase, total 
protein and urinalysis), drug addiction scanning in urine results in negative 
(amphetamine, barbiturate, benzodiazepine, cannabinoid, cocaine, opiate), 
12. Understanding of the study and agreement to give a written informed consent 
according to section 20.3. 
 

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11.2. Exclusion Criteria 
Volunteers presenting any of the following exclusion criteria will not be included in 
the trial: 
1. Who have atopic constitution or asthma or known allergy for lopinavir and 
ritonavir or any other ingredients of the products. 
2. Who have hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption. 
3. Any history or presence of clinical relevance of cardiovascular (myocardial 
infarction/ 
ischaemia 
and/or 
QT 
prolongation 
etc.), 
neurological, 
musculoskeletal, haematological, hepatic, gastrointestinal, renal, pulmonary, 
endocrinological, metabolism or psychiatric disease, any type of porphyria. 
4. Baseline ECG should be performed at screening. Exclude subjects having a 
QTc > 440 ms 
5. 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), 
6. Presence or history of malabsorption or any gastrointestinal surgery except 
appendectomy or except herniotomy. 
7. 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. 
8. 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. 
9. 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). 
10. Use of any vitamins or herbal products within 7 days prior to the initial dose of the 
study medication. 
11. Subjects who have any chronic disease which might interfere with absorption, 
distribution, metabolism or excretion of the drug. 
12. Subjects who regular consumed of beverages or food containing methylxanthines 
(e.g. coffee, tea, cola, caffeine, chocolate, sodas,) equivalent to more than 500 mg 
methylxanthines per day. 
13. Subjects who has taken any grapefruit or grapefruit juice during 7 days prior to 
drug administration, during the study. 
14. History of allergic response to heparin. 

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15. History of drug abuse. 
16. 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). 
17. Positive blood test for HBV, HCV and HIV. 
18. Who have relationship to the investigator. 
19. Who are not suitable to any of inclusion criteria. 
20. History of difficulty of swallowing. 
21. Intake of depot injectable solutions (including study medications) within 6 months 
before start of the study. 
22. Intake of enzyme-inducing, organotoxic or long half-life drugs within 4 weeks 
before start of the study. 
23. Special diet due to any reason, e.g. vegetarian.  
 
11.3. Other Conditions 
Diseases present at entry into the study are regarded as concomitant illnesses and 
generally as an exclusion criteria. Illnesses occurring during the study period 
(intercurrent illnesses) are to be regarded as adverse events and will be documented on 
a separate page (“adverse event form” and “drop-out sheet”) in the Case Report Forms 
(CRF) (see Appendix II). 
 
11.4. Coding Subjects 
 
The subject screening number will be also assigned as the subject code throughout the 
study.  
A volunteer code will be assigned to each subject.  
 

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12.  MEDICATION 
12.1. Study Medication 
The study medications will be supplied together with certificates of analysis by the 
company responsible for manufacturing the product, World Medicine Ilaç San. ve 
Tic. A.Ş.-Turkey.  The packaging and labelling will be done according to the GMP 
and GCP requirements.  
The reference drug marketing authorisation holder is AbbVie Tıbbi İlaçlar Sanayi ve 
Ticaret Limited Şirketi-İstanbul,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 Üniversitesi FARMAGEN GCP Center 
Gaziantep Üniversitesi Teknoloji Geliştirme Bölgesi (Teknopark), 
Burç Yolu, Şahinbey 27260, Gaziantep-TURKEY 
 

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12.1.1. Test Drug: 
Active substance: 
 
Lopinavir and ritonavir 
Formulation: 
 
Film Tablets for oral administration 
Strength: 
 
200/50 mg  
Manufacturer:                   
World Medicine Ilaç San. ve Tic. A.Ş. - Turkey 
 
Marketing Authorisation Holder:  
 World Medicine Ilaç San. ve Tic. -Turkey 
Batch Number: 
00400892 
        Expiry Date: 
04.2022 
        Trade name: 
Orvical 200 mg/50 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: 
 
Lopinavir and ritonavir   
Formulation: 
 
Film Tablets for oral administration  
Strength: 
 
200/50 mg  
Manufactured:                   
AbbVie Deutschland GmbH & Co. - Germany  
Marketing Authorisation Holder:  
  AbbVie Tıbbi İlaçlar San. ve Tic. Ltd Şirketi-İstanbul-Turkey 
Batch Number: 
1121788 
        Expiry Date: 
07.2022 
Trade name: 
 
 Kaletra 200 mg/50 mg Film Kaplı Tablet  
Storage requirements:      
Store below 25°C at room temperature. 
Certificate of analysis: 
To be provided by the Sponsor together with medication 
   
