Clinical trial NCT03537404
Conditions: Healthy
Keywords: hepatitis C chronic pharmacokinetics HIV coinfection concomitant therapy
Sponsor: R-Pharm
Start date: 2017-04-24; Completion date: 2017-06-30
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study purpose is to evaluate the potential for a pharmacokinetic drug-drug interaction, safety and tolerability when Narlaprevir, Ritonavir (used as a metabolic inhibitor) and Tenofovir disoproxil fumarate (part 1) and Narlaprevir, Ritonavir and Raltegravir (part 2) are administered in combination to healthy volunteers.

Detailed description:
The current study includes 2 parts, as the following drugs may be used concomitantly to treat hepatitis C virus (HCV)/HIV coinfection:

* Part 1 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of narlaprevir with ritonavir and tenofovir disoproxil fumarate.
* Part 2 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of narlaprevir/ritonavir and raltegravir.

Each part of the study is designed as a randomized 3-period crossover study and will assess if there is any effect of tenofovir disoproxil fumarate or raltegravir on the pharmacokinetics of narlaprevir and vice versa.

Subjects will be screened within 28 days before dosing in this multi-part study. All subjects eligible for protocol criteria will be randomized 1:1:1 to receive one of the following treatment sequences: A/B/C, or B/C/A, or C/A/B. Every subject will receive only one treatment (A or B or C) in one Period. Subjects will be confined to the study center throughout treatment in each period. Following completion of study procedures for each treatment period, subjects will be released from the clinic. After a 7-14 (maximum) days interval between dosing, subjects will return to start hospitalization for the next treatment period. Subjects will be discharged from the study upon completion of all study related procedures in Period 3. Phone call will be conducted after 5-7 days of follow-up period to assess safety data.

This drug interaction study is designed to investigate pharmacokinetic drug-drug interactions between Narlaprevir coadministered with Ritonavir and antiretroviral drugs (Tenofovir disoproxil fumarate and Raltegravir) for labeling and clinical dosing guidance purposes.

Arms: arm 1: Narlaprevir 200 mg once daily with Ritonavir 100 mg once daily for 5 days arm 2: Tenofovir disoproxil fumarate 300 mg once daily for 5 days arm 3: Raltegravir 400 mg twice daily for 5 days arm 4: Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and Tenofovir disoproxil fumarate 300 mg once daily for 5 days arm 5: Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and 400 mg raltegravir twice daily for 5 days
Interventions: intervention 1: Narlaprevir intervention 2: Ritonavir intervention 3: Tenofovir Disoproxil Fumarate intervention 4: Raltegravir
Intervention descriptions: intervention 1: 100 mg, film-coated tablets, taken as 200 mg per os daily intervention 2: 100 mg, film-coated tablets, taken as 100 mg per os daily intervention 3: 300 mg, film-coated tablets, taken as 300 mg per os daily intervention 4: 400 mg, film-coated tablets, taken as 400 mg per os daily

Protocol documents:
Prot_SAP_000.pdf: 
 
Confidential 
 
Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
 
Page 1 of 83 
Clinical Trial Protocol 
 
 
 
 A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral 
Drugs 
 
 
Product / formulation: 
 Narlaprevir (J05013, Arlansa), 100 mg tablets 
Indication: 
 
   
Treatment of HCV 
Sponsor: 
 
 
R-Pharm JSC, Russia 
 Legal address:  
19 build. 1, Berzarina str., 123154, Moscow, Russia 
 
 Mailing address:  
 
111Б, Leninsky prosp. 119421, Moscow, Russia 
 
 
Protocol Number:  
 
CJ05013019 
Phase:  
 
 
Phase I  
 
 
 
  
Version of protocol: 
  
Version 8.0 (Incorporated Amendment #5) 
Date:  
 
 
 20 February 2017 
 
Confidentiality Statement 
This document is a confidential communication of R-Pharm JSC. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained within will be 
published or disclosed without prior written approval, except that this document may be disclosed 
to the appropriate ethics committee and regulatory authority under the condition that they are 
requested to keep it confidential. 
 
 
 


 
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1 ADMINISTRATIVE INFORMATION 
1.1 
Protocol approval and signatures 
Hereby I confirm that the Protocol CJ05013019: “A Drug Interaction Study to Assess the 
Pharmacokinetics of Narlaprevir and Antiretroviral Drugs” is created in accordance with the 
following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
 
 
 
 
Mikhail Samsonov, MD, PhD 
Chief Medical Officer,  
“R-Pharm” JSC 
 
 
 
 
 
 _________________________ 
 Date / Signature 
 
 
Emilia Krasavina, MD 
Scientific Advisor 
“R-Pharm” JSC 
 
 
 
 
 _________________________ 
 Date / Signature 
 
 
 


 
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1.2 
Investigator Agreement 
This protocol СJ05013019 “A Drug Interaction Study to Assess the Pharmacokinetics of 
Narlaprevir and Antiretroviral Drugs” is a confidential communication of R Pharm.   
I confirm that I have read this protocol, I understand it, and I will work according to this protocol.   
I will also work consistently with the ethical principles that have their origin in the Declaration of 
Helsinki and that are consistent with GCPs and the applicable laws and regulations.   
Acceptance of this document constitutes my agreement that no unpublished information contained 
herein will be published or disclosed without prior written approval from R Pharm. 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
 
Investigator name:  
 
Center name and address 
 
 
 _________________________________ 
 Date / Signature 
 


 
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1.3 
Trial contact list 
1) Sponsor: R-Pharm JSC 
Legal address:  
 
19/1, Berzarina str., 123154, Moscow, Russia  
Mailing address:  
 
111Б, Leninsky prosp. 119421, Moscow, Russia  
Office phone:   
+7 (495) 956-79-37  
Office fax:  
 
 
+7 (495) 956-79-38 
 
2) Scientific Advisor (R-Pharm JSC) 
Name:  
 
 
Emilia Krasavina 
Address: 
 
 
111Б, Leninsky prosp. 119421, Moscow, Russia 
Office phone:  
 
+7 (495) 956-79-37 
Office fax: 
 
 
+7 (495) 956-79-38 
Email:  
 
 
krasavina@rpharm.ru 
 
3) Almedis LLC 
Address: 
 
 
5, Malaya Pirogovskaya str., office 22 
 
 
 
 
119435 Moscow, Russia 
Office phone:  
 
+7 495 937 43 18 
Office fax: 
 
 
+7 495 937 43 19 
Email:  
 
 
elena.akimova@almedis.ru 
 
4) Central PK laboratory (ChromSystemsLab ) 
Name:  
 
 
LLC Chromatography Systems Laboratory    
Address: 
 
 
117485 Russia, Moscow, Butlerova St,, 12  
Office phone:  
 
+7-495-510-43-51 
Office fax: 
 
 
 
Email:  
 
 
www.chromsystemslab.com, info@chromsystemslab.com 
 
 


 
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In case of emergency 
For urgent medical advice Emilia Krasavina, Scientific Advisor on duty is available 24 h per day 
under the following: 
 
 
 
 
For reporting of serious adverse events, please follow the procedures described in Section 7.7.2.2. 
The occurrence of SAEs will be notified by the Investigator to “Almedis” by fax or e-mail within 24 
hours after becoming aware of their occurrence. The completed SAE form must be sent to the 
following number or address:  
 
 
 
 
Emergency number
Phone: +7 (916) 210-35-76 
24 h SAE reporting
Fax: Number: +7 495 937 43 19 
safety@almedis.ru 


 
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2 TABLE OF CONTENTS 
Page 
1 
ADMINISTRATIVE INFORMATION .............................................................................. 2 
1.1 
Protocol approval and signatures .......................................................................... 2 
1.2 
Investigator Agreement ........................................................................................... 3 
1.3 
Trial contact list ....................................................................................................... 4 
2 
TABLE OF CONTENTS ................................................................................................ 6 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................... 10 
4 
SYNOPSIS .................................................................................................................. 13 
4.1 
Study Design Diagram ........................................................................................... 23 
4.1.1 
Part 1 ................................................................................................................... 23 
4.1.2 
Part 2 ................................................................................................................... 24 
4.2 
Study Flow Chart ................................................................................................... 25 
4.2.1 
Part 1 ................................................................................................................... 25 
4.2.2 
Part 2 ................................................................................................................... 27 
Amendment #4 ................................................................................................................. 29 
5 
INTRODUCTION ......................................................................................................... 30 
5.1 
Background ............................................................................................................ 30 
5.2 
Class or Type of Drug Being Studied/Description of Drug ................................. 31 
5.3 
Preclinical Profile ................................................................................................... 32 
5.4 
Clinical Profile ........................................................................................................ 33 
5.4.1 
Pharmacokinetics .............................................................................................. 33 
5.4.2 
Safety and Tolerance ......................................................................................... 35 
5.5 
Rationale ................................................................................................................ 37 
5.5.1 
Study Conduct Rationale ................................................................................... 37 
5.5.2 
Study Design Rationale ..................................................................................... 37 
5.5.3 
Dose Rationale ................................................................................................... 40 
6 
STUDY OBJECTIVES ................................................................................................ 40 
6.1 
Primary Objectives ................................................................................................ 40 
6.2 
Secondary Objectives ........................................................................................... 40 
7 
INVESTIGATIONAL AND ANALYSIS PLAN .............................................................. 40 


 
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7.1 
Design of the Study/Methodology ........................................................................ 40 
7.2 
Participation in and Completion of the Study ...................................................... 43 
7.3 
Study Population ................................................................................................... 43 
7.3.1 
Subject Inclusion Criteria .................................................................................. 43 
7.3.2 
Subject Exclusion Criteria ................................................................................. 44 
7.3.3 
Subject Discontinuation Criteria ....................................................................... 46 
7.3.4 
Replacement of Subjects ................................................................................... 47 
7.4 
Treatments ............................................................................................................. 47 
7.4.1 
Study Treatments ............................................................................................... 47 
7.4.2 
Non-Study Treatments ....................................................................................... 54 
7.4.3 
Dietary, Tobacco, Alcohol, Caffeine, and Other Restrictions .......................... 55 
7.4.4 
Procedures for Monitoring Subject Compliance .............................................. 56 
7.5 
Blood Sampling ..................................................................................................... 56 
7.6 
Study Procedures .................................................................................................. 57 
7.6.1 
Explain Study and Obtain Written Informed Consent ...................................... 57 
7.6.2 
Review Inclusion/Exclusion Criteria Including Concomitant Medications ..... 58 
7.6.3 
Demographic Profile .......................................................................................... 58 
7.6.4 
Physical Examination ........................................................................................ 58 
7.6.5 
Medical History ................................................................................................... 58 
7.6.6 
Body Weight (kg) and Height Measurements (cm) Without Shoes ................. 58 
7.6.7 
Body Mass Index (BMI) ...................................................................................... 58 
7.6.8 
Test for HCV, hepatitis B Surface Antigen and HIV Antibodies, RW .............. 58 
7.6.9 
Screen for Drugs With a High Potential for Abuse .......................................... 59 
7.6.10 
Clinical Laboratory Safety Tests ....................................................................... 59 
7.6.11 
Screening Number Assignment ........................................................................ 60 
7.6.12 
Randomization/Dosing Number Assignment ................................................... 60 
7.6.13 
Record Adverse Events and Concomitant Medications .................................. 60 
7.6.14 
Clinical Assessment of Electrocardiograms .................................................... 60 
7.6.15 
Vital Signs ........................................................................................................... 61 
7.6.16 
Treatment Administration .................................................................................. 61 
7.6.17 
Blood Samples for Determination of Plasma Concentrations of narlaprevir . 61 


 
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7.6.18 
Blood Samples for Determination of Plasma Concentrations of Ritonavir .... 61 
7.6.19 
Blood Samples for Determination of Plasma Concentrations of Tenofovir ... 62 
7.6.20 
Urine Samples for Determination of Tenofovir Pharmacokinetics ................. 62 
7.6.21 
Blood Samples for Determination of Plasma Concentrations of Raltegravir . 62 
7.7 
Study Assessments and Analysis ........................................................................ 63 
7.7.1 
Pharmacokinetics/Pharmacodynamics/Safety ................................................. 63 
7.7.2 
Safety Monitoring and Assessments ................................................................ 65 
7.8 
Criteria for Early Termination of the Trial ............................................................ 71 
8 
STATISTICAL ANALYSIS AND REPORTING PLANS .............................................. 71 
8.1 
Data Sets ................................................................................................................ 71 
8.2 
Demographic and Other Baseline Characteristics .............................................. 71 
8.3 
Pharmacodynamic and Pharmacokinetic Analyses ............................................ 71 
8.3.1 
Pharmacokinetic Parameters ............................................................................ 71 
8.3.2 
Pharmacodynamics ........................................................................................... 72 
8.3.3 
Pharmacokinetic-Pharmacodynamic Analysis ................................................ 72 
8.3.4 
Pharmacodynamic-Pharmacodynamic Analysis ............................................. 72 
8.4 
Determination of Sample Size/Power/Level of Significance ............................... 72 
8.5 
Interim Analysis ..................................................................................................... 73 
8.6 
Safety ...................................................................................................................... 73 
8.6.1 
Adverse Events .................................................................................................. 73 
8.6.2 
Clinical Laboratory Tests................................................................................... 73 
8.6.3 
Vital Signs ........................................................................................................... 73 
8.6.4 
Physical Examination ........................................................................................ 73 
8.6.5 
Electrocardiogram.............................................................................................. 73 
8.6.6 
Other Safety ........................................................................................................ 73 
9 
ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS ........................................................................................................... 74 
9.1 
Ethical Conduct of the Study ................................................................................ 74 
9.1.1 
Independent Ethics Committee or Institutional Review Board ....................... 74 
9.1.2 
Subject Information and Consent ..................................................................... 74 
9.1.3 
Subject Identification Card ................................................................................ 75 


 
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9.2 
Reporting Trial Data to the Sponsor ..................................................................... 75 
9.2.1 
Data Collection Forms ....................................................................................... 75 
9.2.2 
Preparing Case Report Forms for All Subjects ................................................ 76 
9.3 
Publications and Other Rights .............................................................................. 76 
9.3.1 
Use of Trial Information in a Publication .......................................................... 76 
9.4 
Trial Documents and Records Retention ............................................................. 76 
10 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........................ 77 
10.1 
Sponsor .............................................................................................................. 77 
10.2 
Investigators ....................................................................................................... 77 
10.2.1 
Selecting Investigators ...................................................................................... 77 
10.2.2 
Clinical Study Report Coordinator Investigator ............................................... 77 
11 
REFERENCES ........................................................................................................ 79 
            Appendix 1………………………………………………………………………………….81 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
(S)AE 
All Adverse Events, including Serious Adverse Events 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT  
Alanine aminotransferase (SGPT) 
AST  
Aspartate aminotransferase (SGOT) 
AUC  
Area Under the Concentration-time curve 
AUC(tau)  
Area under the concentration-time curve during a dosing interval 
τ at steady state 
BID  
Twice Daily 
BMI  
Body Mass Index 
BP 
Arterial blood pressure 
BSA  
Body Surface Area 
CBC  
Complete Blood Count 
CCDS  
Company Core Data Sheet 
CD 
Compact Disk 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL/F or CL  
Apparent total body clearance or clearance 
Cmax  
Maximum observed plasma Concentration 
Cmin  
Minimum observed plasma Concentration 
CRF  
Case Report Form 
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
CTC  
Clinical Trial Coordinator 
CTD  
Clinical Trial Directive 
DNA  
Deoxyribonucleic Acid 
DSMB  
Data and Safety Monitoring Board 
DRSP  
Drosperinone 
DSS  
Drug Safety Surveillance; the Schering-Plough department 
responsible for the receipt, regulatory assessment, and, in the 
USA, reporting to FDA of all post marketing adverse events and 
all serious adverse events from clinical trials 


 
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ECG  
Electrocardiogram 
EDC  
Electronic Data Capture 
EU  
European Union 
FDA  
Food and Drug Administration, USA 
GCP 
Good Clinical Practice 
GCSP  
Global Clinical Supply Planning 
IATA  
International Air Transport Association 
IB  
Investigator’s Brochure  
ICH  
International 
Conference 
on 
Harmonization 
of 
Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
ICMJE  
International Committee of Medical Journal Editors 
IEC  
Independent Ethics Committee 
IMP  
Investigational Medicinal Product 
IMPQC 
Investigational Medicinal Product Quality Complaint 
IND 
Investigational New Drug Application; legal instrument in the USA 
that allows study of unapproved, investigational new drugs in 
human subjects 
Investigational Product  
The drug, biologic, and/or device being investigated in the current 
trial 
IRB 
Institutional Review Board 
LDH  
Lactate Dehydrogenase 
LLOQ  
Lower Limit Of Quantification 
MedDRA  
Medical Dictionary for Regulatory Activities 
NA, N/A  
Not applicable 
PD  
Pharmacodynamics 
PDF  
Portable Document Format 
PK  
Pharmacokinetics 
PQC  
Product Quality Complaint 
QD  
Once Daily 
RBC  
Red Blood Cell 
RNA  
Ribonucleic Acid 
RSI  
Reference Safety Information 


 
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SAE  
Serious Adverse Event 
SGOT  
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
 
Serum glutamic pyruvic transaminase (ALT) 
SmPC 
 
Summary of Product Characteristics 
SOP 
 
Standard Operating Procedure 
t1/2 
 
Terminal phase half-life 
TEAE 
 
Treatment-emergent adverse event 
Tmax 
 
Time to Maximum observed plasma concentration 
User ID 
 
User Identification 
ULN 
 
Upper limit of normal 
V/F or V 
 
Apparent volume of distribution 
WBC 
 
White Blood Cell 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4 SYNOPSIS 
Title of Study: 
A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs 
(Protocol No. CJ05013019) 
Abbreviated Title: Drug interaction study for narlaprevir
Study Centers: 
1-2
Protocol Type: Clinical Pharmacology
Clinical Project Phase: 1
Overview
This will be a two-part study conducted in healthy adult subjects in compliance with Good Clinical 
Practices.  
Study Duration:
8 -12 months 
Purpose:
The study purpose is to evaluate the potential for a pharmacokinetic drug-drug interaction, safety 
and tolerability when narlaprevir, ritonavir (used as a metabolic inhibitor) and tenofovir dizoproxil 
fumarate (part 1) and narlaprevir, ritonavir and raltegravir (part 2) are administered in combination 
to healthy volunteers 
Objectives:  
Part 1 
Primary Objective 
To evaluate the pharmacokinetic (PK) drug-drug interaction between narlaprevir/ritonavir and 
tenofovir (disoproxil fumarate) in healthy subjects. 
Secondary Objective(s) 
To evaluate the safety and tolerability of narlaprevir/ritonavir when coadministered with tenofovir in 
healthy subjects. 
Part 2 
Primary Objective 
To evaluate the PK drug-drug interaction between narlaprevir/ritonavir and raltegravir in healthy 
subjects. 
Secondary Objective(s) 
To evaluate the safety and tolerability of narlaprevir/ritonavir when coadministered with raltegravir 
in healthy subjects. 
Rationale:
a) 
Therapeutic Rationale: Approximately 50% of patients infected with the hepatitis C virus 


