Clinical trial NCT02993250
Conditions: Hepatitis C, Chronic
Sponsor: Janssen Pharmaceutical K.K.
Start date: 2016-12-21; Completion date: 2018-05-07
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of a combination treatment of AL-335, odalasvir (ODV), and simeprevir (SMV) for 8 weeks in Japanese participants with genotype 1 or 2 chronic hepatitis C virus (HCV) infection without cirrhosis and for 12 weeks in direct-acting antiviral (DAA)-naive Japanese participants with genotype 1 or 2 chronic HCV infection with compensated cirrhosis.

Detailed description:

Arms: arm 1: Participants will receive 800 milligram (mg) AL-335 +odalasvir (ODV) 25 mg+simeprevir (SMV) 75 mg once daily for 8 weeks in Cohort 1. arm 2: Participants will receive AL-335 800 milligram (mg)+ODV 25 mg+SMV 75 mg once daily for 12 weeks in Cohort 2. Dosing in cohort 2 will be started according to decision of Data Review Committee (DRC).
Interventions: intervention 1: AL-335 intervention 2: Odalasvir (ODV) intervention 3: Simeprevir (SMV)
Intervention descriptions: intervention 1: Participants will receive AL-335 800 mg once daily for 8 weeks in cohort 1 and 12 weeks in cohort 2. intervention 2: Participants will receive ODV 25 mg once daily for 8 weeks in cohort 1 and 12 weeks in cohort 2. intervention 3: Participants will receive SMV 75 mg once daily for 8 weeks in cohort 1 and 12 weeks in cohort 2.

Protocol documents:
Prot_001.pdf: 
1 
Status: Approved,  Date: 27 July 2017  
 
Janssen Pharmaceutical K.K.* 
 
Clinical Protocol 
 
A Phase 2a, Multicenter, Open-label Study to Investigate the Safety, Pharmacokinetics, 
and Efficacy of Combination Treatment of AL-335, Odalasvir, and Simeprevir in Japanese 
Subjects With Chronic Hepatitis C Genotype 1 or 2 Virus Infection, With or Without 
Compensated Cirrhosis who are Direct-acting Antiviral Treatment-naïve  
 
Protocol 64294178HPC2003; Phase 2a 
AMENDMENT 5 
 AL-335, odalasvir, TMC435 (simeprevir) 
 
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used 
throughout the protocol to represent Janssen Pharmaceutical K.K. 
 