  12.2. Blinding 
 
12.2.1. For Clinical Phase 
 
This trial is planned as open-labelled in clinical phase. Investigator will have the 
information of which subject will take which tablet [Test or Reference] in study. Also, 
the subjects will have the information about the tablets which will be administered in 
the 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 in each period once daily either test drug or reference drug 
as 200 mg lopinavir and 50 mg ritonavir (in Period II and Period IV, the subjects will 
be administered by the other drug that they will not administered in the Period I and 

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Period III).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(s) and nurse(s) and supervised by a second medical 
professional to ensure the correctness of drug administration. Also, a personnel 
(monitor) from ALPAN Farma 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 
or at ALPAN Farma 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 
ALPAN Farma or World Medicine Ilaç San. ve Tic. A.Ş. after completion of the 
study. It is not allowed to use the study medication for any other purpose. 
12.6. Concomitant Medication 
Concomitant medication is generally not allowed for the duration of the trial. If this is 
considered  necessary for the volunteer's welfare, it may be given at the decision of the 
investigator. The volunteers have to inform the investigator about any intake of other 
drugs in the course of the trial. If necessary, for the treatment of ordinary pain (e.g. 
headache), some analgesics (paracetamol etc.) which have no drug interaction with 
study products, may be given by investigator. Any intake of concomitant medication 
has to be documented in the Case Report Form (“concominant medication form”, 
“adverse event form” and “drop-out sheet”) specifying the substance, dose, time and 
reason for use of concomitant medication and may be regarded as an exclusion 
criterion. 
12.7. Rescue Medication 
No specific rescue medication is planned for the present trial since it is not a 
therapeutic trial and the safety / tolerability profiles of the administered drug substance 
are well known. 

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12.8. Storage of Study Medication 
The investigator will be responsible for proper storage of the investigational products. 
All drug supplies must be stored in original package to protect from light and moisture 
in a dry place at room temperature below 25°C, and separately from normal 
hospital/practice stocks, locked and only accessible for authorized personnel, in 
accordance with the manufacturer's instructions. All supplies must be accounted for at 
the end of the study. A drug inventory form is to be filled in for this purpose.  

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13. STUDY PROCEDURE 
13.1. General Procedure 
Volunteers eligible for inclusion within the age limits as defined in section 11.1 will be 
asked for informed consent as described in Appendix 7 due to the Covid-19 outbreak 
precautions and as described in section 20.3 and will be thereafter screened with 
respect to inclusion and exclusion criteria.  
The initial examination will be carried out on the day of  the beginning of the isolation 
as described in Appendix 7. The standard clinical screening includes demographic 
data, brief anamnestic data (medical history with information about relevant previous 
diseases of all body systems), physical examination, determination of body 
temperature, weight and height, standard ECG (12 lead), measurements of blood 
pressure (BP) and pulse rate (PR) after 5 minutes supine rest. 
The standard laboratory screening includes serum levels of “CBC, glucose, urea, uric 
acid, creatinine, estimated GFR (eGFR), total bilirubin, sodium, potassium, calcium, 
chloride, SGOT (AST), SGPT (ALT), GGT, alkaline phosphatase, total protein and 
urinalysis”. The blood specimen (20 mL* for entry and 12 mL for final) for the safety 
laboratory will be taken under fasting conditions. Total blood sampling for both 
laboratory examinations (entry and final) will be 32 mL. The volunteers will also be 
checked for presence of HBsAg, HCV-Ab and HIV-Ab in serum and Covid-19 Rapid 
Test and Covid-19 PCR test.  
Clinical laboratory tests will be performed using the auto analyser at a contracted and         
certified laboratory (GAMA Tıp Merkezi-G.Antep). Covid-19 PCR test will be 
performed at “Gaziantep University Şahinbey Research Hospital, Molecular 
Genetic Diagnosis, Hematology and Tissue Typing Laboratory”. 
*  At entry examination the blood sample amount will be 20 mL and 8 mL sample of 
20 mL sample will be divided into tubes and one of this tube will be used for the anti-
coagulant validation purpose during the analytical validation process. This plasma 
sample will send to Novagenix with master and back-up samples. 
The following parameters are determined in urine (30 mL): pH, protein, glucose (semi 
quantitatively by means of strip test), ketones, blood, leukocytes, bilirubin, nitrites. If 
the strip test for any urine parameter is positive, a microscopic examination of the 
sediment has to be done. 
At screening volunteers will be requested to provide a urine sample for a drug screen 
which will include “amphetamines, cannabinoids, benzodiazepines, cocaine, opioids 
and barbiturates” and for an alcohol breath test. All laboratory tests will be carried out 
in a certified local laboratory. A list of the normal ranges and units of measurement of 
the laboratory parameters to be determined during the study and the certificate of the 
laboratory will be provided by the investigator before the start of the study. The 
reference ranges and the results of the individual laboratory examination will be 
documented in each CRF. The investigator will be provided with a print-out or 
authorized copy of the original laboratory values. 
If in the course of initial screening any clearly pathological value (laboratory value 
outside reference range, clinically relevant or significant) is observed, this finding will 
be regarded as an exclusion criterion. 