 
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(HCV) fail to respond to pegylated interferon/ribavirin combination therapy. Most of these 
nonresponders are infected with the more difficult to treat HCV genotype 1. Thus, there an urgent 
unmet medical need remains to offer new therapies that may eradicate HCV infection and prevent 
the serious sequelae (cirrhosis, hepatocellular carcinoma, liver failure and transplant) associated 
with persistent infection. Narlaprevir is a potent, orally administered, serine protease inhibitor 
specifically designed to inhibit the HCV NS3 (non structural protein 3) protease, preventing 
cleavage of the HCV polyprotein into functional viral proteins, thereby inhibiting viral replication in 
infected host cells. HCV NS3 protease inhibitors, combined with peginterferon/ribavirin have been 
shown to be an effective method for treating HCV. 
b) 
Study Conduct Rationale: In vitro data show that narlaprevir is metabolized by CYP3A4, 
and there is some evidence of CYP enzyme induction preclinically and CYP3A4 inhibition in human 
liver microsomes. However, a clinical study of high dose narlaprevir with midazolam showed no 
clinically relevant effect of narlaprevir on midazolam PK, indicating no relevant induction/inhibition 
of CYP3A4 by narlaprevir. In vivo, narlaprevir is a sensitive CYP3A4 substrate and co-
administration with ritonavir markedly increases narlaprevir exposure. In addition, in vitro data 
suggest narlaprevir is a P-gp substrate. Narlaprevir is being developed to be part of a therapeutic 
regimen that includes ritonavir, a metabolic inhibitor of CYP3A4, to boost the concentration of 
narlaprevir. This drug interaction study is designed to investigate pharmacokinetic drug-drug 
interactions between narlaprevir coadministered with ritonavir and antiretroviral drugs (tenofovir 
disoproxil fumarate and raltegravir) for labeling and clinical dosing guidance purposes. 
c) 
Study Design Rationale: The current protocol includes 2 parts and additional parts may be 
added on an ongoing basis. 
Part 1 
Part 1 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of 
narlaprevir with ritonavir and tenofovir, as the drugs may be used concomitantly to treat HCV/HIV 
coinfection. Tenofovir disoproxil fumarate is the oral prodrug of tenofovir, a nucleotide reverse 
transcriptase inhibitor used in the treatment of HIV and hepatitis B. Tenofovir disoproxil fumarate is 
rapidly absorbed and converted in the plasma to tenofovir; tenofovir is largely eliminated 
unchanged through renal excretion.  
P-glycoprotein (P-gp) is thought to mediate tenofovir disoproxil fumarate absorption from the 
intestine, as tenofovir disoproxil fumarate efflux has been decreased by several inhibitors including 
cyclosporin A [1]. As a clinical correlate, HIV protease inhibitors, often coadministered with 
tenofovir disoproxil fumarate, have variably increased tenofovir plasma concentrations based on 
their ability to inhibit P-gp mediated efflux, induce P-gp expression and inhibit tenofovir disoproxil 
fumarate hydrolysis at the level of the intestine [1]. In addition, other transporters are thought to 
participate in the renal elimination of tenofovir; tenofovir is a substrate for both human organic 
anion transporters 1 and 3 (hOAT1 and hOAT3) and inhibition of either transporter may alter 
plasma concentrations of tenofovir and decrease elimination. 
Narlaprevir has been shown to be a P-gp substrate; it is unknown whether it is a P-gp 
inhibitor/inducer or alters hOAT1 and hOAT3 activity. Thus it is unknown whether narlaprevir could 
affect tenofovir exposure. As tenofovir disoproxil fumarate has affected HIV protease inhibitor (PI) 
drug absorption [1] and these PIs are peptidomimetics similar to narlaprevir, there is also the 


 
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potential for tenofovir disoproxil fumarate to affect narlaprevir absorption and plasma 
concentrations. From the other side tenofovir disoproxil fumarate was widely studied with first 
generation HCV PIs boceprevir, telaprevir, simeprevir, and ritonavir-boosted paritaprevir. Non-
significant changes in pharmacokinetic parameters were shown when tenofovir was co-
administered with all of them. The most prominent tenofovir exposure changes were reported in 
combination with telaprevir (30% increase in AUC and Cmax), but these changes didn’t lead to 
safety profile worsening. That is why no dose correction is recommended during concomitant use 
of tenofovir with telaprevir. Exposure of HCV PIs was not significantly affected by tenofovir in 
conducted drug-drug interaction studies. 
This study is designed as a randomized 3-period crossover study and will assess if there is any 
effect of tenofovir disoproxil fumarate/tenofovir on the pharmacokinetics of narlaprevir and vice 
versa. 
Part 2 
Part 2 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of 
narlaprevir/ritonavir and raltegravir. A considerable percentage of HIV infected patients are also 
infected with HCV. HIV/HCV co-infected patients commonly use HIV and HCV medications 
simultaneously. Therefore, it is important to know whether drug-drug interactions occur when 
combining those treatments or not. 
Raltegravir is an HIV integrase inhibitor. In clinical trials in healthy volunteers in the presence of 
ritonavir, raltegravir pharmacokinetics were just weakly affected and did not require dose 
adjustment [2]. In the presence of protease inhibitors (atazanavir and tenofovir) boosted by ritonavir 
pharmacokinetics of raltegravir changed differently: PK parameters increased in the presence of 
atazanavir (direct inhibitor of UDP-GT1A1) and decreased in the presence of tenofovir. In both 
cases it was not considered as clinically significant [2]. When drug-drug interactions were 
investigated with HCV PIs boceprevir, telaprevir and simeprevir exposure parameters of raltegravir 
were slightly increased (up to 30% in combination with telaprevir), while exposure of PIs was 
changed up to 11% (in combination with simeprevir). That is why combinations of raltegravir with 
HCV PIs were considered safe and recommended for use in standard dosage regimens in patients 
with HCV/HIV-coinfection.  
Combined use of narlaprevir/ritonavir and raltegravir is not expected to lead to a major drug-drug 
interaction as raltegravir is not a CYP3A substrate and thus will not be affected by the inhibition of 
CYP3A by narlaprevir/ritonavir. Raltegravir is metabolized by UGT but narlaprevir is not known to 
influence UGT. However, recent data indicate that raltegravir is a P-gp substrate and narlaprevir is 
a substrate and a moderate inhibitor of P-gp in vitro. 
This study is designed as a randomized 3-period crossover study and will assess if there is any 
effect of raltegravir on the pharmacokinetics of narlaprevir and vice versa. 
Study Design:  
Both parts: Randomized, 3-period crossover study. 
 


 
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Study Plan 
Subjects will be screened within up to 28 days before dosing in this two-part study. Subjects will be 
admitted to the study center the evening before the first dose for baseline assessments to confirm 
eligibility. 
Part 1 
Subjects will participate in a randomized 3-period crossover study.  
In Part 1 subjects will receive the following: 
• 
Treatment A: narlaprevir 200 mg once daily + ritonavir 100 mg once daily orally for 5 days  
• 
Treatment B: tenofovir disoproxil fumarate 300 mg once daily, orally for 5 days 
• 
Treatment C: narlaprevir 200 mg once daily + ritonavir 100 mg once daily + tenofovir 
disoproxil fumarate 300 mg once daily, orally for 5 days 
On Day 1 of the first period, subjects will be randomized to one of 3 treatment sequences (A/B/C, 
or B/C/A, or C/A/B) and receive the first dose. Every subject will receive only one treatment (A or B 
or C) in one Period. 
All treatments will be administered following a standard breakfast. Subjects will be confined to the 
study center throughout treatment in each period. Following completion of study procedures for 
each treatment period, subjects will be released from the clinic. Subjects will return to start 
hospitalization for the next treatment period after a 7-14 days interval. 
Blood samples for determination of narlaprevir, ritonavir trough, and tenofovir concentrations will be 
collected as specified in the Study Flow Chart. Urine samples will be collected to evaluate the 
amount of tenofovir excreted (Treatment B and C). 
Safety assessments including vital signs, ECGs, and clinical laboratory tests will be performed, and 
adverse events will be recorded, throughout the study. Subjects will be discharged from the study 
upon completion of all study related procedures in Period 3. 
Part 2 
Subjects will participate in a randomized 3-period crossover study.  
Subjects in Part 2 will receive the following: 
• 
Treatment A: narlaprevir 200 mg once daily + ritonavir 100 mg once daily orally for 5 days  
• 
Treatment B: raltegravir 400 mg twice daily, orally for 5 days 
• 
Treatment C: narlaprevir 200 mg once daily + ritonavir 100 mg once daily + raltegravir 400 
mg twice daily, orally for 5 days 
On Day 1 of the first period, subjects will be randomized to one of 3 treatment sequences (A/B/C, 
or B/C/A, or C/A/B) and receive the first dose. Every subject will receive only one treatment (A or B 
or C) in one Period. 
All treatments will be administered following a standard breakfast, evening dose of raltegravir will 
be administered after standard dinner. Subjects will be confined to the study center throughout 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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treatment in each period. Following completion of study procedures for each treatment period, 
subjects will be released from the clinic. After a 7-14 (maximum) days interval between dosing, 
subjects will return to start hospitalization for the next treatment period. 
Blood samples for determination of narlaprevir, ritonavir trough, and raltegravir concentrations will 
be collected as specified in the Study Flow Chart.  
Safety assessments including vital signs, ECGs, and clinical laboratory tests will be performed, and 
adverse events will be recorded, throughout the study. Subjects will be discharged from the study 
upon completion of all study related procedures in Period 3. 
Sample Size Calculation:
Based on study P04986, the inter-subject variability (CV%) for narlaprevir (tablet) Cmax and AUC 
is estimated to be about 33%; the inter- subject variability (CV%) for narlaprevir Cmax and AUC 
when coadministered with ritonavir is estimated to be about 20%. Assuming the intra-subject 
variability (CV%) is about 70% of the inter, the intra-subject variability (CV%) for narlaprevir and 
narlaprevir coadministered with ritonavir Cmax and AUC is estimated to be about 23% and 14%, 
respectively. 
Part 1 
The sample size for Part 1 will be 18.  
The intra-subject variability (CV%) for tenofovir is assumed approximately 20% (10-15% for 
AUC24h and 15-20% for Cmax) as a maximum value estimated from the published CIs, the 
expected difference is set to 0 (Ratio = 1.00).  
The study with 18 subjects will detect an increase in exposure of 22% or a decrease of 18% 
between tenofovir coadministered with narlaprevir and ritonavir vs. tenofovir alone with 80% power 
and alpha=0.1 two sided. 
The study with 18 subjects will detect an increase of 15% or a decrease of 13% exposure between 
narlaprevir coadministered with ritonavir and tenofovir vs. narlaprevir coadministered with ritonavir 
with 80% power and alpha=0.1 two sided.. 
Part 2 
The sample size for Part 2 is 18.  
For raltegravir, sample size calculations were based on intrasubject CV% of 45% for AUC12h and 
60% for Cmax. CVs estimated from the published CIs are 35-50% for AUC and 40-70% for Cmax. 
The study with 18 subjects will detect an increase of 55% or a decrease of 35% exposure (AUC)  
as well as detect an increase of 76% or a decrease of 43% Cmax between raltegravir 
coadministered with narlaprevir and ritonavir vs. raltegravir alone with 80% power and alpha=0.1 
two sided. 
The study with 18 subjects will detect an increase of 15% or a decrease of 13% exposure between 
narlaprevir coadministered with ritonavir and raltegravir vs. narlaprevir coadministered with ritonavir 
with 80% power and alpha=0.1 two sided.. 
So, it is planned that 36 subjects complete the study overall. In case of premature withdrawal 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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subjects will be replaced by volunteers from among the subjects who signed the informed consent 
form. Considering 50% drop-out rate maximum 54 subjects will be enrolled in the study. 
Subject Replacement Strategy 
In case of premature withdrawal subjects will be replaced by volunteers from among the subjects 
who signed the informed consent form. Subjects may be replaced at the discretion of the sponsor. 
Randomization: 
Both parts: Subjects will be randomized to one of the treatment sequences on Day 1 of Period 1, 
according to the computer generated randomization schedule. 
Stratification: 
Not applicable.  
Type of Blinding 
Not applicable 
Inclusion Criteria: 
The subject must meet ALL the criteria listed below for entry at baseline and at Days -1 and 1 
before each treatment Period: 
1. 
Subjects must be willing to give written informed consent for the trial and able to adhere to 
dose and visit schedules. 
2. 
Subjects of either sex and of any race between the ages of 21 and 55 years (both parts), 
inclusive, having a Body Mass Index (BMI) between 18,5 and 30, inclusive. BMI = weight 
(kg)/height2(m).  
3. 
Volunteers should diagnosed as "healthy": no pathology of the gastrointestinal tract, liver, 
kidneys, cardiovascular system, central nervous system (previously carried out by standard clinical 
and lab tests which did not reveal the presence of any diseases. AST and ALT must not exceed the 
normal range; QTcB for men should be ≤ 450 ms and ≤ 470 ms for women, the interval PR should 
be ≤ 200 ms). 
4. 
Vital sign measurements (taken after ~3 minutes in a supine or sitting position) must be within 
the following ranges: 
a. 
systolic blood pressure, 100 – 130 mm Hg 
b. 
diastolic blood pressure, 60 -90  mm Hg 
c. 
pulse rate, 60-80 bpm 
5. 
Female subjects must be: 
a. 
postmenopausal (defined as 12 months with no menses; age > 40 years and with a FSH level 
of >40 u/mL). 
b. 
surgically sterilized at least 3 months prior to baseline (e.g., documented hysterectomy or 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
Page 19 of 83 
tubal ligation). 
6. 
Men must agree to use a medically accepted method of contraception (condom and 
spermicide) during the trial and for 3 months after stopping the medication. 
 
Exclusion Criteria: 
The subject will be excluded from entry if ANY of the criteria listed below are met at baseline: 
1. 
Females with childbearing potential  
2. 
Subjects who, in the opinion of the investigator, will not be able to participate optimally in 
the study. 
3. 
Positive results for hepatitis B surface antigen, hepatitis C antibodies or HIV, positive RW 
results. 
4. 
Allergic reactions in history; 
5. 
Intolerance to medication; 
6. 
Chronic disease of cardiovascular, bronchopulmonary, and/or neuroendocrinal systems, 
gastrointestinal, liver, pancreas, kidney and/or blood disease; 
7. 
History or presence of impaired renal function, lactase deficiency, lactose intolerance, 
glucose-galactose malabsorption; 
8. 
History of urinary obstruction or difficulty in voiding; 
9. 
 Gastrointestinal surgery in history (except of appendectomy); 
10. 
Acute infections less than 4 weeks before participation in the study  
11. 
Subjects with a medical history of osteopenia and/or osteoporosis. 
12. 
Regular administration of any medicines less than 4 weeks before participation in the 
study  
13. 
Administration of medicines with marked influence on hemodynamics, liver function et al 
(barbiturates, omeprazole, cimetidine et al) less than 30 days before participation in the study; 
14. 
Blood donation (450 ml or more of blood or plasma) less than 2 months before 
participation in the study; 
15. 
Intake of more than 10 units of alcohol in a week (1 unit of alcohol is equal to 0.5 L of beer, 
200 mL of wine or 50 mL of spirits) or history of drug abuse or alcoholism; 
16. 
Smoking of more than 10 cigarettes or equivalent tobacco use per day; 
17. 
Participation in phase 1 clinical trial less than 3 months before participation in the study; 
18. 
Positive screen for drugs abuse and drugs use. 
19. 
 Subjects with a medical history of psychiatric or personality disorders that in the opinion of 
the investigator and sponsor, affects the subject’s ability to participate in the trial. 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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20. 
Subjects who are part of the study staff personnel or family members of the study staff 
personnel. 
 
Subject Key Inclusion/Exclusion Criteria 
Healthy adult male and female subjects will be selected for all Parts of the study. 
Test Product, Dose, Mode of Administration 
Oral administration will be used for all studying drugs. 
Part 1 
Treatment C: narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and 
tenofovir disoproxil fumarate 300 mg once daily for 5 days. 
Part 2 
Treatment C: narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and 
400 mg raltegravir twice daily for 5 days. 
Reference Therapy, Dose, Mode of Administration 
Part 1 
Treatment A: narlaprevir 200 mg once daily with ritonavir 100 mg once daily for 5 days;  
Treatment B: tenofovir disoproxil fumarate 300 mg once daily for 5 days. 
Part 2 
Treatment A: narlaprevir 200 mg once daily with ritonavir 100 mg once daily for 5 days;  
Treatment B: raltegravir 400 mg twice daily for 5 days. 
Duration of Treatment 
Part 1 
Subjects will be treated with each of narlaprevir, ritonavir, and tenofovir disoproxil fumarate for 5 
days on 3 separate occasions for a total of 15 days. Total treatment duration excluding wash out 
intervals is 15 days (total duration maximum 43 days). 
Part 2 
Subjects will be treated with each of narlaprevir, ritonavir, and raltegravir for 5 days on 3 separate 
occasions for a total of 15 days. Total treatment duration excluding wash out intervals is 15 days 
(total duration maximum 43 days). 
Number of Sites and Patients 
36 healthy volunteers in approximately 1-2 sites in Russia. 
Criteria for Evaluation 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
Page 21 of 83 
PK
Part 1 
The following PK parameters will be evaluated for narlaprevir on Day 5 on treatments A and C: 
Cmax, Tmax, Cmin and AUC (tau). Additionally, if data permit, t1/2, CL/F and V/F will be 
calculated. Plasma concentrations of narlaprevir metabolites may be analyzed.  
Ritonavir pre-dose concentrations on Day 4 and Day 5 will be analyzed on treatments A and C.  
Pre-dose concentrations of drugs will be analysed on Days 4-5 to check for steady state. 
The following PK parameters will be evaluated for tenofovir on Day 5 on treatments B and C: 
Cmax, Tmax, Cmin and AUC (tau). Additionally, if data permit, t1/2, CL/F and V/F will be 
calculated. Urine concentrations of tenofovir may be analyzed. 
Part 2 
The following PK parameters will be evaluated for narlaprevir on Day 5 on treatments A and C: 
Cmax, Tmax, Cmin and AUC (tau). Additionally, if data permit, t1/2, CL/F and V/F will be 
calculated. Plasma concentrations of narlaprevir metabolites may be analyzed.  
Ritonavir pre-dose concentrations on Day 4 and Day 5 on treatments A and C will be analyzed. 
Pre-dose concentrations of drugs will be analysed on Days 4-5 to check for steady state. 
The following PK parameters will be evaluated for raltegravir on Day 5 on treatments B and C: 
Cmax, Tmax, Cmin and AUC (tau). Additionally, if data permit, t1/2, CL/F and V/F will be 
calculated.  
Safety 
Vital signs, ECGs, and clinical laboratory tests will be performed, and adverse events recorded. 
Efficacy Assessments / Variables: 
Not applicable. 
Statistical Methods 
Safety 
Adverse events will be tabulated by treatment group, body system organ class, and severity. ECGs 
and clinical safety laboratory values will be listed by date and time, values and changes from 
baseline will be tabulated using summary statistics. Vital signs will be listed by day and time. 
PK 
Mean plasma concentrations of narlaprevir along with the derived PK parameters will be 
summarized by treatment separately for each part (cohort). 
The primary PK parameters for Parts 1-2 are narlaprevir Cmax and AUC. All data will be log-
transformed before analysis. An ANOVA model with treatment, period, sequence treated as fixed 
effects and subject nested within sequence treated as random effect will be performed separately 
for each part. Estimates of the adjusted mean differences (test-reference) and corresponding 90% 
confidence intervals will be constructed using the estimates of intrasubject variability obtained from 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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the model. The resulting estimates will then be exponentiated to provide the adjusted geometric 
mean ratios for the untransformed parameters (test/reference) with the corresponding 90% CIs for 
the ratios.  
In addition for Parts 1 and 2 tenofovir and raltegravir Cmax and AUC will also be analyzed. 
Part 1 
Log transformed Cmax and AUC for narlaprevir and tenofovir will be analyzed separately. For 
narlaprevir, the primary comparison will be treatment C vs. A; and for tenofovir the primary 
comparison will be treatment С vs. В. 
Part 2 
Log transformed Cmax and AUC for narlaprevir and raltegravir will be analyzed separately. For 
narlaprevir, the primary comparison will be treatment C vs. A; and for raltegravir the primary 
comparison will be treatment С vs. В. 
Day and Visit Structure 
See Section 4.2, Study Flow Chart for further details. 
Data Analysis:
Data analysis will be performed by the Central Laboratory and CRO designated by Sponsor in 
appropriate way described in the protocol.  


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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4.1 
Study Design Diagram 
4.1.1 
Part 1 
 
Scree-
ning 
 
Treatment  
period 1 
Wash-Out1 
Treatment  
period 2 
Wash-Out 
Treatment  
period 3 
Follow-up 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N2 
Treatment A 
 
Treatment B 
 
Treatment C 
 
Treatment B 
Treatment C 
Treatment A 
Treatment C 
Treatment A 
Treatment B 
Day 
-28 
-1 
1 
2 
3 
4 
5 
6 
7-18 
-1 
1 
2 
3 
4 
5 
6 
7-18 
-1 
1 
2 
3 
4 
5 
6 
7-133 
 
Hospitalization 
Out-
patient 
Hospitalization 
Out-
patient 
Hospitalization 
 
1Wash-out period will be from 7 to maximum 14 days 
2Randomization will be conducted at Day 1 before dispensing of study medication 
3Phone call will be conducted at Day 11-13 
Treatment Administration: 
• 
Treatment A: narlaprevir 200 mg QD + ritonavir 100 mg QD, given orally for 5 days 
• 
Treatment B: tenofovir disoproxil fumarate 300 mg QD, given orally for 5 days 
• 
Treatment C: narlaprevir 200 mg QD + ritonavir 100 mg QD + tenofovir disoproxil fumarate 300 mg QD, given orally for 5 days  
Every subject will receive one of 3 treatment sequences: (A/B/C, or B/C/A, or C/A/B). Only one treatment will be administered per 
period.  
Dosing in each period must be separated by wash-out interval (from 7 to maximum 14 days).  