Status: 
Approved 
Date: 
27 July 2017 
Prepared by: Janssen Pharmaceutical K.K. 
EDMS number: 
EDMS-ERI-125944899, 7.0 
 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
2 
Approved, Date: 27 July 2017  
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
LIST OF ATTACHMENTS ............................................................................................................................ 4 
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 5 
PROTOCOL AMENDMENTS ....................................................................................................................... 6 
SYNOPSIS .................................................................................................................................................. 12 
TIME AND EVENTS SCHEDULE .............................................................................................................. 21 
TIME AND EVENTS SCHEDULE: WEEK/DAY AND TIME WINDOWS ................................................... 25 
TIME AND EVENTS SCHEDULE: RICH SERIAL PK ASSESSMENTS ................................................... 25 
ABBREVIATIONS ...................................................................................................................................... 26 
DEFINITIONS OF TERMS .......................................................................................................................... 27 
1. 
INTRODUCTION ................................................................................................................................ 28 
1.1. 
Background .................................................................................................................................... 28 
1.1.1. 
HCV Infection .............................................................................................................................. 28 
1.1.2. 
Treatment of HCV Infection ........................................................................................................ 29 
1.1.3. 
Background of AL-335 ................................................................................................................ 30 
1.1.4. 
Background of ODV .................................................................................................................... 32 
1.1.5. 
Background of SMV .................................................................................................................... 35 
1.2. 
Background to All-oral DAA Combination Regimens ..................................................................... 37 
1.3. 
Risk/Benefit Section ....................................................................................................................... 43 
1.3.1. 
Known Benefits and Risks .......................................................................................................... 43 
1.3.2. 
Potential Benefits and Risks ....................................................................................................... 47 
1.3.2.1. 
Potential Benefits ..................................................................................................................... 47 
1.3.2.2. 
Potential Risks ......................................................................................................................... 48 
1.3.3. 
Overall Benefit/Risk Assessment ............................................................................................... 54 
1.4. 
Overall Rationale for the Study ...................................................................................................... 55 
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS ........................................................................... 56 
2.1. 
Objectives and Endpoints .............................................................................................................. 56 
2.1.1. 
Objectives ................................................................................................................................... 56 
2.1.2. 
Endpoints .................................................................................................................................... 56 
2.2. 
Hypothesis ..................................................................................................................................... 57 
3. 
STUDY DESIGN AND RATIONALE ................................................................................................. 57 
3.1. 
Overview of Study Design .............................................................................................................. 57 
3.2. 
Study Design Rationale .................................................................................................................. 60 
4. 
SUBJECT POPULATION .................................................................................................................. 64 
4.1. 
Inclusion Criteria ............................................................................................................................ 64 
4.2. 
Exclusion Criteria ........................................................................................................................... 67 
4.3. 
Prohibitions and Restrictions ......................................................................................................... 70 
5. 
TREATMENT ALLOCATION AND BLINDING ................................................................................. 70 
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 70 
6.1. 
Timing of Doses ............................................................................................................................. 71 
6.2. 
Dose Adjustment and Treatment Interruption ................................................................................ 71 
6.3. 
Treatment Stopping Rules (for Viral Breakthrough) ....................................................................... 72 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
3 
Approved, Date: 27 July 2017  
6.4. 
Study Treatment Stopping Rules ................................................................................................... 72 
7. 
TREATMENT COMPLIANCE ............................................................................................................ 73 
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 73 
9. 
STUDY EVALUATIONS .................................................................................................................... 76 
9.1. 
Study Procedures ........................................................................................................................... 76 
9.1.1. 
Overview ..................................................................................................................................... 76 
9.1.2. 
Screening Period ........................................................................................................................ 77 
9.1.3. 
Open-label Treatment Period ..................................................................................................... 78 
9.1.4. 
Posttreatment Period (Follow-up) ............................................................................................... 80 
9.2. 
Safety Evaluations ......................................................................................................................... 81 
9.2.1. 
Adverse Events ........................................................................................................................... 81 
9.2.2. 
Clinical Laboratory Tests ............................................................................................................ 81 
9.2.3. 
Electrocardiogram ....................................................................................................................... 83 
9.2.4. 
Echocardiography ....................................................................................................................... 84 
9.2.5. 
Vital Signs ................................................................................................................................... 85 
9.2.6. 
Hepatitis B Virus DNA ................................................................................................................. 85 
9.2.7. 
Physical Examination .................................................................................................................. 85 
9.2.8. 
Management of Specific Toxicities ............................................................................................. 86 
9.2.8.1. 
Rash (Including Photosensitivity Conditions) .......................................................................... 86 
9.2.8.2. 
Acute Allergic Reaction ........................................................................................................... 90 
9.2.8.3. 
Alanine Aminotransferase, Aspartate Aminotransferase, and Bilirubin Elevations ................. 91 
9.2.8.4. 
Clinical Hepatitis ...................................................................................................................... 93 
9.2.8.5. 
Pancreatic Amylase or Lipase Elevations ............................................................................... 93 
9.2.8.6. 
Creatine Kinase ....................................................................................................................... 93 
9.2.8.7. 
Cardiac Safety Monitoring ....................................................................................................... 95 
9.2.8.8. 
Renal Safety Monitoring .......................................................................................................... 96 
9.2.8.9. 
Other Toxicities ........................................................................................................................ 97 
9.3. 