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Laboratory values outside the normal range will be judged by the investigator in a 
written form in the CRF. Single laboratory values outside the normal range will 
generally not be regarded as an exclusion criterion provided that: 
a) they are not accompanied by clinical symptoms, 
b) the context of related laboratory values gives no indication of a pathological 
process and 
c) the investigator regards them as clinically irrelevant in written form in the CRF. 
If Covid-19 PCR test result is positive, the volunteer(s) will be transfer to 
Gaziantep University Şahinbey Research Hospital, Emergency Department* 
under appropriate conditions immediately. This finding will be regarded as an 
exclusion criterion.  
*Contact Physician: Prof. Dr. Şevki Hakan EREN 
 Gaziantep University Şahinbey Research Hospital,  
  
 
 
          Emergency Department 
  
GSM: 0506 2379579 
The test and reference product will be administered under fasting conditions each in a 
randomised manner in four period with at least 48 hours wash-out period. Volunteers 
will be treated under hospitalization conditions in study period and will be hospitalised 
at the Clinical Facility (FARMAGEN-Good Clinical Practice and Research Center)  
from the evening of  Day 0 (hospitalization) normally until taking the last blood 
sample in 4th period and carried out the post-study and final examination to ensure 
subjects’ safety as well as standardised trial conditions during profiling days (e.g. in 
view of food and fluid intake, diet, fasting conditions, drug administration, clinical and 
other procedures). Adverse events will be monitored throughout the study. The medical 
care of the volunteers will be guaranteed by the presence or stand-by of the 
investigator or one of the co-investigators throughout the clinical phase of this trial. 
The volunteers will come to the clinic from isolation, described at Appendix 7, at 
approximately 18:00 on the day before the treatment (Day 0) of study and will remain 
there for 8 days. A measurement of body temperature will be performed once a day in 
the mornings during the study period. They will not be allowed to drink water between 
1 h before to 1 h after administration, except while dosing (the total intake of water on 
the days of dosing will be maximum 1.5 L). The investigator will check on each 
volunteer's wellbeing prior to their discharge from the clinic. If necessary, some 
volunteers will remain at the clinic until any adverse events have resolved. All 
volunteers will be subjected to a post-study examination and final examination and 
laboratory tests on the day of  last sampling in fourth period. 
For each volunteer being withdrawn from the study prior to regular termination of the 
individual study period, due to whatever reason, a complete final examination has to 
be performed at the time of withdrawal as far as possible with regard to the volunteer's 
health conditions and as far as necessary with regard to safety aspects. All taken 
plasma samples will be analysed. But will not be included to statistical 
calculations. 

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13.2. Special Procedures 
Special procedures due to the Covid-19 outbreak will be done as described in 
Appendix 7. 
Study drugs will be administered on the Day 1, Day 3, Day 5 and Day 7. The subjects 
will be fasted overnight (minimum of 10 hours) and administrations will take place in 
the morning approximately  at 08:00 a.m. and the exact time will be recorded on CRFs. 
The subjects will remain fasting until 4 hours after administration. Subjects are not 
allowed to drink water from 1 h before until 1 h after administration, except that 
while dosing. Subjects will be dosed in sitting position in bed for 5 hours after drug 
administration without lying in bed for each period. In this interval (t0.5-t5.00); the 
blood samples will be performed in bed and lunch will be provided on bed.  
During this study all clinical unit personal will be checked daily by Covid-19 PCR test 
for safety.  
 
 
13.3. Daily Activities during the Trial 
Entry examination: 
The entry examination will be carried out on the day of screening of the trial as 
described in Appendix 7. 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, Covid-19 PCR, drug screening, 
alcohol breath test,  urinalysis). 
* Clinical screening and examination wiil be carried out after negative 
“Covid-19 Rapid Test” results 
 
Period 1- Period 2- Period 3-Period 4: 
 Interview (possible presence of exclusion criteria and/or adverse events)  
 Standardised dinner will be served before first 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. 
 Treatments will be given according to randomised administration [single oral dose of 
one tablet of the Test Drug or one tablet of the Reference Drug]* with compliance 
check (approximately 08:00 a.m.)   
 Blood sampling (0.50-36.00 hours) will be done after drug administration with 
separation of plasma 

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 Standardised lunch will be served at 4 hours after the dosing (Day 1, Day 3, Day 5 and 
Day 7).  
 Standardised dinner will be served at 10 hours after the dosing (Day 1, Day 3, Day 5 
and Day 7) 
 Standardised light breakfast will be served at approximately 21.30 pm (Day 1, Day 3, 
Day 5 and Day 7). 
 Questioning for and registration of adverse events at hospitalisation day, pre dose 
and 1.00, 4.00, 10.00, 24.00, 36.00 hours post-dose.  
 Standard breakfast, standard lunch, standard evening meal and a standardised light 
breakfast will be served in Day 2, Day 4 and Day 6. In 8th day of the study standard 
breakfast lunch and dinner will be served.  
 Discharge from the clinic (after final examinations). 
*At the end of the 4th period, subjects will have taken 2 tablets of Test Drug and 2 tablets of Reference 
Drug totally in whole study according to the full-replicated design (TRTR/ RTRT). 
Final examination: 
 