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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4.1.2 Part 2 
 
Scree-
ning 
 
Treatment  
period 1 
Wash-Out1 
Treatment  
period 2 
Wash-Out 
Treatment  
period 3 
Follow-up 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N2 
Treatment A 
 
Treatment B 
 
Treatment C 
 
Treatment B 
Treatment C 
Treatment A 
Treatment C 
Treatment A 
Treatment B 
Day 
-28 
-1 
1 
2 
3 
4 
5 
6 
7-18 
-1 
1 
2 
3 
4 
5 
6 
7-18 
-1 
1 
2 
3 
4 
5 
6 
7-133 
 
Hospitalization 
Out-
patient 
Hospitalization 
Out-
patient 
Hospitalization 
 
1Wash-out period will be from 7 to maximum 14 days  
2Randomization will be conducted at Day 1 before dispensing of study medication 
3Phone call will be conducted at Day 11-13 
Treatment Administration: 
• 
Treatment A: narlaprevir 200 mg QD + ritonavir 100 mg QD, given orally for 5 days 
• 
Treatment B: raltegravir 400 mg BID, given orally for 5 days 
• 
Treatment C: narlaprevir 200 mg QD + ritonavir 100 mg QD + raltegravir 400 mg BID, given orally for 5 days  
Every subject will receive one of 3 treatment sequences: (A/B/C, or B/C/A, or C/A/B). Only one treatment will be administered per 
period.  
Dosing in each period must be separated by wash-out interval (from 7 to maximum 14 days).


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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4.2 
Study Flow Chart 
4.2.1  Part 1 
Table 1 
Study Flow Chart for Part 1 of the study 
Day Relative to First Dose of Study Drug 
Scree-
ning 
Period 1 
Period 2 
Period 3 
FU visit 
(phone 
call) 
Days 
 -28 to -2 
-
1 
1 
2 
3 
4 
5 
6 
-
1 
1 
2 3 
4 
5 
6 
-1 
1 
2 
3 
4 
5 
6
g 
11-13 
Informed consent form 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
x 
x 
x 
 
 
 
 
 
xj  xj 
 
 
 
 
 
xj  xj 
 
 
 
 
 
 
Subject Identification card provided 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
 
Body height (cm) and Weight (kg) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/ HBsAg/ HCV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screen 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Laboratory testsa 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
 
Screening number assignment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/ Treatment Number 
assignment 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG (12-lead) 
x 
x 
x
h 
 
 
 
 
x 
x 
x
h 
 
 
 
 
x 
x 
xh 
 
 
 
 
x 
 
Vital Signs (BP, Pulse rate, Body 
Temperature) 
x 
x 
xi 
 
 
 
 
x 
x 
xi 
 
 
 
 
x 
x 
xi 
 
 
 
 
x 
 
Treatment administration 
 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
PK Blood Sampling 
 
NVR PK blood samplingb 
 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 
Ritonavir PK blood samplingc 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
Tenofovir PK blood samplingd 
 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 
PK Urine sampling 
Tenofovir PK Urine samplinge 
 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
Hospitalizationf 
 
x 
x 
x 
x 
x 
x 
xf 
x 
x 
x 
x 
x 
x 
xf 
x 
x 
x 
x 
x 
x 
xf 
 
BP – arterial blood pressure; ECG – electrocardiogram; HIV – human immunodeficiency virus; NVR – narlaprevir; PK – pharmacokinetic 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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a. 
Complete Blood Count (CBC), differential chemistry panel, and urinalysis collected in the fasted state (after an overnight fast for morning chemistry 
sample collections and at least 4 hours without food for other chemistry sample collections). Urinalysis will be performed at Screening only and results will 
not be captured in the CRF. On treatment days, blood samples should be drawn pre-dose. 
b. 
Narlaprevir blood samples will be collected on Days 4 and 5: pre-dose (0 hr); and on Day 5 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hrs 
post-dose (Treatments A and C). 
c. 
A trough sample for ritonavir will be collected at 0 hr (predose) on Days 4 and 5 (Treatments A and C) 
d. 
Tenofovir blood samples will be collected on Day 4 and Day 5: pre-dose (0 hr), and on Day 5 at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 18  and 24 hr post-dose 
(Treatments B and C).  
e. 
Tenofovir urine samples will be collected on Day 5 in the following blocks: 0-6 hr, 6-12 hr, 12-18 hr, and 18-24 hr post-dose (Treatments B and C). 
f. 
Subjects will be confined during the treatment period and released from the study unit after completion of all Day 6 study procedures.  
g. 
Same procedures should be performed in case of premature determination of the study by any reason. 
h. 
ECG to be recorded pre-dose at 0 (pre-dose) and in 4 hrs after dosing on Day 1 every period 
i. 
Vital signs to be recorded at 0 (pre-dose), 1, 4 and 8 hrs after dosing on Day 1 every period.  
j. 
During subsequent assessment subjects with increased hepatic transaminases not more than 1.5 ULN can be allowed, if the investigator will 
estimate these changes as clinically non-significant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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4.2.2 Part 2 
Table 2 
Study Flow Chart for Part 2 of the study 
Day Relative to First Dose of Study Drug 
Scree-
ning 
Period 1 
Period 2 
Period 3 
FU visit 
(phone 
call) 
Days     
-28 to-
2 
-
1 
1 
2 
3 
4 
5 
6 
-
1 
1 
2 
3 
4 
5 
6 
-
1 
1 
2 
3 
4 
5 
6f 
11-13 
Informed consent form 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
x 
x 
x 
 
 
 
 
 
xj  xj 
 
 
 
 
 
xj  
xj 
 
 
 
 
 
 
Subject Identification card provided 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
 
Body height (cm) and Weight (kg) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/ HBsAg/ HCV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screen 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Laboratory testsa 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
 
Screening number assignment 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization/ Treatment Number 
assignment 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG (12-lead) 
x 
x 
xg 
 
 
 
 
x 
x 
xg 
 
 
 
 
x 
x 
xg 
 
 
 
 
x 
 
Vital Signs (BP, Pulse rate, Body 
Temperature) 
x 
x 
xh 
 
 
 
 
x 
x 
xh 
 
 
 
 
x 
x 
xh 
 
 
 
 
x 
 
Treatment administration 
 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
 
 
PK Blood Sampling 
NVR PK blood samplingb 
 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 
Ritonavir PK blood samplingc 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
x 
x 
 
 
Raltegravir PK blood samplingd 
 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 
 
 
 
x 
x 
x 
 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
Page 28 of 83 
Hospitalizatione 
 
x 
x 
x 
x 
x 
x 
xe 
x 
x 
x 
x 
x 
x 
xe 
x 
x 
x 
x 
x 
x 
xe 
 
BP – arterial blood pressure; ECG – electrocardiogram; HIV – human immunodeficiency virus; NVR – narlaprevir; PK – pharmacokinetic 
a. 
Complete Blood Count (CBC), differential chemistry panel, and urinalysis collected in the fasted state (after an overnight fast for morning chemistry 
sample collections and at least 4 hours without food for other chemistry sample collections). Urinalysis will be performed at Screening only and results will 
not be captured in the CRF. On treatment days, blood samples should be drawn pre-dose. 
b. 
Narlaprevir blood samples will be collected on Days 4 and 5: pre-dose (0 hr); and on Day 5 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hrs 
post-dose (Treatments A and C). 
c. 
A trough sample for ritonavir will be collected a 0 hr (predose) on Days 4 and 5 (Treatments A and C) 
d. 
Raltegravir blood samples will be collected on Days 4 and Day 5: pre-dose (0 hr), and on Day 5 at 0.5, 1, 2, 3, 4, 6, 8, 12 hr post-dose (Treatments 
B and C).  
e. 
Subjects will be confined during the treatment period and released from the study unit after completion of all Day 6 study procedures.  
f. 
Same procedures should be performed in case of premature determination of the study by any reason. 
g. 
ECG to be recorded pre-dose at 0 (pre-dose) and in 4 hrs after dosing on Day 1 every period 
h. 
Vital signs to be recorded at 0 (pre-dose), 1, 4 and 8 hrs after dosing on Day 1 every period.  
j. 
During subsequent assessment subjects with increased hepatic transaminases not more than 1.5 ULN can be allowed, if the investigator will 
estimate these changes as clinically non-significant. 
 
 
 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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Amendment #5 
Amendment rationale 
The following specification was made in the study protocol: 
• 
Trade name of narlaprevir (Arlansa) was added to the narlaprevir description. 
• 
Tenofovir disoproxil fumarate manufactured by Gilead Sciences, Inc was replaced with 
tenofovir disoproxil fumarate (Tenofovir-TL) manufactured by LTD "Drugs Tehnology". 
• 
Information on assessment of hepatic transaminase was added. 
 
Ethical approval 
Before implementing this protocol version with Incorporated Amendment #4 it must be reviewed 
and approved by Health Authorities and Independent Ethics Committee (IECs). In addition the 
changes herein affect the Informed Consent and the sites are required to update and submit for 
approval a revised Informed Consent Form that takes into account the changes made in this 
amended protocol. A signed and dated statement that the protocol, informed consent and other 
documents have been approved by the IEC must be given to the company-sponsor or it’s 
designee before implementation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Protocol CJ05013019, Version 8.0 dated 20 Feb 2017  
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5 
INTRODUCTION 
5.1 
Background 
Narlaprevir is a potent, orally administered, serine protease inhibitor specifically designed to inhibit 
the HCV NS3 (non structural protein 3) protease, preventing cleavage of the HCV polyprotein into 
functional viral proteins, thereby inhibiting viral replication in infected host cells. Boceprevir and 
telaprevir are first in class HCV NS3 protease inhibitors that are precursors to Narlaprevir. 
Combination of boceprevir or telaprevir with pegylated interferon and ribavirin now is not 
recommended for using due to serious side effects. There remains an unmet medical need to offer 
new therapies that may eradicate HCV infection and prevent the serious sequelae (cirrhosis, 
hepatocellular carcinoma, liver failure and transplant) associated with chronic infection.  
Narlaprevir was found to be orally bioavailable in pharmacokinetic (PK) studies in animals, 
including rats, dogs, and monkeys. Following intravenous (IV) administration, narlaprevir is cleared 
rapidly from plasma with mean effective terminal phase half-life (t1/2) values ranging from 0.55 hour 
to 1.5 hours across species. Narlaprevir interconverts to an inactive diastereomer (SCH 782832) in 
plasma. The SCH 782832: narlaprevir exposure ratios are species-specific. Cytochrome P450 
isoenzyme 3A4 (CYP3A4) is primarily responsible for metabolizing narlaprevir and SCH 782832 
into oxidative metabolites [8].  
The nonclinical safety profile of narlaprevir has been characterized in a series of toxicology 
studies, which includes single- and repeated-dose studies (in mice, rats, and dogs), genotoxicity 
studies, and an in vitro osmotic fragility assay. Other toxicity studies include the evaluation of 
different formulations, the use of ritonavir (ritonavir) as a means of potentially increasing exposure, 
an embryo-fetal development studies in rabbits and rats, as well as a number of safety 
pharmacology assessments in a core battery of systems. Longer-term studies conducted to date 
included durations from 1 month to 9 months in mice, rats, or dogs. Based on the limited number of 
preclinical findings identified that tend to be minimal and/or species-specific in nature and/or 
clinically monitorable, it was recommended that clinical studies with narlaprevir continue. 
To date (October 31, 2016) the Phase 1 clinical pharmacology program currently consists of ten 
completed studies (P04694, P04695, P04959, P04986, P05054, P05065, P05353, P05580, 
P05778, and CJ05013007). In overall 376 healthy volunteers, 16 cirrhotic patients (11) and 32 
HCV-infected subjects (P04695) (1) have been exposed to NVR in phase 1 studies. 93 HCV-
infected subjects – in the Phase 2 study and 325 HCV-infected subjects – in Phase 3 study. 
Narlaprevir has been administered from 50 mg up to 2000 mg alone as a single-dose, and up to 
multiple doses of 1600 mg three times daily (TID) alone for 6 days or 1200 mg twice daily (BID) 
with ritonavir for 11 days in healthy subjects, and up to 800 mg TID alone and 400 mg BID with 
ritonavir in HCV-infected subjects. In the Phase II study NVR was administered at a dosage of 200 
mg once daily (QD), 400 mg QD, and 100 mg BID. Achieved plasma narlaprevir concentrations 
have been well above the anticipated therapeutic requirement [9,10]. Dose-normalized daily 
exposures of narlaprevir increase markedly when narlaprevir was coadministered with ritonavir, 
compared with exposures when narlaprevir was administered alone, mainly by inhibiting 
metabolism of narlaprevir. These data support combination of narlaprevir with a CYP3A4 inhibitor 
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patients (QD or BID) [8]. 
In Phase 1 studies, narlaprevir has been shown to be safe and generally well-tolerated when 
administered alone and in combination with ritonavir, as well as with or without PegIntron [11]. 
There have been no dose-related trends in adverse events (AEs) reported with narlaprevir, and the 
majority of AEs have been mild to moderate in intensity. There have been no clinically significant 
patterns of changes in vital signs, clinical laboratory values, or electrocardiogram (ECG) 
recordings. In addition, preliminary viral load data demonstrated potent antiviral activity in HCV 
genotype 1 (HCV-1)-infected subjects when narlaprevir was administered as monotherapy and in 
combination with PegIntron [8].  
A Phase 2a study (P05104) of narlaprevir is completed in the United States. The primary objective 
of this study was to identify the optimal schedule and dose regimen of narlaprevir (coadministered 
with ritonavir) in previously untreated subjects with HCV-1 chronic hepatitis C (CHC) when 
administered in combination with PegIntron. The study evaluated multiple doses, schedules, and 
the utility of a 4-week lead-in period with PegIntron and ribavirin prior to the addition of narlaprevir. 
111 subjects have been randomized in this study. It has been shown that in the 
narlaprevir/ritonavir-Treatment Arms, viral load reduction, measured by the proportion of subjects 
with undetectable HCV RNA, was significantly higher at 4 weeks of treatment with 
narlaprevir/ritonavir 
added 
to 
peginterferon/ribavirin, 
compared 
to 
the 
control 
of 
peginterferon/ribavirin alone. The addition of narlaprevir/ritonavir to the peginterferon/ribavirin 
backbone led to a significant increase in SVR compared to the control (28% Control Arm, 65% to 
85% narlaprevir/ritonavir-Treatment Arms). Overall, the incremental benefit compared to control 
was a two-fold to three-fold increase in SVR [8-10]. 
Narlaprevir was evaluated in large Phase 3, randomized, placebo-controlled, double-blind study 
CJ05013008 investigating the effectiveness and safety of NVR in 420 naive and previously treated 
with pegylated interferon alpha and ribavirin with Genotype 1 HCV infected patients without 
cirrhosis. NVR 200 mg was administered with ritonavir 100 mg once daily, orally, along with 
pegylated interferon alpha and ribavirin for 12 weeks, with subsequent administration of pegylated 
interferon and ribavirin only for another 12 weeks to a total treatment course of 24 weeks. Controls 
were given pegylated interferon and ribavirin for 48 weeks. HCV RNA level was determined by 
TaqMan HCV Quantitative Test Version 2.0 (Roche Diagnostics) with LOD=LLOQ=15 IU/mL. The 
average viral load reduction was found to be 5.3 log10 at Week 2 and 5.9 log10 at Week 4 in the 
NVR group, compared with 1.5 log10 at Week 2 and 2.5 log10 at Week 4 in the control group. 
SVR24 was achieved in 89,1% (163/183) naive and 69,7 % (69/99) previously treated patients in 
NVR group and in 59,6 % (53/89) naive and 24,5 % (12/49) previously treated patients in control 
group. Eleven patients discontinued treatment due to AEs, 7 treated with NVR and 4 with 
pegylated interferon and ribavirin alone. Five patients from NVR group had SAEs, none was 
assessed as related to study drug. NVR significantly increases the antiviral activity and 
effectiveness of pegylated interferon and ribavirin double antiviral therapy in Genotype 1 HCV 
infected patients without cirrhosis, and produces no additional adverse effects [21]. 
5.2 
Class or Type of Drug Being Studied/Description of Drug 
Narlaprevir is a non-ionizable compound containing an alpha-ketoamide moiety. It has a molecular 
formula of C36H61N5O7S and a molecular weight of 707.96 Da. It is the novel serine protease 


 
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inhibitor. The mechanism of inhibition involves narlaprevir covalently, yet reversibly, binding to the 
NS3 protease active site serine (Ser139) through a ketoamide functional group [8, 12].  
The investigational drug product is supplied as a 100-mg immediate-release (IR) film-coated tablet. 
The tablets contain the excipients copovidone, microcrystalline cellulose, lactose monohydrate, 
sodium lauryl sulfate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. 
The tablets are packaged in induction-sealed high-density polyethylene bottles. Experimental and 
clinical batches are monitored in the ongoing stability program to support appropriate shelf life and 
storage conditions.  
5.3 
Preclinical Profile 
Nonclinical PK data in support of oral administration of narlaprevir with and without ritonavir were 
obtained from absorption, distribution, and metabolism studies in rats, dogs, monkeys, and from 
toxicity/toxicokinetic (TK) studies in mice, rats, and dogs[8]. 
PK/TK studies in rats and dogs have been conducted using the amorphous form of narlaprevir 
administered orally as a suspension in 0.4% methylcellulose and IV as a solution in 20% or 40% 
hydroxypropyl-cyclodextrin. Following oral, single-dose administration, narlaprevir was absorbed 
and rapidly cleared from plasma. The effective t1/2 and mean residence time (MRT) values 
following IV administration were less than 1 hour. The longer MATs than t1/2s indicate that 
absorption of narlaprevir is slower than its elimination from plasma. Also, as the dose of orally 
administered drug increased, absolute bioavailability decreased. Administration with food 
increased bioavailability at high doses (>100 mg/kg). Thus, for the toxicity studies, animals were 
fed prior to dosing[8]. 
Narlaprevir interconverts to an inactive diastereomer (SCH 782832) in plasma. Following oral 
administration of narlaprevir, the SCH 782832: narlaprevir plasma concentration ratios, as well as 
AUC ratios, were species-specific (humans>dogs>rats>mice). Variation in extent of absorption of 
narlaprevir and/or rates of metabolism of the individual diastereomers between species may 
contribute to the ratio differences. Following repeated administration, exposure to narlaprevir and 
SCH 782832 in male and female mice, rats, and dogs decreased. Exposure to narlaprevir and 
SCH 782832 in toxicity studies reached a plateau upon administration of increasing doses, 
particularly in mice and rats, and high exposure multiples relative to the human exposure at an 
anticipated clinical dose could not be attained[8].  
Narlaprevir (1800 mg/kg in mice and rats; 800 mg/kg in dogs) was coadministered with ritonavir 
(12.5 mg/kg) to mice, rats, and dogs for 2 weeks in part to assess the PK interaction of narlaprevir 
and ritonavir in these species. The high doses of narlaprevir administered in these studies 
hindered ritonavir absorption in all three species, therefore hampering the PK increasing effect by 
ritonavir. Coadministration of narlaprevir and ritonavir decreased maximum observed plasma 
concentration (Cmax) values for ritonavir by 96% in mice, 100% in rats, and 97% in dogs 
compared with administration of ritonavir alone. Complete inhibition of ritonavir absorption in rats 
resulted in no increase in narlaprevir levels[8]. 
Following IV administration to rats and dogs, narlaprevir had a volume of distribution of 1.6 L/kg 
and 1.2 L/kg, respectively. These values are all significantly greater than (~13-fold) the blood 
volume (L/kg) in these species, indicating extravascular distribution of narlaprevir[8]. Range of 