Pharmacokinetics ........................................................................................................................... 97 
9.3.1. 
Evaluations ................................................................................................................................. 97 
9.3.2. 
Analytical Procedures ................................................................................................................. 99 
9.3.3. 
Pharmacokinetic Parameters ..................................................................................................... 99 
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations .......................................................................... 99 
9.5. 
Efficacy Evaluations ....................................................................................................................... 99 
9.5.1. 
HCV RNA Levels ........................................................................................................................ 99 
9.5.2. 
Resistance Determinations ....................................................................................................... 100 
9.6. 
Pharmacogenomic Evaluations ................................................................................................... 100 
9.7. 
Sample Collection and Handling .................................................................................................. 101 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ......................................................................................................................... 101 
10.1. 
Completion ................................................................................................................................... 101 
10.2. 
Discontinuation of Study Treatment/Withdrawal from the Study ................................................. 101 
11. 
STATISTICAL METHODS ............................................................................................................... 103 
11.1. 
Subject Information ...................................................................................................................... 103 
11.2. 
Sample Size Determination ......................................................................................................... 103 
11.3. 
Interim Analysis ............................................................................................................................ 103 
11.4. 
Safety Analyses ........................................................................................................................... 104 
11.5. 
Pharmacokinetic Analyses ........................................................................................................... 105 
11.6. 
Pharmacokinetic/Pharmacodynamic Analyses ............................................................................ 106 
11.7. 
Efficacy Analyses ......................................................................................................................... 106 
11.8. 
Pharmacogenomic Analyses ....................................................................................................... 107 
11.9. 
Data Review Committee .............................................................................................................. 107 
12. 
ADVERSE EVENT REPORTING .................................................................................................... 108 
12.1. 
Definitions .................................................................................................................................... 108 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
4 
Approved, Date: 27 July 2017  
12.1.1. 
Adverse Event Definitions and Classifications ......................................................................... 108 
12.1.2. 
Attribution Definitions ................................................................................................................ 109 
12.1.3. 
Severity Criteria ........................................................................................................................ 110 
12.2. 
Special Reporting Situations ........................................................................................................ 110 
12.3. 
Procedures ................................................................................................................................... 110 
12.3.1. 
All Adverse Events .................................................................................................................... 110 
12.3.2. 
Serious Adverse Events ........................................................................................................... 111 
12.3.3. 
Pregnancy ................................................................................................................................. 112 
12.4. 
Contacting Sponsor Regarding Safety ......................................................................................... 113 
13. 
PRODUCT QUALITY COMPLAINT HANDLING ............................................................................ 113 
13.1. 
Procedures ................................................................................................................................... 113 
13.2. 
Contacting Sponsor Regarding Product Quality .......................................................................... 113 
14. 
STUDY DRUG INFORMATION ....................................................................................................... 113 
14.1. 
Physical Description of Study Drug(s) ......................................................................................... 113 
14.2. 
Packaging .................................................................................................................................... 114 
14.3. 
Labeling ........................................................................................................................................ 114 
14.4. 
Preparation, Handling, and Storage ............................................................................................. 114 
14.5. 
Drug Accountability ...................................................................................................................... 114 
15. 
STUDY-SPECIFIC MATERIALS ..................................................................................................... 115 
16. 
ETHICAL ASPECTS ....................................................................................................................... 115 
16.1. 
Study-Specific Design Considerations ......................................................................................... 115 
16.2. 
Regulatory Ethics Compliance ..................................................................................................... 115 
16.2.1. 
Investigator Responsibilities ..................................................................................................... 115 
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................. 116 
16.2.3. 
Informed Consent ..................................................................................................................... 117 
16.2.4. 
Privacy of Personal Data .......................................................................................................... 118 
16.2.5. 
Long-term Retention of Samples for Additional Future Research ............................................ 119 
16.2.6. 
Country Selection ..................................................................................................................... 119 
17. 
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 119 
17.1. 
Protocol Amendments .................................................................................................................. 119 
17.2. 
Regulatory Documentation .......................................................................................................... 119 
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 119 
17.2.2. 
Required Prestudy Documentation ........................................................................................... 120 
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 120 
17.4. 
Source Documentation ................................................................................................................. 121 
17.5. 
Case Report Form Completion .................................................................................................... 122 
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 122 
17.7. 
Record Retention ......................................................................................................................... 122 
17.8. 
Monitoring .................................................................................................................................... 123 
17.9. 
Study Completion/Termination ..................................................................................................... 124 
17.9.1. 
Study Completion/End of Study ................................................................................................ 124 
17.9.2. 
Study Termination ..................................................................................................................... 124 
17.10. On-site Audits ............................................................................................................................... 124 
17.11. Use of Information and Publication .............................................................................................. 124 
REFERENCES .......................................................................................................................................... 127 
INVESTIGATOR AGREEMENT ............................................................................................................... 137 
 