The final examination will be carried out on the day of last blood sampling of the 4th 
period. The following parameters will be documented: Interview (occurrence of adverse 
events) 
 
Clinical screening and examination (clinical state: body temperature, BP, PR, ECG, 
registration of pathological findings, if any, clinical chemistry, Covid-19 PCR test 
haematology, urinalysis) 
 
Laboratory screening. The sampling for laboratory screening can be performed together 
with the last sampling for the kinetic profile in 36 hours post-dose. Abnormal laboratory 
findings which are judged by the investigator as adverse event at the final examination 
should be followed up until it will be resolved or is assessed as stable condition or a 
causality other than trial medication was found and whole data that collected during the 
entry examination, study period and final examination will be documented in the 
CRF.  
 
13.4. Restrictions 
The volunteers will be requested not to undertake vigorous exercise during the 2 days before 
the initial screening laboratory tests until after the final laboratory safety tests. 
When confined to the clinical centre, the volunteers have to avoid from alcohol starting one 
week before hospitalization day until the last blood sampling of either period. Smoking will 
not be permitted during the study of blood sampling during hospitalization of study. Chewing 
gum is not allowed. No foods and beverages containing caffeine or other methylxanthines 
(coffee, tea, coke, chocolate) and fruit-juice from 2 days prior to dosing until the last blood 
sampling of study will be allowed. No grapefruit containing products from 7 days prior to the 
dosing until the last sampling will be allowed. The volunteers will abstain from food and 
beverages from 21:00 on the hospitalization evening until lunch time on the following day, i.e. 
until 4 hours post dose.(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 will 
be maximum 1.5 L, beginning 1 hour post-dosing. 
For the ambulatory phases of the study, volunteers will be requested to abstain from alcohol 
containing foods and beverages for the study starting 24 hours before the initiation  of the 
study until confinement to the clinic. Upon admission to the clinic for study, all volunteers will 

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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; Orvical 200 mg/50 mg Film Tablet (World Medicine-Turkey) 
Reference Drug; Kaletra 200 mg/50 mg Film Kaplı Tablet (AbbVie Tıbbi İlaçlar Sanayi ve 
Ticaret Limited Şirketi-İstanbu-Turkey)  
 
The precise instructions for drug administration are given in Ethical Committee (EC) and 
Ministry of Health (MoH) submission file. 
 
Immediately after pre-dose sampling, the volunteers will swallow one tablet of the test 
drug or one tablet of the reference drug (200 mg lopinavir and 50 mg ritonavir in 
each case) with 240 mL water, under fasting conditions. After the washout period; 
in Period II and Period IV, the subjects will be administered by the other drug that 
they will not administered in the Period I and Period III.  
    
This will be followed by a mouth check. The investigator or the co-investigator will 
administer the study medication and this will be supervised by a second medical 
professional to ensure the correct drug administration.  
 
The subjects will be dosed in ascending numerical order according to the 
randomisation list whilst sitting position and they will be instructed to remain in 
sitting position in bed for 5 hours after drug administration without lying in bed for 
each period. In this interval (t0.5-t5.00); the blood samples will be performed in bed and 
lunch will be provided on bed. Dosing will commence at approximately 08:00 a.m. 
 
 
13.6. Dietary Regimen  
An evening meal (total caloric value of approximately 1200 kcal) will be served no 
later than 21:00 on the hospitalization day (Day 0) in study.  
In treatment days (Day 1, Day 3, Day 5 and Day 7); 
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.  
A standardised light breakfast will be served approximately 21:30 p.m. 
In treatment days (Day 2, Day 4, Day 6 and Day 8); 
Also standard breakfast, standard lunch, standard evening meal and a standardised 
light breakfast will be served in Day 2, Day 4 and Day 6. In 8th day of the study 
standard breakfast lunch and dinner will be served. 

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The same meal composition has to be served in all study of the trial. This will be 
documented in the CRF. 
 