 
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14C-narlaprevir Plasma Protein Binding from Various Species 82,4-97,8%[8].  
Narlaprevir caused direct inhibition of CYP2D6 and CYP3A4/5 (as measured by dextromethorphan 
O-demethylation and midazolam 1’-hydroxylation, respectively, with HLM) with IC50 values of 88 
µM (62,300 ng/mL) and 41 µM (29,000 ng/mL), respectively. Further examination of the direct 
inhibition of CYP3A4/5 indicated that narlaprevir was a competitive inhibitor of CYP3A4/5 with a 
Ki* value of 22 µM (15,600 ng/mL). Additionally, upon coadministration with the potent CYP3A4 
inhibitor, ritonavir, inhibition of CYP3A4 by narlaprevir would presumably be inconsequential[8]. 
An extensive nonclinical safety program has been conducted to support the oral administration of 
narlaprevir. Narlaprevir was found to have a low order of toxicity in single and repeat-dose studies 
conducted in mice (up to 3 months), rats (up to 6 months), and dogs (up to 9 months). Bacterial 
mutagenicity, potential carcinogenicity and chromosome aberration studies revealed no evidence 
of genotoxic potential from narlaprevir batches tested[8]. 
The major findings observed in repeat-dose toxicity studies were: (1) testicular tubular epithelial 
degeneration and Sertoli cell cytoplasmic vacuolation in male rodents, (2) a minimal decrease 
(~7%-8%) in erythrocyte mass (red blood cells [RBCs], hemoglobin, and hematocrit) in female rats, 
(3) thyroid hyperplasia, hypertrophy, and/or increased thyroid weight in rats, (4) accumulation of 
eosinophilic precipitates in the gallbladder of mice, (5) hepatocellular cytoplasmic inclusions in 
mice, and (6) nasal cavity epithelial necrosis in mice. Based on the available nonclinical and 
clinical data, as well as relevant published literature [3], the Sponsor believes these findings are 
species-specific for mice and non clinically significant.  
The toxicological findings associated with administration of narlaprevir have been well 
characterized in the nonclinical program, and are not believed to pose a risk to humans. Based on 
the well characterized findings observed nonclinically in rats, mice, and dogs, and the likelihood 
that the findings (gallbladder precipitate, thyroid hyperplasia/ hypertrophy, hepatocellular 
cytoplasmic inclusions, testicular atrophy, nasal epithelial necrosis) observed are species-specific 
and/or can be readily monitored in the clinic, it is the Sponsor’s position that all findings to date in 
the nonclinical program and additional planned studies support continued clinical development of 
narlaprevir for the treatment of HCV[8]. 
5.4 
Clinical Profile 
5.4.1 Pharmacokinetics 
When the tablet formulation of narlaprevir was administered under fed conditions, mean total 
AUC(I) and Cmax were increased by 1.8- to 2.8-fold relative to fasted conditions, respectively. No 
apparent delays in Tmax under fed conditions were observed compared with fasted conditions. 
Thus, narlaprevir should be given with food[8]. 
Narlaprevir is moderately bound to human plasma protein; protein binding ranged from 86.5% to 
91.4% in human plasma. narlaprevir has a large volume of distribution, suggesting extensive 
distribution into tissues[8].  
Narlaprevir is extensively metabolized by humans through oxidation, cleavage, and a combination 
of these processes when narlaprevir was administered alone (P05065). In humans, 
coadministration of narlaprevir with the potent CYP3A4 inhibitor ritonavir increases exposure to 


 
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narlaprevir and SCH 782832[8].  
Elimination of narlaprevir was studied in a radiolabeled study in which an oral dose of 400 mg 14C-
narlaprevir alone or in combination with ritonavir was administered to healthy subjects (P05065). 
Co-administration of ritonavir decreased the elimination and substantially increased the half-life of 
narlaprevir. A mean total of 84.2% of the radioactive dose was recovered 144 hours after a single 
PO administration of 400 mg [14C] narlaprevir alone as oral suspension. Total radioactivity 
recovered in urine and feces accounted for 3.14% and 81.1% of the dose, respectively, indicating 
that renal clearance is a minor elimination pathway for narlaprevir-related entities when narlaprevir 
is administered alone[8]. 
Forty-one subjects were enrolled in Study P04695, a randomized, placebo-controlled, evaluator 
blind study to assess the safety, tolerability, PK, and pharmacodynamics of narlaprevir, in naive or 
treatment-experienced subjects infected with HCV-1[11,13]. PK results indicated similar PK 
between healthy and HCV-infected subjects. Narlaprevir was eliminated more slowly when 
coadministered with ritonavir than when administered alone. Dose-normalized daily exposures of 
narlaprevir (AUC) on Day 14 (in the presence of PegIntron), when coadministered with ritonavir, 
increased 7.6- and 7.1- fold in HCV treatment-naive and treatment-experienced subjects, 
respectively compared with those when narlaprevir was administered alone. PK of narlaprevir 
(Cmax, Ctrough, and area under the plasma concentration-time curve from time 0 to dosing interval 
[AUC[τ]]) when coadministered with ritonavir were comparable with and without coadministration of 
PegIntron for both HCV treatment naive and treatment-experienced subjects; therefore, no dose 
adjustment is warranted when narlaprevir in the presence of ritonavir is coadministered with 
PegIntron.  
32 subjects were enrolled in the Study CJ05013007 (013012cRPh), an open label multicenter 
study in parallel groups to assess PK of single 200 mg oral dose of narlaprevir (with and without 
100 mg oral dose of ritonavir) in patients with hepatic disease and corresponding healthy 
volunteers. In Part I of the study mean Cmax, and AUC(0-inf) was 1.6 and 2.7 times higher in patients 
vs. healthy subjects, respectively. Increased narlaprevir exposure in patients with Child-Pugh 
Class A was not associated with increased adverse events rate. Simulated steady-state (tau=24 h) 
Cmax, and AUCtau, in patients with Child-Pugh class A were 167% and 237% vs. healthy subjects, 
respectively. Increased NVR exposure in patients with Child-Pugh Class A was not associated with 
increased adverse events rate. Taking into account significant increase in NVR exposure in 
patients with Child-Pugh class A cirrhosis vs. healthy volunteers after single dose 200 mg and 
expected further increase due to RTV coadministration, NVR dose was decreased to 100 mg in 
the second part of the study. In Part II of the study mean Cmax, and AUC(0-inf) did not differ 
significantly in patients with Child-Pugh class A vs. healthy subjects (104% and 107% in patients 
vs. healthy volunteers, respectively) after single dose NVR 100 mg with RTV 100 mg (Part II of the 
study). Simulated steady-state (tau=24 h) Cmax, and AUCtau, in patients with Child-Pugh class A 
were 105.3% and 107.0%, vs. healthy subjects, respectively[8]. 
When a single 400-mg dose of 14C-narlaprevir amorphous suspension was given with ritonavir to 
healthy male subjects, AUC(I) and Cmax of narlaprevir were increased 10 and four times, 
respectively, compared with narlaprevir administered alone representing a significant 
enhancement of narlaprevir exposures under CYP3A4 inhibition by ritonavir[8]. 


 
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Results from a small drug-drug interaction study evaluating effects of narlaprevir on the PK of 
midazolam (MDZ, a sensitive substrate of CYP3A4) showed that the AUC of MDZ did not change 
significantly in four of five female subjects after multiple doses of narlaprevir 400 mg TID (P04694), 
suggesting that CYP3A4/5 activity was not induced. Mean AUC ratios (%CV) of 1'OH-MDZ to MDZ 
with and without multiple doses of narlaprevir were similar, 0.3 and 0.25 for five subjects, 
respectively[8]. 
5.4.2 Safety and Tolerance 
To date (January 10, 2017) the Phase 1 clinical pharmacology program currently consists of ten 
completed studies (P04694, P04695, P04959, P04986, P05054, P05065, P05353, P05580, 
P05778, and CJ05013007). In overall 376 healthy volunteers, 16 cirrhotic patients and 32 HCV-
infected subjects (P04695) have been exposed to NVR in phase 1 studies [8]. The Phase 2 clinical 
program currently includes one Phase 2a study (P05104) with 111 randomized subjects who were 
receiving PegIntron/ribavirin/NVR plus RTV for 12 weeks followed by standard of care 
PegIntron/ribavirin for either an additional 12 weeks or 36 weeks depending on their HCV-RNA 
status at 4 weeks of the PegIntron/ribavirin/NVR/RTV combination or PegIntron/ribavirin only 
(control group) [8]. Open-label extension part of phase 3 study CJ05013008 (PIONEER) is 
currently ongoing. NVR is administered in combination with RTV (used as a metabolic inhibitor) 
along with pegylated interferon and ribavirin. In the double-blind part of PIONEER study all eligible 
patients both treatment naive and treatment failure are randomized into one of the two treatment 
arms: NVR/RTV plus PEG/RBV and Placebo plus PEG/RBV in a 2:1 ratio. NVR dose was 200 mg 
per os QD, RTV - 100 mg per os QD. Totally 282 patients were randomized into NVR/RTV group 
and received at least one dose of NVR [21]. Within of open-label extension part of PIONEER study 
43 patients have taken at least one dose of NVR. 
Narlaprevir has been administered from 50 mg up to 2000 mg alone as a single-dose, and up to 
multiple doses of 1600 mg three times daily (TID) alone for 6 days or 1200 mg twice daily (BID) 
with ritonavir for 11 days in healthy subjects, and up to 800 mg TID alone and 400 mg BID with 
ritonavir in HCV-infected subjects. In the Phase II study narlaprevir was administered at a dosage 
of 200 mg once daily (QD), 400 mg QD, and 100 mg BID [8].  
Narlaprevir has been shown to be safe and generally well tolerated in healthy subjects when 
administered as single doses and multiple doses alone and in combination with ritonavir. These 
early studies have achieved plasma narlaprevir concentrations well above the anticipated 
therapeutic requirement [8]. 
Fifty-five percent of healthy subjects dosed with narlaprevir reported at least one treatment-
emergent adverse event (TEAE). The percentage of TEAEs reported in placebo-treated subjects, 
and subjects treated with other drugs only, were similar (56% and 59% respectively). 
Gastrointestinal disorders (55 subjects, 30%), and nervous system disorders (52 subjects, 28%) 
were the most frequently reported TEAEs after any narlaprevir administration, with the majority of 
these events being headache, nausea, and abdominal pain. The majority of TEAEs were 
considered related to treatment; however, there have been no dose-related trends in AEs reported 
with narlaprevir, and all AEs but one (generalized edema) were considered mild to moderate in 
severity regardless of treatment. The severe AE was reported in one female who received 1200 
mg BID of narlaprevir with ritonavir for 10 days. The subject was noted to have an elevation of 


 
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creatinine at the completion of the study, and at follow up she was found to have severe edema 
which resolved in approximately 2 weeks without treatment. There have been no clinically 
significant patterns of changes in vital signs, clinical laboratory values (including inhibin B levels in 
male subjects), or ECG recordings [8]. 
Seven healthy subjects administered narlaprevir in the Phase 1 clinical program discontinued due 
to an AE (P05054, P5580). 2 female subjects experienced moderate nausea and vomiting during 
treatment with narlaprevir (800 mg BID) with ritonavir (200 mg BID). Five subjects (3 men, 2 
female) discontinued treatment with narlaprevir (1500 mg QD) with ritonavir (100 mg QD) due to 
AEs (1 case of vomiting, 4 cases of increase in serum creatinine). There have been no serious 
adverse events (SAEs) reported in healthy subjects to date[8]. 
In Phase 1 Studies in HCV-Infected Subjects (Study P04695), narlaprevir was generally safe and 
well tolerated during 7 days of monotherapy (Period 1) and 14 days of combination therapy with 
PegIntron (Period 2). A similar number of subjects reported a TEAE during each period (88% 
Period 1; 97.5% Period 2). The number of AEs reported by placebo-treated (75% to 88%) and 
narlaprevir-treated (91% to 100%) subjects did not significantly differ. The greatest incidence of 
TEAEs was gastrointestinal disorders such as diarrhea and nausea (Part 1) and general disorders 
and administration site conditions, primarily influenza-like illness (Part 2). The most commonly 
reported individual TEAE in Part 1 was headache (11 subjects, 33%, all of whom received active 
drug), which was reported in a similar percentage of subjects in three of the four active drug 
treatment groups (not reported in treatment-experienced subjects receiving narlaprevir 800 mg 
TID). In Part 2, the most commonly reported individual TEAE was influenza-like illness in 30 (94%) 
subjects who received narlaprevir and PegIntron with or without ritonavir, and six (75%) subjects 
who received placebo and PegIntron with or without ritonavir. No dose-related increase in the 
number of AEs was reported among HCV-infected subjects.[11,13] No significant difference in AEs 
was noted between subjects that were treatment-naive vs. treatment-experienced. Most events 
were mild in intensity and considered unlikely related to study drug. There were no deaths, 
lifethreatening AEs, or discontinuations due to an AE. There were two severe AEs of influenza-like 
illness which resolved and were considered by the investigator to be probably related to study 
treatment (PegIntron) [8]. 
In Study P04695, there were three SAEs reported (one instance of elevated C-reactive protein and 
two instances of pyrexia) in one HCV-infected subject. This SAE was first reported 3 weeks after 
completing narlaprevir treatment. The subject was hospitalized for the evaluation of this SAE. At 
the time of the admission, the subject was receiving pegylated interferon and ribavirin and had a 
prior history of prolonged fevers while receiving a prior interferon treatment. The Investigator 
reported the SAE as unlikely related to the blinded study drug and possibly related to the 
pegylated interferon. No clinically significant patterns of changes in blood chemistry or 
hematological parameters, vital signs, or ECGs occurred in any treatment group[8]. 
Phase 2a study P05104 was completed. The most common treatment-emergent AEs included 
nausea, fatigue, anemia, influenza-like illness, diarrhea, headache and other events that are 
commonly reported with PR. AEs commonly associated with PR resulted in discontinuation in 
narlaprevir/ritonavir-treated subjects, including one subjects each with gastrointestinal-symptoms, 
homicidal ideation, tinnitus, depression, and lethargy. Narlaprevir/ritonavir was not associated with 


 
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rash. Serious AEs and discontinuations due to AEs were infrequent in the control and 
narlaprevir/ritonavir-treatment arms, and no subject died on study. There were no lifethreatening 
AEs [8-10].  
In the study P05104 the adverse event profile and number of discontinuation were consistent with 
those reported using peginterferon alpha + ribavirin therapy. Nearly all subjects reported AEs that 
the investigator considered treatment related. Treatment with narlaprevir and ritonavir with 
peginterferon alpha 2b + ribavirin was generally safe and well tolerated[8-10]. 
In the double-blind part of phase 3 study CJ05013008 (PIONEER), in which NVR is administered 
in combination with RTV (used as a metabolic inhibitor) along with pegylated interferon and 
ribavirin, therapy with NVR and ritonavir was safe and well tolerated. Eleven patients of 420 
discontinued treatment due to AEs, 7 treated with NVR and 4 with pegylated interferon and 
ribavirin alone. Five patients from NVR group had SAEs, none was assessed as related to study 
drug. In general adverse event profile observed in the study was comparable in NVR/RTV and 
control group [21]. 
In single dose PK Study CJ05013007 16 patients with hepatic disease class A by Child-Pugh 
score and 16 healthy volunteers with normal liver function were included. Open-label extension 
part of phase 3 study CJ05013008, in which NVR is administered in combination with RTV (used 
as a metabolic inhibitor) along with pegylated interferon and ribavirin is currently ongoing, and 43 
patients received at least one dose of NVR. Studies conducting by JSC R-Pharm (CJ05013008, 
CJ05013007) have not revealed significant safety concerns [8]. 
5.5 
Rationale 
5.5.1 Study Conduct Rationale 
In vitro data show that narlaprevir is metabolized by CYP3A4, and there is some evidence of CYP 
enzyme induction preclinically and CYP3A4 inhibition in human liver microsomes. However, a 
clinical study of high dose narlaprevir with midazolam showed no clinically relevant effect of 
narlaprevir on midazolam PK, indicating no relevant induction/inhibition of CYP3A4 by narlaprevir. 
In vivo, narlaprevir is a sensitive CYP3A4 substrate and co-administration with ritonavir (ritonavir) 
markedly increases narlaprevir exposure. In addition, in vitro data suggest narlaprevir is a P-gp 
substrate. Narlaprevir is being developed to be part of a therapeutic regimen that includes ritonavir 
(ritonavir), a metabolic inhibitor of CYP3A4, to boost the concentration of narlaprevir[8].  
This drug interaction study is designed to investigate pharmacokinetic drug-drug interactions 
between narlaprevir coadministered with ritonavir and antiretroviral drugs (tenofovir disoproxil 
fumarate and raltegravir), for labeling and clinical dosing guidance purposes. 
5.5.2 Study Design Rationale 
The current protocol includes 2 parts and additional parts may be added on an ongoing basis as 
an amendment to the protocol. 
Part 1 
Part 1 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of 


 
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narlaprevir and tenofovir, as the drugs may be used concomitantly to treat HCV/HIV coinfection. 
Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate) is the oral prodrug of tenofovir 
(tenofovir), a nucleotide reverse transcriptase inhibitor used in the treatment of HIV and hepatitis B. 
Tenofovir disoproxil fumarate is rapidly absorbed and converted in the plasma to tenofovir; 
tenofovir is largely eliminated unchanged through renal excretion.  
P-glycoprotein (P-gp) is thought to mediate tenofovir disoproxil fumarate absorption from the 
intestine, as tenofovir disoproxil fumarate efflux has been decreased by several inhibitors including 
cyclosporin A [1]. As a clinical correlate, HIV protease inhibitors, often coadministered with 
tenofovir disoproxil fumarate, have variably increased tenofovir plasma concentrations based on 
their ability to inhibit P-gp mediated efflux, induce P-gp expression and inhibit tenofovir disoproxil 
fumarate hydrolysis at the level of the intestine [1]. In addition, other transporters are thought to 
participate in the renal elimination of tenofovir; tenofovir is a substrate for both hOAT1 and hOAT3 
and inhibition of either transporter could both alter plasma concentration of tenofovir and decrease 
elimination. 
Narlaprevir has been shown to be a P-gp substrate; it is unknown whether it is a P-gp inhibitor or 
affects hOAT1 and hOAT3. Thus it is unknown whether narlaprevir could affect tenofovir exposure. 
As tenofovir disoproxil fumarate has affected HIV protease inhibitor (PI) drug absorption [1]; and 
these PIs are peptidomimetics similar to narlaprevir, there is also the potential for tenofovir 
disoproxil fumarate to affect narlaprevir absorption and plasma concentrations.  
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP 
enzymes. At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir 
did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: 
CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant 
reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro 
experiments and the known elimination pathway of tenofovir, the potential for CYP mediated 
interactions involving tenofovir with other medicinal products is low. [14]. 
Tenofovir disoproxil fumarate does not significantly affect the pharmacokinetics of HCV PIs 
boceprevir, telaprevir, or simeprevir [15-17]. The coadministration with simeprevir and boceprevir 
didn’t significantly change exposure parameters of tenofovir. Only coadministration with telaprevir 
led to 30% increase in AUC and Cmax of tenofovir, which was not associated with worsened safety 
profile of this combination. That is why concomitant use of tenofovir disoproxil fumarate with all 
approved HCV PIs is recommended without any dose adjustment [7,14]. 
So no major drug-drug interaction is expected between narlaprevir/ritonavir and tenofovir disoproxil 
fumarate. 
This study is designed as a randomized 3-period crossover study and will assess if there is any 
effect of tenofovir disoproxil fumarate/tenofovir on the pharmacokinetics of narlaprevir and vice 
versa. 
Part 2 
Part 2 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of 
narlaprevir/ritonavir and raltegravir (raltegravir). A considerable percentage of HIV infected patients 


 
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are also infected with HCV. HIV/HCV co-infected patients commonly use HIV and HCV 
medications simultaneously. Therefore, it is important to know whether drug-drug interactions 
occur when combining those treatments or not. 
Raltegravir is an agent used for the treatment of HIV and is commonly used in HIV/HCV coinfected 
patients because it does not inhibit or induce CYP enzymes and its primary route of elimination is 
glucuronidation. Since the current treatment paradigm for HIV involves the administration of anti-
HIV agents in combination, to boost efficacy and to control the emergence of resistance, it is 
currently planned that raltegravir will be administered in combination with other anti-HIV/ HCV 
drugs, including ritonavir and narlaprevir.  
Raltegravir is an HIV integrase inhibitor. In clinical trials in healthy volunteers in the presence of 
ritonavir, raltegravir pharmacokinetics were just weakly affected and did not require dose 
adjustment. [2]. In the presence of protease inhibitors (atazanavir and tenofovir) boosted by 
ritonavir pharmacokinetics of raltegravir changed differently: PK parameters increased in the 
presence of atazanavir and decreased in the presence of tenofovir. In both cases it was not 
considered as clinically significant. [2]. 
Raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or 
CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter 
the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect 
of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, 
raltegravir is not an inhibitor (IC50>50 µM) of UGT1A1 or UGT2B7, and raltegravir does not inhibit 
P-glycoprotein-mediated transport. Based on these data, raltegravir is not expected to affect the 
pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease 
inhibitors) [18]. Besides raltegravir has a wide therapeutic index and even in 300% raltegravir 
exposure increase (when coadministered with omeprazole) no safety profile worsening was shown 
(combination of omeprazole and raltegravir is allowed for use without dose adjustment) [18-20]. 
Ritonavir is a potent inhibitor of cytochrome 3A (CYP3A) and CYP2D6 and also appears to induce 
CYP3A and other drug metabolizing enzymes, including glucuronosyl transferases. Based on 
reported clinical trials no dose adjustment is required for raltegravir with coadministration with 
ritonavir only [2]. 
Drug-drug interaction studies were conducted of raltegravir with HCV PIs boceprevir, telaprevir and 
simeprevir. Boceprevir and simeprevir had no impact on the raltegravir pharmacokinetics (4% and 
8% increase in AUC, respectively), while telaprevir coadministered with raltegravir led to 31% 
increase in raltegravir AUC [18]. All these changes were considered not clinically meaningful [18-
20]. Raltegravir had no impact on boceprevir, telaprevir or simeprevir pharmacokinetics. That is 
why concomitant use of raltegravir with all approved HCV PIs is recommended without any dose 
adjustment [15-17]. 
Narlaprevir is not a CYP3A4 inducer/inhibitor, but its effect on the UGT1A1 pathway and other 
transporters such as P-gp is unknown. It is important to investigate if any drug-drug interaction 
exist in case of co-administration of raltegravir and narlaprevir / ritonavir combination. 