LIST OF ATTACHMENTS 
Attachment 1: 
WHO Scale for Determining the Severity of Adverse Events ................................... 129 
Attachment 2: 
Cardiovascular Safety – Abnormalities .................................................................... 134 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
5 
Approved, Date: 27 July 2017  
Attachment 3: 
Visit Schedule for Rash Management ...................................................................... 135 
 
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES 
Table 1: 
Disallowed Medications ............................................................................................................ 74 
Table 2: 
Concomitant Medication to be Used With Caution ................................................................... 76 
Table 3: 
Guidelines for Subjects Developing Rash Grade 1 to Grade 4 ................................................ 87 
Table 4: 
Guidelines for Subjects Developing Allergic Reactions ............................................................ 90 
Table 5: 
Treatment-emergent Grade 1 to Grade 4 ALT or AST Elevation and Grade 1 to Grade 
4 Total Bilirubin Elevation ......................................................................................................... 91 
Table 6: 
Guidelines for Subjects Developing ALT and/or AST Elevations ............................................. 92 
Table 7: 
Guidelines for Subjects Developing Bilirubin Elevations .......................................................... 92 
 
FIGURES 
Figure 1: 
Schematic Overview of the Study ............................................................................................. 59 
 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
6 
Approved, Date: 27 July 2017  
PROTOCOL AMENDMENTS 
 
Protocol Version  
Issue Date 
Original Protocol 
15 September 2016 
Amendment 1 
07 November 2016 
Amendment 2 
05 December 2016
Amendment 3 
31 January 2017 
Amendment 4 
24 March 2017 
Amendment 5 
27 July 2017 
 
Amendments below are listed beginning with the most recent amendment. 
Amendment 5 (27 July 2017) 
The overall reason for the amendment: This amendment is being written to increase monitoring of liver function 
tests based on ALT and AST elevation reported in Phase 2 studies. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: To date, two similar cases of isolated, asymptomatic but marked ALT and AST elevation have been 
reported in the 3-DAA combination Phase 2 program (in 64294178HPC2003 and AL-335-604 study respectively). 
Approximately 470 subjects have already been exposed to 3-DAA combination in the Phase 2 program. Overall 
incidence of Grade 4 ALT elevation is 0.4% and its ALT/AST ratio is >1. No Grade 3 or Grade 4 ALT and AST 
elevations observed in 64294178HPC2001 study (N=365). Based on these laboratory abnormalities, sponsor 
decided to increase monitoring of liver function tests in 64294178HPC2003 study to weekly or biweekly instead of 
every 4 weeks during the treatment period. 
Time And Events Schedule 
9.2.8.3. Alanine Aminotransferase, 
Aspartate Aminotransferase, and Bilirubin 
Elevations 
Updated to add biochemistry tests including ALT and AST at on 
treatment Week 6 visit, and added the summary of observed ALT 
and AST abnormalities in Phase 2 program. 
 