 
13.7. Blood Sampling for Drug Analysis 
 
Venous blood will be drawn at the following times: 
Period 
Day 
Time (hour)* 
Tube No 
1-2-3-4 
1 
t0.00 
P01 
t0.50 
P02 
t1.00 
P03 
t1.50 
P04 
t2.00 
P05 
t2.50 
P06 
t3.00 
P07 
t3.33 
P08 
t3.66 
P09 
t4.00 
P10 
t4.33 
P11 
t4.66 
P12 
t5.00 
P13 
t5.50 
P14 
t6.00 
P15 
 
t7.00 
P16 
 
t8.00 
P17 
 
t10.00 
P18 
 
t14.00 
P19 
2 
t24.00 
P20 
t36.00 
P21 
 
* 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 lopinavir and rotinavir concentrations.  
* 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 lopinavir and ritonavir analysis [for details see section 13.7 (Blood 
Sampling for Drug 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 479 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”]. 
After sampling the blood samples for pharmacokinetic analysis, the tubes will be 
immediately refrigerated at 2 - 8°C and will remain there for not more than 30 minutes. 
After centrifugation (3.000 rpm, 4 - 6°C, 10 min), the separated plasma from each 

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sample will be transferred into two 3 mL transparent, polypropylene tubes per sample 
(at least 1.5 mL per tube). All the aliquoted plasma samples will be flash freezing 
immediately. The flash frozen samples (aliquoted plasma samples) will be 
transferred to a deep-freezer and stored at -70°C.  
 
At the end of the study one aliquot will be shipped on dry ice (solid CO2) according to 
the sample transport SOP of FARMAGEN-Good Clinical Practice and Research 
Center by courier for the determination of plasma drug concentrations to the analytical 
laboratory: 
Novagenix Bioanalytical Drug R&D Centre  
Esenboğa Yolu 25. Km.  
Ankara-Turkey 
As precautionary measure, the other aliquot will at first be retained at the clinical unit 
in case that any adverse conditions, for example due to transport damage of the first 
shipment.Once the bioanalytical laboratory confirms receipt of the first shipment, the 
second set of aliquots will be sent. 
The samples will be packed on dry ice for transport, no interruption of the freeze chain 
is allowed and also data loggers will be included for temperature recording. 
All labels for blood and plasma samples will be provided by NOVAGENIX and will 
contain the following information: active ingredient name, study code, subject number, 
period, tube number and time (e.g. 2 h post-dosing). An example is given below: 
 
 
Lopinavir; Ritonavir 
Study # :    NOV01911 
Subj #    1 
Period : 1 
Time: 0 h  P # : P1 
 
13.8. Endpoint(s) For The Study 
 
Primary Endpoint: AUC0-tlast and Cmax of lopinavir and ritonavir   
 
Secondary Endpoint: AUC0-∞, t1/2, tmax of lopinavir and ritonavir 
 
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 Covid-19 PCR test result is positive, the volunteer(s) will be dropped out from 
study. 
 if subjects who have intaked or administrated of any prescribed systemic or topical 
medication (including OTC medication) within 2 weeks of the start of the study 
(except singles doses of analgesics which have no drug interaction with study 
products) given in case of an adverse event (e.g. headache) during the study, 
 if circumstances defined as exclusion criteria are registered, 
 if administration of any drug is necessary, which is not permitted according to the 
exclusion criteria (see section 11.2), independently of its necessity due to the 
occurrence of adverse events (including intercurrent illnesses) or of its use due to other 
reasons, 
 if vomiting occurs at or before 2 times median tmax.  
 if diarrhea exists during screening and /or medication day. 
 
14.2. Replacement of Drop-outs 
 
A total of 30 volunteers will be enrolled in the trial. If drop-out exists in isolation or 
in study period, then these dropouts WILL NOT BE replaced.  
For each volunteer being withdrawn from the study prior to regular termination of the 
individual study period, due to any reason, a complete final examination has to be 
performed 1 day after the day of drop-out, as far as possible with regard to the 
volunteer's health conditions and as far as necessary with regard to safety aspects and 

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

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

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

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15.3. Reporting and Documentation of Adverse Event(s) 
AEs/ADR will be assessed by spontaneous, unsolicited reports of the volunteers, by 
observation and by routine open questionings of the volunteers. Questionings will be 
done by experienced staff of FARMAGEN-Good Clinical Practice and Research 
Center during admission to the clinical facility and at least at the following times of 
the study period: at hospitalization day, pre dose and t1.00, t4.00, t10.00, t24.00, t36.00 
hours after the drug administrations. 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 World Medicine Ilaç San. ve Tic. A.Ş. or to ALPAN FARMA 
as an initial report. 
As soon as new information about the SAE becomes known, the investigator has to 
forward it without any delay to World Medicine Ilaç San. ve Tic. A.Ş. or to ALPAN 
FARMA. 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 and SAE documentation will be forwarded to 
ALPAN FARMA or World Medicine Ilaç San. ve Tic. A.Ş. as soon as possible. 
The responsible sites for the upper procedure are: 
World Medicine Ilaç San. ve Tic. A.Ş.  
Contact Person  
Alpan Farma Ltd.Şti. 
Contact Person 
Evrim Aksel   
Phone: (+90) 212 474 70 50 
Fax: +90 212 474 09 01 
E-mail: evrim.aksel@worldmedicine.com.tr  
Prof. Dr. Aydın Erenmemişoğlu 
Phone: +90 352 2242322 
Fax: +90 352 2242322 
GSM: +90 532 5510082  
E-mail: erenmemis@gmail.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 ALPAN Farma 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 lopinavir and ritonavir will be determined by means of a 
validated LC method, according to Novagenix’s SOP NOV-ENG-08-TEC1.  
Detailed characteristics of the analytical method applied will be described in the 
“Analytical Study Plan” (see Appendix III: Analytical Study Plan). All assay 
validations will be performed in consideration of the Guideline on Bioanalytical Method 
Validation,EMA,21 July 2011 and  US FDA Guidance for Industry, Bionalytical Method 
Validation May 2018 or current guidance on method validation date. 
Volunteer’s all samples will be measured in a single analytical run in order to 
eliminate the influence of the inter-assay variance on the assessment. The analyst has 
to provide a final analytical report with tables for all samples that were analysed. 
Already measured samples will be stored at <-20°C for at least 6 months (storage 
period can be prolonged in exceptional cases, e.g. upon special request of authorities) 
after termination of bio-analysis. At that point a further decision by the Sponsor will 
be taken. 
20% of the chromatograms are to be included in printed Final Study Report. But 100 
% of chromatograms will be given also as electronically. 
 