 
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This study is designed as a randomized 3-period crossover study and will assess if there is any 
effect of raltegravir on the pharmacokinetics of narlaprevir and vice versa. 
5.5.3 Dose Rationale 
Narlaprevir will be administered at a dose of 200 mg with ritonavir 100 mg QD, the anticipated 
clinical dose.  
All other drugs (Tenofovir disoproxil fumarate and Raltegravir) will be administered at their clinically 
relevant doses. 
 
6 
STUDY OBJECTIVES 
6.1 
Primary Objectives 
The primary objectives of this study are: 
Part 1 
To evaluate the pharmacokinetic drug-drug interaction between narlaprevir/ritonavir and tenofovir 
(disoproxil fumarate) in healthy subjects. 
Part 2 
To evaluate the pharmacokinetic drug-drug interaction between narlaprevir/ritonavir and raltegravir 
in healthy subjects. 
 
6.2 
Secondary Objectives 
The secondary objectives of this study are: 
Part 1 
To evaluate the safety and tolerability of narlaprevir/ritonavir when coadministered with tenofovir in 
healthy subjects. 
Part 2 
To evaluate the safety and tolerability of narlaprevir/ritonavir when coadministered with raltegravir 
in healthy subjects. 
 
7 
INVESTIGATIONAL AND ANALYSIS PLAN 
7.1 
Design of the Study/Methodology 
This will be a study in 2 parts conducted in healthy adult subjects, in conformance with Good 
Clinical Practices. This study will be conducted in 1-2 sites in Russia. This study supposes that 36 
subjects should complete the study per protocol. In order to reach this amount all subjects who 
withdraw the study prematurely will be replaced by new subject. Considering possible 50% drop-
out rate maximum 54 subjects will be administered study drug. For enrollment of 54 subjects about 


 
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80 healthy volunteers may be screened.  
This study may be amended to include additional parts that assess other potential drug 
interactions and PK considerations that are necessary to support the registration of narlaprevir.  
Both parts will be a randomized, 3-period crossover study. Subjects will be screened within 28 
days before dosing in this multi-part study. Subjects will be admitted to the study center the 
evening before the first dose for baseline assessments to confirm eligibility. 
Part 1 
Subjects will participate in a randomized 3-period crossover study. Every subject will be 
randomized 1:1:1 to receive one of following treatment sequences: A/B/C, or B/C/A, or C/A/B 
according to randomization scheme. Only one treatment will be administered per period. 
On Day 1 of the first period, subjects will be randomized to one of the treatment sequences and 
receive the first dose. 
Subjects in Part 1 will receive the following: 
• 
Treatment A: narlaprevir 200 mg once daily + ritonavir 100 mg once daily orally for 5 days  
• 
Treatment B: tenofovir disoproxil fumarate 300 mg once daily, orally for 5 days 
• 
Treatment C: narlaprevir 200 mg once daily + ritonavir 100 mg once daily + tenofovir 
disoproxil fumarate 300 mg once daily, orally for 5 days 
All treatments will be administered following a standard breakfast. Subjects will be confined to the 
study center throughout treatment in each period. Following completion of study procedures for 
each treatment period, subjects will be discharged from the clinic. After a 7-14 days interval 
between dosing, subjects will return to start hospitalization for the next treatment period. 
Blood and urine samples for determination of narlaprevir, ritonavir (Ctrough) and tenofovir 
concentrations will be collected as specified in the Study Flow Chart. 
Safety assessments including vital signs, ECGs, and clinical laboratory tests will be performed, 
and adverse events will be recorded, throughout the study. Subjects will be discharged from the 
clinic upon completion of all study related procedures in Period 3. Phone call will be conducted 
after 5-7 days of follow-up period to assess safety data. 
Part 2 
Subjects will participate in a randomized 3-period crossover study. Every subject will be 
randomized 1:1:1 to receive one of following treatment sequences: A/B/C, or B/C/A, or C/A/B 
according to randomization scheme. Only one treatment will be administered per period. On Day 1 
of the first period, subjects will be randomized to one of the treatment sequences and receive the 
first dose. 
Subjects in Part 2 will receive the following: 
• 
Treatment A: narlaprevir 200 mg once daily + ritonavir 100 mg QD orally for 5 days  
• 
Treatment B: raltegravir 400 mg twice daily, orally for 5 days 


 
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• 
Treatment C: narlaprevir 200 mg once daily + ritonavir 100 mg QD + raltegravir 400 mg 
twice daily, orally for 5 days 
All treatments will be administered following a standard breakfast and evening dose of raltegravir 
will be taking after standard dinner. Subjects will be confined to the study center throughout 
treatment in each period. Following completion of study procedures for each treatment period, 
subjects will be discharged from the clinic. After a 7-14 days interval between dosing, subjects will 
return to start hospitalization for the next treatment period. 
Blood samples for determination of narlaprevir, ritonavir (Ctrough) and raltegravir concentrations will 
be collected as specified in the Study Flow Chart. 
Safety assessments including vital signs, ECGs, and clinical laboratory tests will be performed, 
and adverse events will be recorded, throughout the study. Subjects will be discharged from the 
clinic upon completion of all study related procedures in Period 3. Phone call will be conducted 
after 5-7 days of follow-up period to assess safety data. 
 
Screening 
Within 28 days prior to treatment, the investigator shall discuss with each subject the nature of the 
study, its requirements, and its restrictions. Written informed consent will be obtained from each 
subject prior to any study related procedures being performed, and a signed copy will be given to 
the volunteer. The inclusion/exclusion criteria will be reviewed, a complete medical history, 
physical examination, laboratory evaluations and other assessments will be performed as 
delineated in Section 4.2 and Section 7.6. A screening number will be assigned to each subject 
on completion of the study-specific informed consent. 
 
Baseline 
Subjects will be confined to the study center at least 12 hours prior to dosing. The investigator will 
review the inclusion/exclusion criteria and record adverse events (AEs) and medications taken 
within the last 14 days. Laboratory evaluations, vital signs and other assessments will be 
performed and recorded as delineated in Section 4.2 and Section 7.6.  
 
Treatment Day(s) 
Inclusion/exclusion criteria will be reviewed with each subject on the morning of treatment 
administration. Subjects in both parts of the study will be assigned a randomization number. The 
randomization number will be used to determine the treatment according to a randomization code 
(see Section 7.4.1.3). Laboratory evaluations, vital signs and other assessments, delineated in 
Section 4.2 and Section 7.6 will be performed and recorded. Serial pharmacokinetic samples will 
be obtained prior to dosing and as outlined in the Study Flow Chart (Section 4.2). 
 


 
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Study Completion/Subject Discharge/Follow-Up 
On the last day of their study participation (including premature discontinuation), subjects will be 
discharged following collection of the last blood sample/assessment. In addition, concomitant 
medications, adverse events and vital signs will be recorded and a physical exam, and laboratory 
evaluations, and other assessments required as delineated in Section 4.2 and Section 7.6 will be 
performed. 
 
7.2 
Participation in and Completion of the Study 
Each subject is considered enrolled in the trial when the subject has provided written informed 
consent. All subjects will have their information entered into the screening log maintained by the 
study site. Those subjects, including screened subjects, who experience a serious adverse event, 
or have a therapeutic intervention (e.g., change in medication administered, dietary therapy, 
administration of study medication), will have information entered into the case records (e.g., 
CRF). Those subjects who fail to qualify for further study participation based on the initial interview 
and initial screening laboratory tests, should have information only recorded in the site screening 
log. 
Each subject is considered to have fulfilled participation in the trial when he/she has completed the 
last protocol-specified contact (e.g., visits or telephone contacts). 
A subject is considered discontinued after he/she has withdrawn consent or has been discontinued 
under the conditions specified in Section 7.3.3. 
A subject is considered lost to follow-up, if the investigator is unable to contact the subject. The 
end of participation for a subject lost to follow-up is the last known contact (e.g., visit or telephone 
contact). 
The overall trial begins when the first subject is enrolled (i.e., signs the informed consent form). 
The overall trial ends when the last remaining subject has ended participation in the trial, by 
completing the trial, being discontinued from the trial, or being lost to follow-up. 
Follow-up procedures related to pregnancy or (S)AEs may continue beyond the end of the clinical 
trial. 
 
7.3 
Study Population 
Healthy adult male and female subjects will be selected for both Parts of the study. It is planned 
that 36 subjects will complete the study overall. In case of premature withdrawal subjects will be 
replaced by volunteers from among the subjects who signed the informed consent form. Subjects 
must meet all the inclusion criteria and none of the exclusion criteria to receive treatment 
assignment. Considering 50% drop-out rate maximum 54 subjects will be enrolled in the study. 18 
subjects should complete each of two parts.  
7.3.1 Subject Inclusion Criteria 


 
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The subjects must meet ALL the criteria listed below for entry at baseline: 
1. 
Subjects must be willing to give written informed consent for the trial and able to adhere to 
dose and visit schedules. 
2. 
Subjects of either sex and of any race between the ages of 21 and 55 years (both parts), 
inclusive, having a Body Mass Index (BMI) between 18,5 and 30, inclusive. BMI = weight 
(kg)/height2(m).  
3. 
Volunteers should be diagnosed as "healthy": no pathology of the gastrointestinal tract, 
liver, kidneys, cardiovascular system, central nervous system (previously carried out by standard 
clinical and lab tests which did not reveal the presence of any diseases. AST and ALT must not 
exceed the normal range; QTcB for men should be ≤ 450 ms and ≤ 470 ms for women, the interval 
PR should be ≤ 200 ms). 
4. 
Vital sign measurements (taken after ~3 minutes in a supine or sitting position) must be 
within the following ranges: 
a. systolic blood pressure, 100 – 130 mm Hg 
b. diastolic blood pressure, 60 -90  mm Hg 
c. pulse rate, 60-80 bpm 
5. 
Female subjects must be: 
a. postmenopausal (defined as 12 months with no menses; age > 40 years and with a 
FSH level of >40 u/mL). 
b. surgically sterilized at least 3 months prior to baseline (e.g., documented 
hysterectomy or tubal ligation). 
6. 
Men must agree to use a medically accepted method of contraception (condom and 
spermicide) during the trial and for 3 months after stopping the medication. 
 
 
7.3.2 Subject Exclusion Criteria 
The subject will be excluded from entry if ANY of the criteria listed below are met at baseline: 
The subject will be excluded from entry if ANY of the criteria listed below are met at baseline: 
1. 
Females with childbearing potential; 
2. 
Subjects who, in the opinion of the investigator, will not be able to participate optimally in 
the study; 
3. 
Positive results for hepatitis B surface antigen, hepatitis C antibodies or HIV, positive RW 
results; 
4. 
Allergic reactions in history; 
5. 
Intolerance to medication; 


 
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6. 
Chronic disease of cardiovascular, bronchopulmonary, and/or neuroendocrinal systems, 
gastrointestinal, liver, pancreas, kidney and/or blood disease; 
7. 
History or presence of impaired renal function, lactase deficiency, lactose intolerance, 
glucose-galactose malabsorption; 
8. 
History of urinary obstruction or difficulty in voiding; 
9. 
Gastrointestinal surgery in history (except of appendectomy); 
10. 
Acute infections less than 4 weeks before participation in the study; 
11. 
Subjects with a medical history of osteopenia and/or osteoporosis. 
12. 
Regular administration of any medicines less than 4 weeks before participation in the study;  
13. 
Administration of medicines with marked influence on hemodynamics, liver function et al 
(barbiturates, omeprazole, cimetidine et al) less than 30 days before participation in the 
study; 
14. 
Blood donation (450 ml or more of blood or plasma) less than 2 months before participation 
in the study; 
15. 
Intake of more than 10 units of alcohol in a week (1 unit of alcohol is equal to 0.5 L of beer, 
200 mL of wine or 50 mL of spirits) or history of drug abuse or alcoholism; 
16. 
Smoking of more than 10 cigarettes or equivalent tobacco use per day; 
17. 
Participation in phase 1 clinical trial less than 3 months before participation in the study; 
18. 
Positive screen for drugs abuse and drug use; 
19. 
 Subjects with a medical history of psychiatric or personality disorders that in the opinion of 
the investigator and sponsor, affects the subject’s ability to participate in the trial; 
20. 
Subjects who are part of the study staff personnel or family members of the study staff 
personnel; 
 
 
Table 3 
Prohibited Medications for Entry into the Study 
Prohibited Medications
Washout Period Prior to Dosing
Prescription and non prescription medication except 
acetaminophen 
14 days 
Potent inhibitors and inducers of CYP 3A4
14 days
Herbal supplements
14 days
Vitamins at doses that exceed daily replacement 
requirements
14 days 
Oral contraceptives 
2 months 
 


 
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Table 4 
Human CYP Enzyme Drug-Interactions 
Enzyme
Inhibitors
Inducers
CYP3A 
cimetidine, clarithromycin, diltiazem, 
erythromycin, fluoxetine, fluvoxamine, 
indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, paroxetine, 
ritonavir, saquinavir, telithromycin, 
venlafaxine, verapamil 
carbamazepine, dexamethasone, 
efavirenz, ifosfamide, nevirapine, 
modafinil, oxcarbazepine, pioglitazone, 
phenobarbital, phenytoin, rifabutin, 
rifampin, St. John’s wort, troglitazone 
 
7.3.3 Subject Discontinuation Criteria 
Subject participation may be terminated during the study for any of the following reasons: 
• 
Serious or severe adverse event (AE); 
• 
Does not meet Inclusion / Exclusion Criteria prior to Treatment Periods 2 and 3 except of 
clinically not significant increase of ALT or/and AST before Periods 2 and 3 (see Study Flow 
Charts). 
• 
Failure to comply with the dosing, evaluations, or other requirements of 
the study; 
• 
Request of the subject (subjects have the right to discontinue treatment at 
any time for any reason); 
• 
Any situation or condition which may threaten the subject’s health or well 
being by continuing in the study; 
• 
Administrative (e.g., study termination). 
 
 
At a minimum collect the following information when a subject discontinues: 
Table 5 
The information that is necessary when a subject discontinues study 
1) 
The reason the subject discontinued; 
2) 
The date of the last dose of test products from the trial; 
3) 
The date of the last assessment and/or contact (telephone or visit) will be arranged as 
appropriate; 


 
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4) 
(Serious) Adverse events; 
5) 
Compliance with the test product administration as specified in this protocol; 
6) 
Final Assessments; 
7) 
Every effort should be made to ensure that all procedures and evaluations scheduled 
for the final trial visit are performed (Section 4.2, Trial Flow Chart). 
 
It is the right and the duty of the investigator to interrupt treatment of any subject if he/she feels 
that study discontinuation is necessary to protect the subject, or that there are unmanageable 
factors that may interfere significantly with the study procedures and/or the interpretation of results. 
If a subject prematurely discontinues, or is discontinued from the study, the primary reason for the 
discontinuation will be obtained and recorded on the CRF. At the time of discontinuation, every 
effort (e.g., telephone contact, certified letter) should be made, and documented, to ensure and all 
procedures and evaluations scheduled for the final study visit are performed (see Section 4.2, 
Study Flow Chart and Section 7.6, Study Procedures). 
 
7.3.4 Replacement of Subjects 
After consultation between the sponsor and the principal investigator, enrollment may be extended 
to replace subject(s) discontinued during the study by volunteers from among the subjects who 
signed the informed consent form. 
 
7.4 
Treatments 
7.4.1 Study Treatments 
7.4.1.1 
Treatments Administered 
Part 1 
• 
Treatment A: 200 mg of narlaprevir (2 x 100 mg coated tablets), QD, per os (PO) 
coadministered with 100 mg of ritonavir QD, PO, for 5 days  
• 
Treatment B: 300 mg tenofovir disoproxil fumarate (1 x 300 mg tablet), QD, PO, for 5 days 
• 
Treatment C: 200 mg of narlaprevir (2 x 100 mg coated tablets), QD, PO coadministered 
with 100 mg of ritonavir QD, PO and 300 mg tenofovir disoproxil fumarate (1 x 300 mg film coated 
tablets), QD, PO, for 5 days 
 
Part 2 
• 
Treatment A: 200 mg of narlaprevir (2 x 100 mg coated tablets), QD, PO, coadministered 
with 100 mg of ritonavir QD, PO, for 5 days 


 
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• 
Treatment B: 400 mg raltegravir (1 x 400 mg tablet), BID, PO, for 5 days 
• 
Treatment C: 200 mg of narlaprevir (2 x 100 mg coated tablets), QD, PO coadministered with 
100 mg of ritonavir QD, PO and 400 mg raltegravir (1 x 400 mg film coated tablets), BID, PO, for 5 
days 
For all parts, all doses will be administered following a standard breakfast (for all drugs) and 
standard dinner (for raltegravir administered twice daily only). Standard breakfast and standard 
dinner will be similar during the treatment periods and for all patients. Center may refer to 
recommendations of Diet N 15 for standard meals.  
Narlaprevir doses are to be administered at each dose with approximately 200 mL of room 
temperature noncarbonated drinking water. All treatments should be swallowed whole, not chewed 
or crushed. 
 
7.4.1.2 
Timing of Dose for Each Subject 
In Parts 1, 2 the dosing of narlaprevir is once a day in the morning following a standard breakfast.  
 
In Part 1, tenofovir disoproxil fumarate and ritonavir should be administered in the morning 
following a standard breakfast. 
 
In Part 2, ritonavir and raltegravir should be administered in the morning following a standard 
breakfast. Raltegravir should be administered again following standard dinner approximately 12 
hours after the morning dose. 
 
Each treatment should be administered, if possible, at approximately the same time each day. 
 
7.4.1.3 
Method of Treatment Assignment, Randomization, and/or Stratification 
7.4.1.3.1 Screening Number Assignment 
A screening number will be assigned to each subject on completion of the study-specific informed 
consent by the site. Screening numbers will be recorded on the CRF. 
 