 
Amendment 4 (24 March 2017) 
The overall reason for the amendment: This amendment is being written to implement study treatment stopping 
rules upon US Food and Drug Administration (FDA) feedback. In addition, changes are made to the definitions of 
on-treatment failure and relapse, and clarifications, corrections and updates are made in other section. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Following FDA feedback, treatment stopping rules for all subjects (study treatment stopping rules) are 
added to the protocol. 
The occurrence of any one of the following treatment-emergent events in any ongoing study using ODV at 
therapeutic doses: 
 2nd degree Mobitz Type 2 or 3rd degree heart block; 
 drop in ejection fraction (EF) by ≥10 points with absolute EF <50%; 
 a cardiac event that is serious, severe or life-threatening; 
will lead to stop of recruitment and dosing in all subjects in the study if adjudicated by the DRC to be at least 
possibly related to the study regimen. Such event(s) will be reported to the sponsor medical monitor within 24 
hours. Upon this notification, a safety assessment of the event by the DRC will take place within 72 hours and the 
outcome of the assessment and its associated action towards the study will be reported to Health Authorities and 
Ethics Committees in compliance with safety reporting regulations, as applicable. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
7 
Approved, Date: 27 July 2017  
Applicable Section(s) 
Description of Change(s) 
1.3.2.2. Potential Risks 
1.3.3. Overall Benefit/Risk Assessment 
6.4. Study Treatment Stopping Rules 
9.2.8.7. Cardiac Safety Monitoring 
10.2. Discontinuation of Study 
Treatment/Withdrawal from the Study 
11.9. Data Review Committee 
Updated to add the treatment stopping rules. 
Rationale: The definition of on-treatment failure and viral relapse are adjusted to align with FDA guidance on the 
development of direct-acting antivirals (DAAs) for the treatment of HCV infection. 
DEFINITIONS OF TERMS 
The definition of on-treatment failure and viral relapse are adjusted. 
Rationale: Minor errors and inconsistencies were corrected, and clarifications were added where required. 
TIME AND EVENTS SCHEDULE: RICH 
SERIAL PK ASSESSMENTS 
ABBREVIATIONS 
9.2.8.6.  Creatine Kinase 
9.2.8.7. Cardiac Safety Monitoring 
 
Minor errors and inconsistencies were corrected, and clarifications 
were added where required. 
 
Amendment 3 (31 January 2017) 
The overall reason for the amendment: In patients with compensated cirrhosis, based on preliminary data from 
Phase 2 study AL-335-604, suggesting further benefit, treatment durations of 8 and 12 weeks are studied in 
additional cohorts (Phase 2b). The outcome of this study will inform the duration evaluated in phase 3 for patients 
with compensated cirrhosis. To assess safety, PK and efficacy of the potentially longest treatment duration in 
Japanese subjects with compensated cirrhosis before going to phase 3, the Sponsor decided to extend the treatment 
duration of the cirrhotic cohort 2 in this study from 8 to 12 weeks. 
In addition, clarifications, corrections and updates have been made in other sections, such as an update for the 
disallowed medication list, etc. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Extended treatment duration of Cohort 2 to 12 weeks from 8 weeks to assess the safety, PK and 
efficacy.  
Synopsis  
Objectives 
Overview Of Study Design 
Dosage And Administration 
1.1.2. Treatment of HCV Infection 
1.4. Overall Rationale for the Study 
2.1.1. Objectives 
3.1. Overview of Study Design 
3.2. Study Design Rationale 
6. Dosage And Administration 
9.1.1. Overview 
9.2.2. Clinical Laboratory Tests 
Updated treatment duration for cohort 2 to 12 weeks and other 
related parts (eg. update of total study duration to 42 weeks from 38 
weeks). 
Rationale: Added an additional sparse PK sampling point for cohort 2 in accordance with the treatment extention.  
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
8 
Approved, Date: 27 July 2017  
Applicable Section(s) 
Description of Change(s) 
Synopsis  
Pharmacokinetic Evaluations 
3.1. Overview of Study Design 
9.3.1. Evaluations 
Added sparse PK sampling time point at Week 8 for cohort 2 and 
clarified description about the time points for each cohort.  
Rationale: Updated Time and Events Schedule in accordance with the treatment extention for cohort 2, and added 
separated Time and Events Schedule for Week and Day of each visit schedule to show the required visit and day for 
each cohort at a glance.  
Time And Events Schedule 
Time And Events Schedule: Week/Day 
Added Week 8 and 10 visit for cohort 2 and corresponding 
evaluations. 
Added separated Time and Events Schedule for Week and Day. 
Rationale: Updated disallowed concomitant therapy and medication 
8. Prestudy And Concomitant Therapy 
Added phlebotomy as disallowed concomitant therapy and clarified 
Prescription drugs for improvement of hepatic function which could 
potentially affect to hepatic function including AST and ALT as 
disallowed concomitant medication. 
Rationale: Updated total blood volume to be drawn in this study in accordance with the treatment extention for 
cohort 2. 
9.1.1. Overview 
Updated total blood volume to be drawn in this study in accordance 
with the treatment extention for cohort 2. 
Rationale: Minor errors and inconsistencies were noted and corrected and clarifications were added where required.
Time And Events Schedule 
Synopsis  
Data Review Committee 
3.1. Overview of Study Design 
4.2. Exclusion Criteria, #12 
9.1.4. Posttreatment Period (Follow-up) 
9.1.1. Overview 
9.2.2. Clinical Laboratory Tests 
Minor errors were corrected and clarifications were added. 
 