17.1. Reanalysis of study samples 
The reasons for reanalysis of study samples are presented in Appendix III: Analytical 
Study Plan. 
 
17.2. Incurred Sample Reanalysis 
Incurred Sample Reanalysis (ISR) will be performed at any time after starting subject 
analysis by choosing two sampling points near or at Cmax and two sampling points in 
the elimination phase per period (total 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 lopinavir and ritonavir 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, full-replicated, cross-over study the 
following pharmacokinetic parameters will be calculated:  
Primary pharmacokinetic parameters: 
Cmax: Maximum observed plasma concentration 
AUC0-tlast: Area under the plasma concentration-time curve from zero to the last 
measurable concentration, calculated by the linear log trapezoidal rule. 
Secondary pharmacokinetic parameters: 
AUC0-∞: Area under the plasma concentration-time curve, calculated by extrapolation 
to infinity. 
tmax: Time to maximum observed plasma concentration 
t1/2 :  Terminal half-life 
Additional pharmacokinetic parameters: 
MRT:  Mean residence time 
λz: Terminal rate constant. 
For pharmacokinetic calculations, the program package Phoenix WinNonlin (Version 
8.1, Certara L.P.) or above will be employed. Phoenix WinNonlin will also be used to 
generate concentration/time plots. 
 
 

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19. STATISTICAL PROCEDURES 
The statistical analysis of the pharmacokinetic data described in this section 
corresponds with provisions 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. 
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 acceptance ranges for Cmax and AUC0-tlast 
for lopinavir and ritonavir.  
The acceptance ranges for Cmax will be widened to a maximum of 69.84 -143.19% 
using scaled-average-bioequivalence (SABE) and for AUC0-tlast will be taken as 80.00-
125.00% regardless of variability according to the EMA guideline (Guideline on the 
Investigation of Bioequivalence-CPMP/EWP/QWP/1401/98 Rev. 1/Corr, London 20 
January 2010).  
The extent of the widening is defined, as below, based upon the intra-subject 
coefficient of variation of Reference Drug (CVWR): 
 If CVWR for Cmax is greater than 30%: 
Acceptance ranges will be determined using scaled-average-bioequivalence 
(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 CVWR 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. 

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The table below gives examples of how different levels of variability lead to 
different acceptance limits using this methodology; 
 
The other criteria for SABE: The geometric mean ratio should lie within the 
conventional acceptance range 80.00- 125.00% for Cmax and AUC0-tlast. 
 
If CVWR is equal or less than 30%: 
Assessment of bioequivalence will be determined using average bioequivalence 
methods. 80.00-125.00% acceptance range will be used for the assessment of 
bioequivalence. 
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. 
Differences in tmax will be evaluated non-parametrically. 
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 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. 

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19.1.4. 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 variability is estimated between 30-35% for Cmax and AUC0-tlast for 
both lopinavir and ritonavir according to literatures. A total number of 30 subjects is 
estimated in order to demonstrate bioequivalence with a power of 80% and a 
test/reference parameter ratio between 0.90 and 1.10. 
19.3. Statistical Code and Randomisation 
The randomisation table will be provided by Novagenix. 30 subjects, who will be 
included in the study, will be determined to receive either Test or Reference Product 
by a randomisation table. [at the end of the 4th period, subjects will have taken 2 
tablets of Test product and 2 tablets of Reference product totally in whole study 
according to the replicated design (TRTR/RTRT)]. 
30 subjects, who will be included in the study, will be determined to receive either 
Treatment A or Treatment B in each period by a randomisation table generated with a 
computer programme  (in Period II and Period IV, the subjects will be administered 
by the other drug that they will not administered in the Period I and Period III).  
Which one of the Test or Reference administration will be Treatment A or Treatment B 
is randomised by the Investigator. All the analytical analyses are done without the 
knowledge of the Test and the Reference product. These products will be named and 
known as Treatment A or Treatment B by CRO. Then the form defining Treatment-
Period relationship will be enveloped, sealed and sent to CRO by the Investigator. 
CRO will open the sealed envelope in the “Project Evaluation Meeting” which will be 
held after the laboratory analyses are completed. Once the seal is opened, no new 
reanalyse or no data change/exclusion will be allowed. 
 