7.4.1.3.2 Randomization/Dosing Number Assignment 
A subject or randomization number will be assigned to each volunteer by the site using the 
subject/randomization numbers provided in Section 7.4.1.3. prior to the administration of 
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For both parts on Day 1 of Period 1 visit all eligible subjects will be randomized using envelopes 
with codes into one of the treatment sequences (A/B/C, B/C/A or C/A/B). For both parts 
responsible statisticians will generate the randomization schedule prior to the start of this study. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel 
 
Part 1 
On Day 1 of Period 1, subjects who have met all of the eligibility requirements indicated in Section 
7.3 will be assigned a Subject Randomization Number by the site. Subjects will be assigned 
Randomization Numbers (1001 and subsequent numbers). This 4-digit randomization number will 
be used by the clinical site to facilitate the prelabeling of PK samples, and will be the only subject 
identifier used on all PK sample collections.  
Randomization numbers for replacement subjects are included in these numbers. For replacement 
subject the second digit in 4-digit number is changed from “0” to “1” etc.  
Study treatment will be assigned to a subject according to Randomization List. 
 
Part 2 
On Day 1 of Period 1, subjects who have met all of the eligibility requirements indicated in Section 
7.3 will be assigned a Randomization Number by the site. Subjects will be assigned 
Randomization Numbers (2001 and subsequent numbers). This 4-digit randomization number will 
be used by the clinical site to facilitate the prelabeling of PK samples, and will be the only subject 
identifier used on all PK sample collections.  
Randomization numbers for replacement subjects are included in these numbers. For replacement 
subject the second digit in 4-digit number is changed from “0” to “1” etc. 
Study treatment will be assigned to a subject according to Randomization List. 
 
7.4.1.4 
Management of Blinding of Study Treatments 
Both parts are open-label. 
 
7.4.1.5 
Investigational Product(s) 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, handling, storage, distribution, and usage of these materials in 
accordance with the protocol and any applicable laws and regulations. 
The following Investigational product(s) will be used in the study and will be supplied in sufficient 


 
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quantities for subjects and any replacement subjects. 
Table 6 
Investigational Product(s) 
Part
Treatment 
Group 
Drug 
Dose 
(mg) 
Dosage 
strength 
(mg) 
Dosage 
forms 
per 
dose
Dosing 
periods 
per 
day
Sub-
jects 
Days 
of 
Treat-
ment
Total 
dosage 
forms 
Addi-
tional 
Infor-
mation
Part 
1 
A 
narlaprevir 
200 
100 
2 
1 
12 
5 
120 
 
C 
200 
100 
2 
1 
12 
5 
120 
 
A 
ritonavir 
100 
100 
1 
1 
12 
5 
60 
 
C 
100 
100 
1 
1 
12 
5 
60 
 
B 
tenofovir 
disoproxil 
fumarate
300 
300 
1 
1 
12 
5 
60 
 
C 
300 
300 
1 
1 
12 
5 
60 
 
Part 
2 
A 
narlaprevir 
200 
100 
2 
1 
12 
5 
120 
 
C 
200 
100 
2 
1 
12 
5 
120 
 
A 
ritonavir 
100 
100 
1 
1 
12 
5 
60 
 
C 
100 
100 
1 
1 
12 
5 
60 
 
B 
raltegravir 
400 
400 
1 
2 
12 
5 
120 
 
C 
400 
400 
1 
2 
12 
5 
120 
 
 
7.4.1.5.1 Route and administration 
All trial medications will be administered with appropriate intervals between subjects to allow for 
sample collection and any necessary additional clinical observations. All trial medication 
administrations will be performed by the investigator or responsible designee and will be witnessed 
by a second person. Trial medication administration will be carried out by a physician with the 
subject in standing position. Tablet(s) will be taken orally together with 200 mL water after standard 
breakfast and raltegravir will be taken after dinner in Part 2 of the study. Subjects will have to 
remain in sitting (semi-recumbent) position for 4 hours after administration (visiting the restrooms 
under supervision is allowed). In this time, entertainment will not include any exciting or thrilling 
movies or similar TV programs. 
Information on dietary restrictions is given in Section 7.4.3. 
 
7.4.1.5.2 Identity of Investigational Product(s) 
Narlaprevir 
ARLANSA 


 
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Test drug:  
 
 
narlaprevir 
Dosage form: 
 
film-coated tablet formulation 
Strength: 
 
100 mg 
Dose: 
 
200 mg single oral dose 
Developer/Manufacturer:  
R-Pharm JSC  
Manufacturing site: 
 
Hovione FarmaCiencia SA Sete Casas, 2674-506 Loures, Portugal.  
The tablets contain the excipients copovidone, microcrystalline cellulose, lactose monohydrate, 
sodium lauryl sulfate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. 
The tablets are packaged in induction-sealed high-density polyethylene bottles. 
This packaging configuration provides sufficient protection from light and humidity.  
 
Ritonavir 
NORVIR® 
Dosage form: 
 
film-coated tablet formulation 
Strength: 
 
100 mg 
Dose: 
 
100 mg single oral dose 
Developer/Manufacturer:  
Abbott GmbH & CoKG 
 
 
 
 
Knollstrasse 50, 67061 Ludwigshafen, Germany 
Ritonavir packed in vials containing 30 tablets. 
Please refer to Package Insert for additional information on ritonavir (NORVIR®). 
 
Tenofovir disoproxil fumarate 
TENOFOVIR-TL 
Dosage form:  
 
film-coated tablet  
Strength: 
 
 
300 mg 
Developer/Manufacturer:  
LTD "Drugs Tehnology" 
Tenofovir-TL packed in vials containing 30 tablets. 
Please refer to Package Insert for additional information on tenofovir disoprozil fumarate 
(Tenofovir-TL,,LTD "Drugs Tehnology"). 
 
Raltegravir 
ISENTRESS® 


 
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Dosage form:  
 
film-coated tablet  
Strength: 
 
 
400 mg 
Developer/Manufacturer:  
Merck Sharp & Dohme  
Insentress packed in unit-of-use bottles of 60 tablets. 
Please refer to Package Insert for additional information on raltegravir (ISENTRESS®). 
 
7.4.1.5.3 Source 
The sponsor will provide narlaprevir, ritonavir and all other study medication (Section 7.4.1.5) for 
this study. It should be always from the same batch/lot for each particular Study Part.    
 
7.4.1.5.4 Labeling, Storage and Dispensing 
The labels will include  
• 
Name of study drug  
• 
Protocol number 
• 
Sponsor name, address and contact phone number  
• 
CRO name, address and contact phone number 
• 
Formulation 
• 
Rout of administration 
• 
Dosage 
• 
Number of Units 
• 
Batch # 
• 
Investigator name 
• 
Site number 
• 
Patient number 
• 
Identification “For clinical trials only” 
• 
Storage conditions 
• 
Note to “Keep out of children reach” 
• 
Expiry date 
 
 
Local requirements and other information may be added as required. The label should be 


 
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produced in a language appropriate for the study site. 
Receipt and dispensing of study medication must be recorded by an authorized person at the 
investigator's site. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, handling, storage, distribution, and usage of these materials in 
accordance with the protocol and any applicable laws and regulations.  
Study drug supplies must be stored at the clinical site in a secure, limited-access location under 
the storage conditions specified on the medication labels. Clinical sites must maintain temperature 
logs for study drug storage areas on a daily basis. Study drug(s) will be dispensed by the 
investigators named on the Authorized Signature Log. The study drug(s) will be dispensed only to 
study subjects who have provided written informed consent, and have met all entry criteria. Clinical 
supplies may not be used for any purpose other than that stated in the protocol. 
 
An adequate quantity of study drug will be provided to replace units damaged in 
shipment/handling, to replace subjects. 
 
7.4.1.5.5 Investigational Product Accountability 
Accurate and current accounting of the dispensing and return of investigational product(s) and 
concomitant medications supplied by the Sponsor will be maintained on an ongoing basis by a 
member of the trial site staff: 
• 
Investigational medicinal product(s) dispensed to each site will be recorded in the trial-
specific Site Investigational Medicinal Product (IMP) Accountability Log (or equivalent document); 
• 
Investigational medicinal product(s) dispensed to each subject will be recorded in the 
trial-specific Subject IMP Accountability Log (or equivalent document). 
 
The Site IMP Accountability Log and Subject IMP Accountability Log will be verified by the trial 
monitor. The original Site IMP Accountability Log and Subject IMP Accountability Log will be 
approved by the investigator and retained at the trial site and a copy supplied to the sponsor or 
CRO when the trial is complete. 
 
The trial monitor will instruct the site on the return of all investigational product(s) supplies. A final 
inventory of the total amount of investigational product(s) received at each trial site against the 
amount used and returned must be recorded in the Site IMP Accountability Log. Inventory records 
must be readily available for inspection by the trial monitor and/or auditor, and open to government 
inspection at any time. 
 


 
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7.4.2 Non-Study Treatments 
7.4.2.1 
Prior and Concomitant Medications 
All prior medication taken by the subject 14 days prior to treatment intervention and all concomitant 
therapy taken by the subject during the study are to be recorded on the CRF. The identity of the 
therapy, the dose, route, and regimen, the dates started and stopped (or notation of “continuing” if 
that is the case), and the reason for use must be recorded. The use of any concomitant medication 
must relate to an AE or the subject's medical history. 
 
7.4.2.2 
Medications, Supplements, and Other Substances Prohibited Prior to Baseline 
and During the Study 
The medications prohibited prior to Baseline are listed in the table in Section 7.3.2 with the subject 
exclusion criteria. 
The subject must not take the treatments listed in table below (other than as specified in the 
protocol) during the study after Subject Number Assignment or Randomization. 
 
Table 7 - Medications Prohibited During the Study 
Medication Name 
Duration of Prohibition 
Prescription Medications (except those required in the study) 
During the Study 
Nonprescription Medications (except Acetaminophen) 
During the Study 
Vitamins, dietary supplements 
During the Study 
CYP3A4 Inducer (Section 7.3.2) 
During the Study 
CYP3A4 Inhibitor (Section 7.3.2) 
During the Study 
NSAIDS 
During the Study 
 
7.4.2.3 
Medications Allowed During the Study 
The following medications, supplements, and other substances are allowed during the study: 
 
Table 8 
Allowed Medications 
Medication Names 
Acetaminophen (paracetamol) 
Medications necessary to treat adverse events or medical emergencies 
 
Note that the use of any concomitant medication must relate to the documented medical history, 
prophylaxis, or an adverse event of the subject. 
 


 
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7.4.3 Dietary, Tobacco, Alcohol, Caffeine, and Other Restrictions 
7.4.3.1 
Diet 
Meals (breakfast, lunch, dinner and snacks) will be of similar nutritional composition for all 
subjects/groups on hospitalization days, and will be provided at approximately the same time each 
day. 
In accordance with standards approved in Russian Federation [30], daily meal should include 65 - 
117g of proteins for males or 58 – 87g for females (about 30% of daily energy needs), 70 – 154g 
of fats for males or 60 – 102g for females (about 12% of daily energy needs) and 257 – 586g of 
carbohydrates that equal to 50—60% of daily energy needs. There are no special requirements for 
meal composition for study drugs [31]. According to the data in approved drug label information for 
tenofovir disoproxil fumarate, high fat meal impacts tenofovir pharmacokinetics. Administration of 
tenofovir disoproxil fumarate with a light meal has no significant effect on the pharmacokinetics of 
tenofovir compared to fasted administration of the drug. No clinically meaningful effects of meal on 
raltegravir pharmacokinetics were revealed in PK study [31]. To minimize variation in 
pharmacokinetics due to food, standard breakfast containing 20% of the total caloric content from 
fat will be consumed prior to administration of the morning dose of drug(s).  
Grapefruit and grapefruit juice must also be excluded from the diet since substances contained in 
these foods have been reported to inhibit certain drug-metabolizing enzymes. 
When meal and blood draw times coincide, blood will be drawn BEFORE the meal is provided. 
On days prior to serial PK sampling at approximately 21:00 all subjects should have a light snack 
(sandwich, piece of fruit, non-caffeinated beverage) after which an overnight fast will be started. 
Following an overnight fast of at least 10 hours, subjects should start to consume the standard 
breakfast 30 minutes prior to administration of the drug product. Study subjects should eat this 
meal in 30 minutes or less; however, the drug product should be administered 30 minutes after 
start of the meal. The drug product should be administered with 200 mL of water. No food should 
be allowed for at least 4 hours postdose at which time a light lunch will be served. Water can be 
allowed as desired except for one hour before and after drug administration. Subjects should 
receive standardized meals scheduled at approximately the same time in each period of the study. 
Except as required for study procedures, subjects should remain semi- recumbent until 4 hours 
postdose. For BID treatment subjects should receive a meal or snack prior to the evening dose. 
 
7.4.3.2 
Tobacco 
The enrollment of nonsmoking volunteers is preferred. If light smokers (≤10 cigarettes/day) or 
users of equivalent tobacco products (3 pipes/day, 2 cigars/day) are included, they shall have 
stopped smoking at least 14 days prior to study drug administration. Former smokers will have 
their tobacco use history quantified and recorded on the medical history section of CRF. Smoking 
or the use of tobacco products is not allowed during study hospitalization. 
 


 
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7.4.3.3 
Alcohol 
Subjects will not be permitted to drink alcoholic beverages for 48 hours prior to treatment 
administration and during the hospitalization period of the study. 
 
7.4.3.4 
Caffeine 
Subjects will not be permitted to drink caffeine-containing beverages (e.g., coffee, black tea, cola) 
or use caffeine or xanthine-containing products for 48 hours prior to treatment administration and 
during the hospitalization period of the study. 
 
7.4.3.5 
Exercise 
Subjects should refrain from rigorous exercise or physical exertion 48 hours prior to entering into 
the study and during the study. 
 
7.4.3.6 
Other Restrictions 
During non-confined study period, subjects should refrain from the use of nutraceuticals, vitamins 
at doses that exceed daily replacement requirements, and antacids. 
 
7.4.4 Procedures for Monitoring Subject Compliance 
At all protocol-specified visits, the investigator or qualified designee is to note in the administration 
record, and in the appropriate section of the CRF, whether treatment had been taken per protocol 
in the preceding period. If not, the date(s) and reason for each deviation must be recorded. Space 
is provided on the CRF, for explanatory comments. In addition, the study staff will maintain an 
ongoing record of the dispensing, administration and the return of all study medication for each 
subject on the IMP Accountability Log or equivalent document that will be verified by the study 
monitor. 
 
7.5 
Blood Sampling 
Part 1 
Approximately 310 mL of blood (± 5%) in overall will be collected from each subject in 
• 30 samples/subject, 120-mL in overall for narlaprevir pharmacokinetics 
• 4 samples/subject, 16-mL in overall for ritonavir pharmacokinetics 
• 26 samples/subject, 104-mL in overall for tenofovir pharmacokinetics 
• 1 sample/subject, 15-mL in overall for screening laboratory tests 


 
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• 6 samples/subject, 48-mL in overall for clinical laboratory tests 
Part 2 
Approximately 290 mL of blood (± 5%) in overall will be collected from each subject in 
• 30 samples/subject, 120-mL in overall for narlaprevir pharmacokinetics 
• 4 samples/subject, 16-mL in overall for ritonavir pharmacokinetics 
• 20 samples/subject, 80-mL in overall for raltegravir pharmacokinetics 
• 1 sample/subject, 15-mL in overall for screening laboratory tests 
• 6 samples/subject, 48-mL in overall for clinical laboratory tests 
 
Blood sampling has to be done at the indicated time points. In case the deviation is more than the 
criteria mentioned below, a comment has to be given in the comment section of the appropriate 
CRF page. 
 
Table 9 
Allowed time deviation without CRF comments 
Time period after dosing
Comment in CRF is needed when deviation is more 
0h < scheduled time ≤ 4h
2 min
4h < scheduled time ≤ 24h
10 min
scheduled time > 24h
60 min
Note: For pre-dose samples, a comment is required when the sample is withdrawn after dosing 
 
7.6 
Study Procedures 
An overview of the study is provided in the Study Design Diagram in Section 4.1.The Study Flow 
Chart in Section 4.2 summarizes the study procedures and the timing of the procedures to be 
performed at each visit. Individual study procedures are described below. 
For details of the procedures for assessment and reporting of AEs, see Section 7.7.2.4, 
Assessment and Reporting of Adverse Events. 
In order to minimize variability of evaluations, it is preferred that the same individuals perform the 
same types of evaluations on the same equipment for all subjects at each study site. 
 
7.6.1 Explain Study and Obtain Written Informed Consent 
The investigator or qualified designee will explain the study and all study requirements to the 
subject, answer all of his/her questions, and obtain written informed consent before performing any 
study-related procedure. A copy of the informed consent(s) will be given to the subject. 
Issue or Collect Subject Identification Card  
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after the subject provides written informed consent.  
7.6.2 Review Inclusion/Exclusion Criteria Including Concomitant Medications 
The inclusion and exclusion criteria will be reviewed by the investigator to ensure that the subject 
qualifies for the study. All appropriate medication and washout times will be discussed with the 
subject. All medications used during the 14 days prior to first drug administration or treatment 
intervention, will be recorded on the CRF. 
 
7.6.3 Demographic Profile 
The demographic profile required by the study CRF and permitted by local regulations should be 
entered. This information may include the subject's age (at baseline), ethnicity, gender and race. 
 
7.6.4 Physical Examination 
The investigator will perform a physical examination of the following organ systems at the times 
specified in Section 4.2, Study Flow Chart: Eyes, oropharynx, thyroid, respiratory system, 
cardiovascular system, abdomen, skin, extremities and reflexes 
Clinically significant changes from physical examinations will be recorded as adverse events. 
 
7.6.5 Medical History 
A detailed medical history will be obtained by the investigator. Subject history should include 
information on clinically significant family and personal history, smoking history, history of diseases 
including past history of hepatitis, allergies or reactions to medications and food, seizures, and 
previous surgery, trauma, syncope, arrhythmias. Any clinically relevant changes found at any time 
during the study will be recorded as adverse events on the CRF. 
 
7.6.6 Body Weight (kg) and Height Measurements (cm) Without Shoes 
Body weight should be performed on the same scale for the same individual. Measurements 
should be recorded to the nearest kg and cm and on the CRF. 
 
7.6.7 Body Mass Index (BMI) 
BMI should be calculated using the formula and recorded in the source document but not be 
recorded on the CRF: 
BMI = Weight (kg)/Height2 (m) 2. 
 
7.6.8 Test for HCV, hepatitis B Surface Antigen and HIV Antibodies, RW 


 
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Tests will be performed according to standard local procedures. A plan must be in place at the 
site(s) for the management of a positive test result according to local requirements. Results will be 
recorded on the CRF. 
 
7.6.9 Screen for Drugs With a High Potential for Abuse 
Urine tests for amphetamine, marijuana, morphine/heroin, cocaine, methamphetamine, 
barbiturates, benzodiazepines, phencyclidine, methadone and ecstasy (MDMA) will be conducted 
according to standard procedures. Positive results will be recorded on the Comment section of 
the CRF, and will be reported to the sponsor or CRO. 
 
7.6.10 
Clinical Laboratory Safety Tests 
The following will be performed according to standard laboratory procedures. Samples should be 
collected in the fasted state, (after an overnight fast for morning sample collections and at least 4 
hours without food for other samples) and prior to study drug administration. 
Table 10 
Standard laboratory procedures specification 
Hematology
Chemistry
Urinalysis
RBC
Sodium
pH
Hematocrit 
Potassium 
Specific gravity 
Hemoglobin
Chloride
Protein
Platelets
Glucose
Glucose
WBC 
Blood urea nitrogen (BUN) or UREA 
Ketones 
Neutrophils
Creatinine
Blood
Lymphocytes
Calcium 
Microscopic exam 
Monocytes 
Inorganic phosphorus 
 
Basophils
Total protein
Eosinophils
Albumin
AST (SGOT)
ALT (SGPT)
GGT
Total bilirubin
Alkaline phosphatase
Uric acid
LDH
Cholesterol
Triglycerides
 
The laboratory reference ranges should be available at site prior any laboratory testing is 
performed. If during the trial any laboratory result is outside the reference range and is considered 
to be clinically significant by the investigator, the test should be repeated at appropriate time 


 
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intervals until it returns to baseline or becomes a clinically insignificant finding. Any adverse 
clinically significant change will be recorded on the CRF as an Adverse Event. Laboratory tests will 
be recorded on the CRF. 
 
7.6.11 
Screening Number Assignment 
A screening number will be assigned to each subject on completion of the study-specific informed 
consent by the site. Screening numbers will be recorded on the CRF as per Section 7.4.1.3. 
 