19.4. Documentation of the Data 
Measured plasma concentrations will be listed per treatment for each volunteer and 
each sampling point. In addition, mean values, standard deviations and the standard 
error of the mean will be given per sampling point of each treatment. 
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. 

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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 on the day of screening as described 
in Appendix 7 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/her 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. 
The volunteers will be informed about this study by verbal and by reading the 
Volunteer Informed Consent Form from an authorized medical doctor who is in 
the clinical study team. 
Each volunteer will give in writing his authorization that the study data may be given 
for review to the responsible Local and National Authorities. 

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

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21. GOOD CLINICAL PRACTICE 
21.1. Legal Requirements 
This study will be conducted in accordance with the following: 
 
The Guidance for GCP, published by the Ministry of Health of Turkey. Circular, 13.11.2015. 
 
The Guidance on Safety Declaration of Clinical Trials , published by the Ministry of Health of Turkey,  
 
13.11.2015. 
 
Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. Official  
Journal, No: 29474; 13.09.2015. 
 
Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. Official  
 
Journal, No: 29041; 25.06.2014. 
 
Regulation on Clinical Trials of Drugs and Biological Products. Official Journal, No: 28617;  
 
13.04.2013. 
 
Regulation on the Principles of Good Laboratory Practice, Harmonisation of the Test Units,  
 
Supervision of Good Laboratory Practices and the Studies. Official Journal, No: 27516, 09.03.2010. 
 
Regulations on Evaluation of Bioequivalence and Bioavailability of Pharmaceutical Preparations.  
 
Official Journal, No: 21942; 27.05.1994.  
 
Guideline on Bioanalytical Method Validation, EMEA/CHMP/EWP/192217/2009 Rev.1 Corr.2,  
 
London, 21 July 2011. 
 
Guideline on The Investigation of Bioequivalence. CPMP/EWP/QWP/1401/98 Rev.1/Corr., London,  
 
EMA, 20 January 2010. 
 
Bioanalytical Part, Pharmacokinetic and Statistical Analyses of Bioequivalence Trials:  
 
EMEA/INS/GCP/97987/2008, London, 28.05.2008. 
 
Guidance for Industry. Bioavailability and bioequivalence studies for orally administered drug  
 
products- General Considerations. FDA, CDER, March 2003. 
 
Guidance for Industry. Statistical approaches to establishing bioequivalence. FDA, CDER, January  
 
2001. 
 
ICH Topic E 9. Statistical Principles for Clinical Trials. September 1998 (CPMP/ICH/363/96). 
 
ICH E6 (R2)- Guideline for good clinical practice, 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 
ALPAN Farma 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. 
The investigator is responsible for the transfer of CRF and other required documents to 
ALPAN Farma. All CRFs are thereafter delivered to ALPAN Farma. Copies of all 
CRFs will be sent to NOVAGENIX by ALPAN Farma for Final Study Report writing.  
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 sponsor’s authorized 
personnel 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 
ALPAN Farma 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.  
The investigator will permit a representative of 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 Sponsor and Good Clinical Practice regulations. 
Monitoring of this study will be performed by sponsor’s authorized personnel 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 ALPAN 
Farma to the Sponsor after completion of the trial. 
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 
enrolment, visit dates, results of examinations, administrations of medication and 
adverse events. 

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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. 
After completion of the study, all unused study medication and empty sachets will be 
collected by the ALPAN Farma and returned to the Sponsor. 
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 
permission of the Sponsor. It is understood that no study material or information 
developed in this trial in connection with Lopinavir; Ritonavir 200 mg/50 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 ALPAN Farma 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. 
 

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21.10. Subject Payment 
 
It will be paid by ALPAN Farma 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 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, ALPAN Farma 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. 

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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 
ALPAN Farma will store all essential documents (i.e. 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, ALPAN Farma and the Sponsor give their 
consent. 
 
  25.  CONTRACT AND COSTS 
ALPAN Farma and the Investigator conclude an agreement on fees. This agreement 
considers the number of volunteers that are to be included and the costs determined  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. 
ALPAN Farma 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 ALPAN Farma and the Investigator and Sponsor as well as between 
ALPAN Farma and Sponsor. 
 
     

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26. FINAL REGULATIONS 
ALPAN Farma 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 ALPAN Farma 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 she/he 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), Seoul (2008) and Fortaleza, 2013. 
 Text of the ICH Guideline for Good Clinical Practice (2017) 
 A sufficient number of volunteer information sheets, informed consent forms, CRFs 
and forms for reporting serious adverse events (''Serious adverse event in clinical 
study'') to start the study 
 Furthermore, by signing this protocol the investigator affirms that 
 He has been adequately informed on the study drug and agrees that the study 
protocol contains all information required to perform the study as set out in the 
protocol. 
 The first volunteer will not be included in the study until receipt of approval by the 
EC and MoH and/or until all legal requirements have been fulfilled. 
 The study will be conducted in accordance with the moral, ethical and scientific 
principles governing clinical research as set out in the Declaration of Helsinki (last 
revision), with ICH Guideline for Good Clinical Practice (2017) and the Turkish 
Drug Regulations. 
 Informed consent to participate for all volunteers enrolled in the study will be 
obtained according to section 20.3 of this protocol, and that the consent forms as 
well all source data will be kept for 14 years. 
 She/He will submit to the ALPAN Farma an up-to-date Curriculum Vitae. 

Study Code: NOV2020/01911   NCT04386876                                                    
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27. 
REFERENCES 
 
 FDA, Label of Lopinavir/Ritonavir 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021251s052_021906s046lbl.
pdf 
 Summary of Product Characteristics of Lopinavir/Ritonavir 
https://www.ema.europa.eu/en/documents/product-information/lopinavir/ritonavir-
mylan-epar-product-information_en.pdf  
 Summary of Product Characteristics Ritonavir 
https://www.ema.europa.eu/en/documents/product-information/norvir-epar-product-
information_en.pdf  
 EMA, Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic, Version.2 27.03.2020 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
 MHRA, Advice for Management of Clinical trials in relation to Coronavirus, 
12.03.2020 https://mhrainspectorate.blog.gov.uk/2020/03/12/advice-for-management-of-
clinical-trials-in-relation-to-coronavirus/ 
 FDA, FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Pandemic, updated :02.04.2020 
https://www.fda.gov/media/136238/download 
 The Guidance for GCP, published by the Ministry of Health of Turkey. Circular, 13.11.2015. 
 The Guidance on Safety Declaration of Clinical Trials , published by the Ministry of Health 
of Turkey, 13.11.2015.  
 Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. 
Official Journal, No: 29474; 13.09.2015. 
 Regulation Amending the Regulation of Ministry of Health of Turkey for Clinical Trials. 
Official Journal, No: 29041; 25.06.2014. 
 Regulation on Clinical Trials of Drugs and Biological Products. Official Journal, No: 28617; 
13.04.2013. 
 Regulation on the Principles of Good Laboratory Practice, Harmonisation of the Test Units, 
Supervision of Good Laboratory Practices and the Studies. Official Journal, No: 27516, 
09.03.2010. 
 Regulations on Evaluation of Bioequivalence and Bioavailability of Pharmaceutical 
Preparations. Official Journal, No: 21942; 27.05.1994.  
 Guideline on Bioanalytical Method Validation, EMEA/CHMP/EWP/192217/2009 Rev.1 
Corr.2, London, 21 July 2011. 
 Guideline on The Investigation of Bioequivalence. CPMP/EWP/QWP/1401/98 Rev.1/Corr., 
London, EMA, 20 January 2010. 
 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. 

Study Code: NOV2020/01911   NCT04386876                                                    
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 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). 
 ICH E6 (R2)- Guideline for good clinical practice, 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. 

Study Code: NOV2020/01911   NCT04386876                                                    
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28. 
LOCATION OF STUDY DOCUMENTATION 
The following documents are kept in the Project File at FARMAGEN and ALPAN 
Farma with coded 
NOV2020/01911 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 Clinical Personnel *** 
9. Copy of The Sample Volunteer Information Document and Informed Consent 
Form 
10. Copy of the CRF and Additional Related Documents (Form for SAE) 
11. Personnel Assignment List with Signatures ** 
12. Randomisation List 
13. Trial Medication Documents (Record of The Receipt **, Dispensing and 
Disposal of Drug Supplies **, Analytical Certificates, Copy of The Labelling of 
Trial Medication) 
14. Laboratory Reference Ranges and Laboratory Certificate ** 
15. Audit Certificates (if available) ** 
16. Volunteer's Insurance 
17. Screening-log, Identification***- and/or Enrolment-log of Volunteers 
18. Monitoring Reports ** 
19. Documentation of Data Handling, Plausibility Checks, Data Base Codes and 
Closure 
20. CRFs of all Volunteers Including Query Forms * 
21. Reports on Serious and/or Unexpected Adverse Events (Adverse Drug 
Reactions) * 
22. Publications 
23. Records of any Deviation From Planned Procedures 
 
*  original; 
  **  copy will be sent to the Sponsor 
*** only in clinical center 

Study Code: NOV2020/01911   NCT04386876                                                    
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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 and Dietitian 
Appendix 7: Isolation procedure due to Covid-19 pandemic