7.6.12 
Randomization/Dosing Number Assignment 
A subject or randomization number will be assigned to each volunteer by the site using the 
subject/randomization numbers provided in Section 7.4.1.3. prior to the administration of 
narlaprevir treatment on Day1 of Period 1. 
 
7.6.13 
Record Adverse Events and Concomitant Medications 
See Section 7.7.2.4 and Section 7.7.2.5, Assessment and Reporting of Adverse Events; Section 
7.4.2, Non-study Treatments; Section 7.3.3, Discontinuation Criteria. 
 
7.6.14 
Clinical Assessment of Electrocardiograms 
7.6.14.1 
Local ECGs 
The 12-lead ECG (12-lead at 25 mm/sec reporting rhythm, ventricular rate, PR, QRS, and QT 
intervals) will be performed by the principal investigator or designee after the subject has been in 
the supine position for at least 5 minutes. 
A commercial 12-lead electrocardiograph should be used. On the electrocardiograph should be 
recorded the date, time, subject demographics (e.g., age, and sex), subject number, and study- 
related information (e.g., protocol number and nominal time) 
When a study assessment and ECG are in conflict, the ECG should be performed before the meal, 
pharmacodynamic or pharmacokinetic blood sample or at least 5 minutes afterward. This same 
timing for obtaining the ECG (i.e., before or after the blood collection) should be used for all ECG 
recordings. For a given subject all Baseline and post- treatment ECGs should be performed using 
the same ECG machine. Predose ECGs should be performed within 30 minutes prior to the 
scheduled time of drug administration. 
QTcB will be calculated by Bazett's formula: 
 


 
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where QTcB is the QT interval corrected for heart rate, and RR is the interval from the onset of one 
QRS complex to the onset of the next QRS complex, measured in seconds, often derived from the 
heart rate (HR) as 60/HR (here QT is measured in milliseconds). 
 
7.6.15 
Vital Signs 
The pretreatment vital signs will be considered the Baseline values. Vital signs will be obtained by 
the principal investigator or designee. Subjects will be in a seated or supine position for at least 3 
minutes. 
Systolic and diastolic blood pressure (mm Hg), pulse rate (bpm) and axilar body temperature (°C) 
and the actual clock time (24:00) will be recorded on the CRF. Any clinically significant change 
from baseline for vital sign measurement (not associated with another adverse event) will be 
recorded on the adverse event CRF form. 
All blood pressure measurements should be made by consistently using the same arm and type of 
equipment with an appropriate cuff size. Pulse rate should be obtained manually by radial pulse 
palpation over a 30 second count or by a validated automated electronic device. 
Body temperature should be measured consistently using the same approach.  
For detailed schedule of vital signs measurement see Section 4.2. 
If the scheduled time for vital sign measurements coincides with a blood collection, the vital signs 
should be performed prior to the blood collection, or at least 15 minutes afterwards. This same 
timing for obtaining the vital signs (before or after the blood collection) should be used for all vital 
sign measurements. 
 
7.6.16 
Treatment Administration 
Refer to Section 7.4 for Study Treatments to be administered. The time of dose administration 
should be recorded in CRF for each onsite dose administration. 
 
7.6.17 
Blood Samples for Determination of Plasma Concentrations of narlaprevir 
4 mL of blood will be collected at the specified time points indicated in Section 4.2, Study Flow 
Chart, into the appropriate tubes (see Laboratory Manual for sample acquisition, shipping and 
labeling instructions).  
Sample collection times (actual clock time using 24:00) are to be recorded in the CRF. 
Sample collection time deviations will be determined using the actual collection times provided and 
do not need to be recorded in the CRF. However, any other deviation (e.g., missed sample, broken 
sample, inappropriate sample handling, etc) must be recorded on the comments page of the CRF. 
 
7.6.18 
Blood Samples for Determination of Plasma Concentrations of Ritonavir 


 
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4 mL of blood will be collected at the specified time points indicated in Section 4.2, Study Flow 
Chart, into the appropriate tubes (see Laboratory Manual for sample acquisition, shipping and 
labeling instructions). Sample collection times (actual clock time using 24:00) are to be recorded in 
the CRF. 
Sample collection time deviations will be determined using the actual collection times provided and 
do not need to be recorded in the CRF. However, any other deviation (e.g., missed sample, broken 
sample, inappropriate sample handling, etc) must be recorded on the comments page of the CRF. 
 
7.6.19 
Blood Samples for Determination of Plasma Concentrations of Tenofovir 
4 mL of blood will be collected at the specified time points indicated in Section 4.2, Study Flow 
Chart, into the appropriate tubes (see Laboratory Manual for sample acquisition, shipping and 
labeling instructions). 
Sample collection times (actual clock time using 24:00) are to be recorded in the CRF. 
Sample collection time deviations will be determined using the actual collection times provided and 
do not need to be recorded in the CRF. However, any other deviation (e.g., missed sample, broken 
sample, inappropriate sample handling, etc) must be recorded on the comments page of the CRF. 
 
7.6.20 
Urine Samples for Determination of Tenofovir Pharmacokinetics 
Subjects will be instructed to void prior to dose administration and the urine will be collected as the 
predose sample. Two 50 mL aliquots of predose urine will be obtained from the well-mixed 
predose urine collection. All urine will be subsequently collected and pooled according to the 
collection intervals indicated in Section 2.2, Study Flow Chart. At the end of each collection 
interval, subjects will be instructed to empty their bladder, this urine added to the present pooled 
urine, and this will mark the end of the present collection interval and the beginning of the next 
collection interval. The total volume of the urine from postdose collection will be recorded for each 
subject. 
All urine will remain refrigerated or on ice during the collection intervals. Two 50 mL aliquots of 
urine will be obtained from each well- mixed, pooled urine collection interval and transferred into 
the appropriate tubes (see Laboratory Manual for sample acquisition, shipping and labeling 
instructions). Two aliquots will be used for profiling (primary and backup). 
 
7.6.21 
Blood Samples for Determination of Plasma Concentrations of Raltegravir 
4 mL of blood will be collected at the specified time points indicated in Section 4.2, Study Flow 
Chart, into the appropriate tubes (see Laboratory Manual for sample acquisition, shipping and 
labeling instructions). 
Sample collection times (actual clock time using 24:00) are to be recorded in the CRF. 
Sample collection time deviations will be determined using the actual collection times provided and 


 
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do not need to be recorded in the CRF. However, any other deviation (e.g., missed sample, broken 
sample, inappropriate sample handling, etc) must be recorded on the comments page of the CRF. 
 
7.7 
Study Assessments and Analysis 
7.7.1 Pharmacokinetics/Pharmacodynamics/Safety 
7.7.1.1 
Pharmacodynamics 
Not applicable for this study. 
 
7.7.1.2 
Pharmacokinetics 
For detection of study drug concentrations in plasma or urine (for tenofovir) HPLC-MS (High 
performance liquid chromatography - mass spectrometry) method will be used [32-35]. Details on 
the planned methods are provided below: 
Mobile phase A: 0,2 % formic acid 
Mobile phase B: acetonitrile 
Sample preparation will be performed by the protein precipitation with an organic solvent. 
Chromatographic conditions: 
Chromatograph: 
High performance liquid chromatograph Shima-dzu LCMS-
8040, equipped with two high-pressure pumps, online 
degasser of mobile phase, column thermostat, autosampler 
for 192 samples and mass-detector with triple quadrupole or 
similar device can be used. 
Column 
Reprosil Pur Basic C18, 1.9 um, 2x50 mm. An alternate 
column that met the requirements of system can be used 
Mobile phase 
Mixture of  mobile phase А and  mobile phase В 
Flow velocity 
0,5 ml/min for Narlaprevir and Tenofovir; 0,4 ml/min for 
Ritonavir and Raltegravir 
Mass -detector 
Ionization method is electrospray (ES+) for Narlaprevir and 
Tenofovir and positive ionization (MRM (E+)) for Ritonavir 
and Raltegravir. Detection is carried out by the typical ion-
product obtained from the fragmentation of the target 
substance in the collision cell 
Column temperature 
25 °С for Narlaprevir and Tenofovir; 40 °С for Ritonavir and 
Raltegravir 
Sample volume 
20 ul for Narlaprevir and Tenofovir; 10ul for Ritonavir and 
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In order to meet the suitability test requirements of the chromatographic system adjustment of the 
chromatographic conditions will be allowed. 
Standard solution should be chromatographed at least 3 times to check the suitability of the 
system. 
The chromatographic system will be considered suitable if the following conditions are met: 
• 
chromatographic column efficiency calculated by the analyte peak on the chromatogram of 
the standard solution is not less than 2000 theoretical plates; 
• 
asymmetry factor calculated for the analyte peak on the chromatogram of the standard 
solution is not more than 2.0; 
• 
the retention factor (k ') should be greater than 2.0; 
To obtain high accuracy quantitative results with mass-spectrometric detection, analyte labeled 
with stable isotopes will be used as an internal standard (e.g., narlaprevir d5, tenofovir d9, ritonavir 
d6, raltegravir d3). 
Analyte concentration will be calculated using special software (Analyst for Narlaprevir and 
Tenofovir and LabSolutions 5.75 for Ritonavir and Raltegravir) with the calibration curve 
normalized by the chromatographic peak area of the analyte. A linear function normalized as 1/x 
will be used as calibration curve for Narlaprevir and Tenofovir. A linear function normalized as 1/x2 
will be used as calibration curve for Ritonavir and Raltegravir. 
Estimated calibration ranges: 10 - 10000 ng/ml for Narlaprevir, 10 - 2000 ng/ml for Tenofovir, 5 - 
1000 ng/ml for Ritonavir, 10 - 10000 ng/ml for Raltegravir. 
Part 1 
Individual plasma narlaprevir and tenofovir concentration data will be used to estimate the 
following primary pharmacokinetic variables, for the determination of bioavailability comparisons: 
AUC(tau) 
Area under the concentration-time curve during a dosing  interval τ 
at steady state 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration during a dosing interval τ 
at steady state 
 
Tenofovir only: 
Ae (24) - 
Amount excreted in 24 hours at steady-state CLr- Renal clearance 
(Ae/AUC) at steady-state 
The following additional parameters will be evaluated, if appropriate: 


 
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t1/2 
Terminal phase (elimination) half-life 
CL/F 
Apparent total body clearance 
V/F 
Apparent volume of distribution 
 
Predose plasma ritonavir concentration data may be used to estimate Ctrough. 
 
Part 2 
Individual plasma narlaprevir and raltegravir concentration data will be used to estimate the 
following primary pharmacokinetic variables, for the determination of bioavailability comparisons: 
AUC(tau) 
Area under the concentration-time curve during a dosing 
interval τ at steady state 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration during a dosing interval τ 
at steady state 
 
The following additional parameters will be evaluated, if appropriate: 
t1/2 
Terminal phase (elimination) half-life 
CL/F 
Apparent total body clearance 
V/F 
Apparent volume of distribution 
 
Predose plasma ritonavir concentration data may be used to estimate Ctrough. 
 
7.7.1.3 
Pharmacokinetics-Pharmacodynamics 
Not applicable for this study. 
 
7.7.1.4 
Interpharmacodynamic (PD-PD) and Safety-PD Analysis 
Not applicable for this study. 
 
7.7.2 Safety Monitoring and Assessments 
7.7.2.1 
Specification of Safety Variables 
Adverse events will be tabulated by treatment group, BSOC, and severity. ECGs and clinical 


 
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safety laboratory values will be listed by date and time, values and changes from baseline will be 
tabulated using summary statistics. Vital signs will be listed by day and time. 
7.7.2.1.1 Assessment and Reporting of Adverse Events 
Adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical-trial 
subject administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
All adverse events must be recorded into the CRF with the following information: 
• 
the severity grades using the categories mild / moderate / severe;  
• 
its relationship to the study drug(s): unassessable, conditional, unlikely, possible, 
probable, certain, unrelated 
• 
its duration (onset and stop dates or if ongoing at final exam); 
• 
its outcome 
• 
the actions taken (no actions taken; study drug(s) permanently discontinued due to this 
adverse event; concomitant medication given; non-drug therapy given; subject 
hospitalized/subject’s hospitalization prolonged; 
• 
whether it constitutes a serious adverse event (SAE) (see the criteria in the section 
7.7.2.2.1). 
All non-serious AEs must be collected and evaluated from initiation of treatment with study drugs 
through the last study visit. Non-serious AEs that occur before this time are to be listed in the 
«Medical History» section of the CRF.  
Information about common side effects already known about the study drugs can be found in the 
Investigator Brochure (for investigational drug) or in the approved Product Information (for 
marketed medications). This information will be included in the subject informed consent and 
should be discussed with the subject during the study as needed. 
7.7.2.2 
Assessment of Adverse Events Severity and Relationship to Treatment 
Severity  
The investigator should use the following definitions to rate the severity of any adverse event being 
collected:  
• 
Mild: an experience that is usually transient and requires no special treatment or 
intervention. The experience does not generally interfere with usual daily activities. Includes 
transient laboratory test alterations. 
• 
Moderate: an experience that is alleviated with simple therapeutic treatments. The 
experience impacts usual daily activities. Includes laboratory test alterations indicating 
injury, but without long-term risk. 
• 
Severe: an experience that requires therapeutic intervention. The experience interrupts 
usual daily activities. 
 


 
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Relationship to Treatment  
The investigator should use the following definitions for any adverse event being collected to 
assess the relationship of the adverse event to the use of the study treatment combination:  
• 
Unassessable 
• 
Conditional  
• 
Unlikely 
• 
Possible 
• 
Probable 
• 
Certain 
• 
Unrelated 
 
Certain 
• 
Event or laboratory test abnormality, with plausible time 
relationship to drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, 
pathologically) 
• 
Event definitive pharmacologically or phenomenologically (i.e. 
an objective and specific medical disorder or a recognised 
pharmacological phenomenon) 
• 
Rechallenge satisfactory, if necessary 
Probable 
• 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required  
Possible 
• 
Event or laboratory test abnormality, with reasonable time 
relationship to drug intake 
• 
Could also be explained by disease or other drugs 
• 
Information on drug withdrawal may be lacking or unclear 
Unlikely 
• 
Event or laboratory test abnormality, with a time to drug intake 
that makes a relationship improbable (but not impossible) 
• 
Disease or other drugs provide more plausible explanations 
Conditional 
• 
Event or laboratory test abnormality 
• 
More data for proper assessment needed, or 
• 
Additional data under examination 
Unassessable  
• 
Report suggesting an adverse reaction 
• 
Cannot be judged because information is insufficient or 
contradictory 
• 
Data cannot be supplemented or verified 


 
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Unrelated 
• 
Another cause of the event is the most plausible; and/or  
• 
A clinically plausible temporal sequence is inconsistent with the 
onset of the event and the study intervention and/or 
• 
A causal relationship is considered biologically implausible 
If an investigator's opinion of possible, unlikely, unrelated to drug was given, an alternate aetiology 
had to be provided by the investigator for the adverse event (e.g., concomitant treatment, illness, 
study procedures, etc).  
7.7.2.2.1 Monitoring of Adverse Events 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent. An assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drugs, the interventions required 
to treat it, and the outcome. All adverse events should be treated appropriately. Any actions taken 
and follow-up results must be recorded on the appropriate page of the CRF and in the subject’s 
source medical documents.   
Definition of Serious Adverse Events  
Serious Adverse Event (SAE): any untoward medical occurrence or reaction that meets any of 
the following criteria: 
• 
Results in death; 
• 
Is life-threatening (Life threatening in this context refers to a reaction in which the 
subject was at risk of death at the time of the reaction; it does not refer to a reaction 
that hypothetically might have caused death if more severe); 
• 
Requires in-subject hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability or incapacity; 
• 
Is a congenital anomaly/birth defect in fetus or child born to a subject administered the 
drug; 
• 
Other medically important event (Medical and scientific judgment should be exercised 
in deciding whether other situations should be considered serious reactions, such as 
important medical events that might not be immediately life threatening or result in 
death or hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of 
dependency or abuse). 
SAEs must be reported from the time subject’s written consent and enrollment to participate in the 
clinical trial through the time of the last visit. SAEs that occur after this time with suspected 
association to the investigational drug or clinical trial procedures must also be reported to the 
company-sponsor.  
Information about all SAEs is collected and recorded on the standard form «Serious Adverse 
Event Report». Investigator must complete the Serious Adverse Event Report Form and send the 
copy of it to “Almedis” CJSC drug safety responsible person on safety@almedis.ru or by fax +7 
495 937 43 19 immediately or within 24 hours. The original copy of the SAE Report Form must be 


 
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kept with the subject’s documentation at the study site. 
All SAEs should be followed up until stable or resolved, i.e. a final outcome is reached. Any follow-
up information that is obtained must be forwarded to the company-sponsor observing the same 
timelines as for initial reports (within 24 hours). Follow-up information is sent to the same person to 
whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a 
follow-up to the previously reported SAE and giving the date of the original report. The follow-up 
information should describe whether the event has resolved or continues, if and how it was treated 
and whether the subject continued or withdrew from study participation.  
All SAEs will be collected and reported to the competent authorities in accordance with the 
applicable regulations. .Drug safety responsible person or designee is responsible for notification 
of all principal investigators involved in clinical study about all new relevant Suspected Unexpected 
Serious Adverse Reactions (SUSARs), which were revealed in ongoing clinical studies of the 
medicinal product. Investigator notifications are made by fax or e-mail. Cover letter in standard 
format has to be sent along with SUSARs. After receiving and reading of SUSAR notification, the 
Investigator or designee have to fax or send by e-mail signed Investigators Notification Form to 
“Almedis” CJSC  DSPV on +7 495 937 43 19, safety@almedis.ru and submit information about 
SUSAR to the Local Ethics Committee of the medical institution for information. 
7.7.2.2.2 Reporting of Pregnancies  
Each pregnancy in the female partners of any males who took study drugs in this study must be 
reported to the company-sponsor within 24 hours of learning of its occurrence. Pregnancy 
outcomes should be collected.  
The Pregnancy Report Form must be used for reporting pregnancies and must be completed for 
any subject who becomes pregnant after dosing of study drugs. Pregnancy Report Form must be 
submitted to the company-sponsor according to SAE reporting requirements. 
Pregnancy is to be handled as a non-serious event, unless it is falls into one of the following 
categories: 
• 
Reports of congenital anomalies in the foetus/child; 
• 
Reports of foetal death; 
• 
Spontaneous abortions; and 
• 
Reports of adverse reactions in the neonate that are classified as serious. 
7.7.2.2.3 Preplanned Hospitalizations or Procedures  
Not applicable  
7.7.2.3 
Reporting of Investigational Medicinal Product Quality Complaints 
Any defect or possible defect in an investigational medicinal product (defined as a pharmaceutical 
form of an active substance or placebo being tested or used as a reference in a clinical trial) must 
be reported by the investigator to the designated sponsor representative within 24 hours of first 
becoming aware of the possible defect.  This report to the sponsor may be made by telephone, or 


 
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by e-mail, or by faxing the quality complaint to the designated sponsor representative.  The 
product and packaging components in question, if available, must be stored in a secure area under 
specified storage conditions until it is determined whether the product is required to be returned for 
investigation of the defect.  If the product complaint is associated with a SAE, the SAE must be 
reported separately in accordance with the protocol, and the SAE report should mention the 
product quality complaint.  
7.7.2.4 
Monitoring 
Before the study initiation a company-sponsor representative will review the protocol and CRF with 
the investigators. During the study a monitor will visit the clinical sites regularly to check the 
completeness of subject’ source documents, the accuracy of entries on the CRFs, the adherence 
to the protocol, Good Clinical Practice and local regulatory requirement, the progress of 
enrollment, and to ensure that study drugs are being stored, dispensed, and accounted for 
according to specifications. In addition, a monitor will visit the clinical sites to monitor at least the 
first dosing to check the conduction of study procedures at dosing visits, adherence to the protocol, 
Good Clinical Practice and local regulatory requirements. Investigators and other appropriate study 
personnel must be available to assist a monitor during these visits.  
The investigator must maintain source documents, including all demographic and medical 
information, laboratory data, and the results of any other assessments for each subject in the 
study. The investigator also has to keep signed copy of informed consent for each subject.  
The investigator must give a monitor access to all relevant source documents to confirm their 
consistency with the CRF data. Checks of the consistency of the source data with the CRFs will be 
performed according to the study-specific monitoring plan. No information in source documents 
about the identity of the subjects will be disclosed. 
7.7.2.4.1 Monitoring Laboratory Assessments 
The clinical laboratory values will be reviewed by the investigator for significance and consideration 
as an AE. 
 
7.7.2.5 
Discontinuation, Treatment Interruption Due to Safety Reasons 
7.7.2.5.1 Discontinuation 
See Section 7.3.3 for the criteria by which a subject must be discontinued. Should a subject be 
discontinued from the trial, complete the visit activities as specified for discontinuation in the Trial 
Flow Chart in Section 4.2. 
7.7.2.5.2 Temporary Interruption of Treatment for a Subject 
A subject may not temporarily interrupt and then restart treatment. The investigator is to 
discontinue a subject if necessary according to the criteria provided in Section 7.3.3 . 
 


 
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7.8 
Criteria for Early Termination of the Trial 
There are no prespecified criteria for terminating the trial early. 
 
8 
STATISTICAL ANALYSIS AND REPORTING PLANS 
Approximately 36 subjects with 18 in each of two are expected to be randomized/enrolled in the 
study and receive treatments. 
8.1 
Data Sets 
The pharmacokinetic analysis will only include subjects who received at least one dose of 
treatment and who have at least one non-missing measurement of concentration. All subjects who 
are assigned a Randomization Number or Subject Number and who received at least one dose of 
treatment will be included in the safety analyses. 
8.2 
Demographic and Other Baseline Characteristics 
Demographic variables (e.g., sex, race, age, weight) will be listed and summarized using 
descriptive statistics for the entire study population and for each part of study. 
 
8.3 
Pharmacodynamic and Pharmacokinetic Analyses 
8.3.1 Pharmacokinetic Parameters 
Mean plasma concentrations of drug along with the derived PK parameters will be summarized by 
treatment separately for each part (cohort). 
The primary PK parameters for Parts 1 and 2 are narlaprevir Cmax and AUC. All data will be log-
transformed before analysis. An ANOVA model on log-transformed PK parameters with treatment, 
period, sequence treated as fixed effects and subject nested within sequence treated as random 
effect will be used to obtain an estimate of intra-subject variability. Estimates of the adjusted mean 
differences and corresponding 90% confidence intervals will be constructed. The resulting 
estimates will be exponentiated to provide the adjusted geometric mean ratios for the 
untransformed parameters with the corresponding 90% CIs for the ratios. No formal confirmatory 
hypothesis testing is planned. 
Part 1 
Log transformed Cmax and AUC for narlaprevir and tenofovir will be analyzed separately. For 
narlaprevir, the primary comparison will be treatment C vs. A; and for tenofovir the primary 
comparison will be treatment C vs. B. 
Part 2 
Log transformed Cmax and AUC for narlaprevir and raltegravir will be analyzed separately. For 
narlaprevir, the primary comparison will be treatment C vs. A; and for raltegravir the primary 
comparison will be treatment C vs. B. 
 


 
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8.3.2 Pharmacodynamics 
Not applicable for this study. 
 
8.3.3 Pharmacokinetic-Pharmacodynamic Analysis 
Not applicable for this study. 
 
8.3.4 Pharmacodynamic-Pharmacodynamic Analysis 
Not applicable for this study. 
 
8.4 
Determination of Sample Size/Power/Level of Significance 
Based on study P04986 (see Investigator Brochure) and reference [32], the inter-subject variability 
(CV%) for narlaprevir (tablet) Cmax and AUC is estimated to be about 33%; the inter-subject 
variability (CV%) for narlaprevir Cmax and AUC when coadministered with ritonavir is estimated to 
be about 20%. Assuming the intra-subject variability (CV%) is about 70% of the inter, the intra-
subject variability (CV%) for narlaprevir and narlaprevir coadministered with ritonavir Cmax and 
AUC is estimated to be about 23% and 14%, respectively. 
Part 1 
The intra-subject variability (CV%) for tenofovir is assumed approximately 20% (10-15% for 
AUC24h and 15-20% for Cmax) as a maximum value estimated from the published CIs [22, 23, 
24], the expected difference is set to 0 (Ratio = 1.00).  
The study with 18 subjects will detect an increase in exposure of 22% or a decrease of 18% 
between tenofovir coadministered with narlaprevir and ritonavir vs. tenofovir alone with 80% power 
and alpha=0.1 two sided. 
The study with 18 subjects will detect an increase of 15% or a decrease of 13% exposure between 
narlaprevir coadministered with ritonavir and tenofovir vs. narlaprevir coadministered with ritonavir 
with 80% power and alpha=0.1 two sided. 
Part 2 
The sample size for Part 2 will be 18.  
For raltegravir, sample size calculations were based on intrasubject CV% of 45% for AUC12h and 
60% for Cmax [25-29]. CVs estimated from the published CIs are 35-50% for AUC and 40-70% for 
Cmax. 
The study with 18 subjects will detect an increase of 55% or a decrease of 35% exposure (AUC)  
as well as detect an increase of 76% or a decrease of 43% Cmax  between raltegravir 
coadministered with narlaprevir and ritonavir vs. raltegravir alone with 80% power and alpha=0.1 
two sided. 
The study with 18 subjects will detect an increase of 15% or a decrease of 13% exposure between 


 
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narlaprevir coadministered with ritonavir and raltegravir vs. narlaprevir coadministered with 
ritonavir with 80% power and alpha=0.1 two sided. 
8.5 
Interim Analysis 
Data may be analyzed after completion of each part or at the end of the study.  
 
8.6 
Safety 
8.6.1 Adverse Events 
All AEs noted during the study will be listed. Treatment emergent and treatment-related AEs will be 
tabulated by body system/organ class and preferred term. Summaries of severity and relationship 
to treatment will also be provided. 
 
8.6.2 Clinical Laboratory Tests 
The results of hematology and blood chemistry will be listed for each subject. Laboratory values 
outside the normal ranges will be flagged. Summary statistics by treatment will be provided for 
laboratory values at each time point and for change from baseline. Baseline is defined as the 
predose time point. 
 
8.6.3 Vital Signs 
Systolic and diastolic blood pressure, heart rate, and body temperature will be listed for each 
subject. Summary statistics by treatment at each time point will be provided. Baseline is defined as 
the predose time point. 
 
8.6.4 Physical Examination 
The results of the physical examinations at Screening, and Pre-Dose visits will be listed in the 
medical history. Post-baseline findings of the physical examinations that meet the criteria of an AE 
(Section 7.7.2.2.1) will be listed in the relevant AE listings. 
 
8.6.5 Electrocardiogram 
The results of the ECG will be listed for each subject. If applicable, summary statistics of ECG 
results will be provided. 
 
8.6.6 Other Safety 
Not applicable. 
 


 
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9 
ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE CONSIDERATIONS 
This study was designed and shall be implemented and reported in compliance with Good Clinical 
Practice (GCP), with applicable local regulations (including RF National Standard “Good Clinical 
Practice”), and with the ethical principles laid down in the Declaration of Helsinki.  
 
9.1 
Ethical Conduct of the Study 
9.1.1 Independent Ethics Committee or Institutional Review Board 
Prior to initiation of the trial at any site, the trial, including the protocol, informed consent, and other 
trial documents must be approved by an appropriate Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). The IRB/IEC must be constituted according to applicable 
regulatory requirements. As appropriate, amendments to the protocol must also be approved by 
the IRBs/IECs before implementation at the sites, unless warranted to eliminate an immediate 
hazard. The IRB/IEC approval should be obtained in writing, clearly identifying the trial, the 
documents reviewed (including informed consent), and the date of the review. The trial as 
described in the protocol (or amendment), informed consent, and other trial documentation may be 
implemented only after all the necessary approvals have been obtained and the sponsor has 
confirmed that it is acceptable for the investigator to do so. 
In the event that the IRB/IEC requires changes in the protocol, the sponsor shall be advised and 
must approve the changes prior to implementation. The investigator shall not modify the trial 
described in the protocol once finalized and after approval by the IRB/IEC without the prior written 
approval of sponsor. 
If the investigator submits the trial protocol and statement of informed consent to the IRB/IEC, the 
investigator or qualified designee will forward the approvals to the sponsor. 
 
9.1.2 Subject Information and Consent 
The details of the protocol must be provided in written format and discussed with each potential 
subject, and written informed consent must be obtained for all subjects before any trial-related 
procedure is performed. In obtaining informed consent, the information must be provided in 
language and terms understandable to the subject. The subject must give their written consent to 
participate in the trial. The signed and dated consent form itself must be retained by the 
investigator as part of the trial records. A copy of the signed and dated consent form must be given 
to the subject. The consent form must include all of the required elements of informed consent in 
accordance with ICH Guidelines E6 and local laws. In addition, the sponsor specifically requests 
that the consent form identify it as the sponsor and state that use of the investigational product(s) 
is experimental and the side effects of the investigational product(s) are not completely known. The 
consent form must be approved by the appropriate IRB/IEC and sponsor before trial initiation at a 
trial site. Any subsequent changes to the approved informed consent form must be reviewed and 
approved by the appropriate IRB/IEC and sponsor before implementation.  
 


 
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9.1.3 Subject Identification Card  
A Subject Identification Card will be provided to each subject to carry on his or her person (e.g., in 
a wallet) at all times while the subject is participating in the trial, if required in Section 4.2. The 
card is to be shown to caregivers in the event of an emergency. 
At a minimum, the card must contain the following information: 
1. 
Protocol number; 
2. 
The subject’s protocol identification number; 
3. 
A statement identifying the card-carrier as a participant in a clinical trial (e.g., “This person 
is participating in a clinical research trial.”); 
4. 
A statement indicating the person might be taking an investigational drug (e.g., “This 
person is taking an experimental drug which could have interactions with other medications, or 
placebo”); and 
5. 
Contact information in the event of an emergency or hospitalization. The contact 
information on the card is to be the investigator or a designated site contact, rather an contact from 
within the sponsor; 
The cards may also include other trial-specific information to assist with treatment decisions in the 
event of an emergency, such as types of concomitant therapies that may, or may not be, permitted 
as part of emergency treatment. As with any other information provided to subjects, the Subject 
Identification Card must be approved by the IRB/IEC. Monitors will request that Investigators 
provide Subject Identification Cards to each subject. Investigators will be asked to request that 
subjects carry the cards with them while they are participating in the trial. 
 
9.2 
Reporting Trial Data to the Sponsor 
9.2.1 Data Collection Forms 
The sites will be provided with data collection forms (paper Case Report Forms (CRF),); and other 
appropriate data collection forms as the trial requires. The investigator is to provide subject data 
according to the given instructions, in the designated data collection form, compliant with GCP 
practices. The sites will be also provided with instructions for assisting other parties - such as a 
central laboratory - to collect data. As instructed by the Sponsor, a designated central laboratory 
may collect data in a database and provide the completed database to sponsor and/or CRO. All 
data collection forms and the databases from the trial are the exclusive property of sponsor. 
The investigator must maintain records and data during the trial in compliance with all applicable 
legal and regulatory requirements. Each data point must be supported by a source document at 
the trial site. Any records or documents used as the source of information (called the “subject 
source data”) are to be retained for review by authorized representatives of the sponsor or a 
regulatory agency.  
The investigator will ensure that there are sufficient time, staff, and facilities available for the 


 
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duration of the trial to conduct and record the trial as described in the protocol and according to all 
applicable guidances, laws, and regulations. 
All data collection forms (CRFs) should be completed as soon as possible after the evaluation has 
occurred. All dates appearing on the subject data collection forms for laboratory tests, cultures, 
and other data collected, must be the dates on which the specimens were obtained, or the 
procedures performed. 
 
9.2.2 Preparing Case Report Forms for All Subjects  
Subject names, initials, or other personal information that is beyond the scope of the trial from any 
subject should not be collected. Subjects are not to be identified by name or initials on the CRF or 
any trial documents. The only acceptable identification for a subject that may appear on a CRF or 
trial document is the unique subject identification number. The investigator must maintain contact 
information for each participant so that all can be quickly contacted by the investigator, if 
necessary. All entries into CRFs are the responsibility of the investigator and must be completed 
by the investigator or a qualified designee.  
 
9.3 
Publications and Other Rights 
9.3.1 Use of Trial Information in a Publication 
The company-sponsor (R-Pharm) has sole ownership of all data, results, reports, and any other 
information collected and full rights of publication based on data from this study and will maintain 
full access to the database. 
Upon the study completion and finalization of the clinical study report the results of this trial will be 
submitted for publications. Publications will be based on data from all centers, analyzed as 
stipulated in the protocol. The investigator agrees not to publish or publicly present any interim 
results of the study or data gathered from one center or a small group of centers before the global 
publication without the prior written consent of the sponsor. The investigator further agrees to 
provide to the sponsor prior to submission for publication or presentation, review copies of 
abstracts or manuscripts for publication that report any results of the study. The sponsor shall have 
the right to review and comment with respect to publications, abstracts, slides, and manuscripts 
with regard to the following concerns: 
• 
Proprietary information that is protected by the provisions contained in; 
• 
The accuracy of the information contained in the publication;  
• 
To ensure that the presentation is fairly balanced and in compliance with applicable 
regulations; 
• 
Others. 
 
9.4 
Trial Documents and Records Retention 
During the trial and after termination of the trial – including after early termination of the trial – the 
investigator 
must 
maintain 
copies 
of 
all documents and records relating to the conduct of 


 
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the trial. This documentation includes, but is not limited to, protocols, CRFs and other data 
collection forms, advertising for subject participation, adverse event reports, subject source data, 
correspondence with health authorities and IRBs/IECs, consent forms, investigator’s curricula 
vitae/biosketch, monitor visit logs, laboratory reference ranges, and laboratory certification or 
quality control procedures and laboratory director curriculum vitae. Subject files and other source 
data must be kept for the maximum period of time permitted by the hospital, institution or private 
practice, or as specified below. The sponsor must be consulted if the investigator wishes to assign 
the files to someone else, remove them to another location, or is unable to retain them for the 
specified period. 
The investigator must retain trial records for the amount of time specified by applicable laws and 
regulations. At a minimum, trial records must be retained for the amount of time specified by ICH 
Guidelines or the EU Good Clinical Practices Directive, whichever is longer: 
1. 
The ICH Guidelines specify that records must be retained for a minimum of 2 years after a 
marketing application for the indication is approved (or not approved) or 2 years after notifying the 
appropriate regulatory agency that an investigation is discontinued. 
2. 
The EU GCP Directive specifies that trial records must be retained for 5 years after the 
completion of the trial. 
All trial documents shall be made available if required by relevant health authorities, specialists, 
authorized by sponsor, and audits. The investigator should consult with the sponsor prior to 
discarding trial and/or subject files. 
Sponsor will retain all required documentation pertaining to the trial for the lifetime of the 
investigational product.   
 
10 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
10.1 Sponsor 
The sponsor of this study is the JSC «R-Pharm». 
10.2 Investigators 
10.2.1 
Selecting Investigators 
Only investigators qualified by training and experience to perform a clinical investigation with 
narlaprevir are selected. The sponsor will contact and select all investigators (i.e., the legally 
responsible party[ies] at each trial site), who, in turn, will select their staff. 
10.2.2 
Clinical Study Report Coordinator Investigator 
A Clinical Study Report (CSR) will be prepared by the sponsor or its qualified designee to describe 
the results of the trial. One of the investigators shall be selected by the sponsor to provide approval 
of the final CSR in writing. The investigator chosen to review and approve the CSR is to be called 
the CSR Coordinating Investigator. The sponsor is to select the CSR Coordinating Investigator 
from the investigators using the following criteria: 
1. 
Must be the Principal Investigator at a trial site actively enrolling subjects and participating 


 
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in the trial; 
2. 
Must be willing and capable of providing approval of the CSR in writing. 


 
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11 REFERENCES 
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inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob 
Agents Chemother. 2007 Oct;51(10):3498-504. 
2. Iwamoto M, Wenning LA, Petry AS, et al. Minimal effects of ritonavir and efavirenz on the 
pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008 Dec;52(12):4338-43 
3. Summary Basis of Approval for Ritonavir. 
4. Taremi S, Beyer BM, Maher M, et al. Construction, expression, and characterization of a 
novel fully activated recombinant single-chain hepatitis C virus protease. Prot Sci. 
1998;7:2143-2149. 
5. Beyer BM, Zhang R, Hong Z, et al. Effect of naturally occurring active site mutations on 
hepatitis C virus NS3 protease specificity. Proteins. 2001;43:82-88. 
6. Zhang R, Beyer BM, Durkin J, et al. A continuous spectrophotometric assay for the hepatitis 
C virus serine protease. Anal Biochem. 1999;270:268-275. 
7. Van Heeswijk R et al. [abstract 119] and Kassera C et al [abstract 118], 18th Conference on 
Retroviruses and Opportunistic Infections; Boston, MA. February 27-March 2, 2011 
8. Investigator’s Brochure. Information for the Investigational Product narlaprevir (SCH 
900518). 2014. 
9. Vierling J., Poordad F., Lawitz E., et al. Once daily narlaprevir (SCH 900518) in combination 
with PegIntron (peginterferon alfa-2b)/ribavirin for treatment-naive subjects with genotype-1 
CHC: interim results from NEXT-1, a phase 2a study. 60th Annual Meeting of the American 
Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 
1, 2009. Abstract LB4. 
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weeks PR in treatment-naive patients with HCV genotype 1 (G1): SVR results from next-1, a 
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chronic hepatitis C patients. Hepatology, 2010, 52(5), 1590-1599. 
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significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease 
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Biomed Life Sci. 2009 Jul 1; 877(20-21): 1907–1914 
 
 
 


 
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Appendix 1  Known Potential Toxicities of Investigational Products 
Ritonavir 
Raltegravir 
Tenofovir 
Very common (may affect more than 1 in 10 people) 
• upper and lower stomach ache
• diarrhoea, being sick 
(vomiting), feeling sick 
(nausea), dizziness
• vomiting 
 
Tests may also show: 
• diarrhoea (may be severe) 
 
• abnormally low phosphate in 
the blood 
• feeling sick (nausea) 
 
 
• flushing, feeling hot
• headache 
 
 
• dizziness 
 
 
• pain in the throat 
 
 
• cough 
 
 
• upset stomach or indigestion 
 
 
• a tingling sensation or numbness 
in the hands, feet or around the lips 
and mouth 
 
 
• feeling weak/tired 
 
 
• bad taste in the mouth 
 
 
• damage to the nerves that can 
cause weakness and pain 
 
 
• itching 
 
 
• rash 
 
 
• joint pain and back pain 
 
 
Common (may affect up to 1 in 10 people) 
• allergic reactions including skin 
rashes, severe swelling of the skin 
and other tissues 
• decreased appetite 
• headache, stomach pain, 
feeling tired, feeling bloated, 
flatulence 
• changes in fat distribution  
• trouble sleeping; abnormal 
dreams; nightmare; abnormal 
behaviour; feelings of deep 
sadness and unworthiness 
Tests may also show: 
• increase in cholesterol 
• feeling dizzy; headache 
liver problems 
• inability to sleep (insomnia) 
• spinning sensation 
 
• increase in triglycerides 
• bloating; abdominal pain; 
diarrhoea; excessive gas in the 
stomach or bowel; feeling sick; 
vomiting; indigestion; belching 
 
• anxiety 
• certain kinds of rash (more often 
when used in combination with 
darunavir) 
 
• gout
• tiredness, unusual tiredness or 
weakness; fever


 
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• increase in urination
• increased liver blood tests; 
abnormal white blood cells; 
increased fat levels in blood; 
increased level of enzyme from 
salivary glands or pancreas
• reduced kidney function 
 
 
• seizures (fits) 
 
 
• low levels of blood platelets 
 
 
• thirst (dehydration) 
 
 
• abnormally heavy periods 
 
 
• wind (flatulence) 
 
 
• loss of appetite 
 
 
• mouth ulcer 
 
 
• muscle aches (pain), tenderness 
or weakness 
 
 
• fever 
 
 
• weight loss 
 
 
• changes in blood test results 
(such as blood chemistry and blood 
count) 
 
 
• confusion
• difficulty paying attention 
 
 
• fainting 
 
 
• blurred vision 
 
 
• swelling of the hands and feet 
 
 
• high blood pressure
• low blood pressure and feeling 
faint when getting up 
 
 
• coldness in the hands and feet 
 
 
• acne