Amendment 2 (05 December 2016) 
The overall reason for the amendment: Following feedback and inquiries from Health Authority after submission 
of Clinical Trial Notification, the sponsor clarifies that dosing of cohort 2 will be started after no new or unexpected 
events, which are considered as clinically significant, are detected in cohort 1 regardless if the events are 
hepatotoxicity or not. In addition, clarifications, corrections and updates have been made in other sections, such as 
an update for subjects for whom an HBV DNA measurement is performed, clarifications for the disallowed 
medication list, etc. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Clarified dosing of cohort 2 will be started after no new or unexpected events, which are considered as a 
clinically significant, are detected regardless if the events are hepatotoxicity or not.  
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
9 
Approved, Date: 27 July 2017  
Applicable Section(s) 
Description of Change(s) 
Synopsis  
Overview Of Study Design 
Data Review Committee 
3.1. Overview of Study Design 
9.1.1. Overview 
11.9. Data Review Committee 
Clarified dosing of cohort 2 will be started after no new or 
unexpected events, which are considered as a clinically significant, 
are detected regardless if the events are hepatotoxicity or not. 
Rationale: Updated to perform HBV DNA measurement for subject with antiHBs positive status in addition to 
subjects with antiHBc positive status at screening, except for subjects with prior HBV-vaccinated and only antiHBs 
positive. 
Time And Events Schedule 
9.1.3. Open-label Treatment Period 
9.2.2. Clinical Laboratory Tests 
9.2.6. Hepatitis B Virus DNA 
Updated to perform HBV DNA measurement for subject with 
antiHBs positive status in addition to subjects with antiHBc positive 
status at screening, except for subjects with prior HBV-vaccinated 
and only antiHBs positive. 
Rationale: Clarified the contraception methods not approved in Japan. 
4.1. Inclusion Criteria, #9 and 12 
Clarified the contraception methods not approved in Japan. 
Rationale: Clarified that the breast feeding female subjects cannot be enrolled even if they discontinue breast-
feeding. 
4.2. Exclusion Criteria, #15 
Clarified the criteria. 
Rationale: Clarified the period of disallowed medications and added list of “Drugs associated with QT prolongation 
and/or Torsades de Pointes”. 
8. Prestudy And Concomitant Therapy, 
Table 1 
Clarified that the period of disallowed medications and added list of 
“Drugs associated with QT prolongation and/or Torsades de 
Pointes”. 
Rationale: Corrected the expected total blood volume drawn during the study. 
9.1.1. Overview 
Corrected the expected total blood volume. 
Rationale: Added representative ECG parameters as indices. 
9.2.3. Electrocardiogram 
Added representative ECG parameters. 
Rationale: Updated guidelines to discontinue all of study drugs in case of Grade 4 bilirubin elevation in light of 
securing subjects' safety. 
9.2.8.3. Alanine Aminotransferase, 
Aspartate Aminotransferase, and Bilirubin 
Elevations 
Table 7 
10.2. Discontinuation of Study 
Treatment/Withdrawal from the Study 
Updated guidelines for Grade 4 bilirubin elevation. 
Rationale: Minor errors and inconsistencies were noted and corrected and clarifications were added where required.
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
10 
Approved, Date: 27 July 2017  
Applicable Section(s) 
Description of Change(s) 
Synopsis  
Overview Of Study Design 
1.3.2.2. Potential Risks 
1.3.3. Overall Benefit/Risk Assessment 
3.1. Overview of Study Design 
4.1. Inclusion Criteria, #9 
9.1.3. Open-label Treatment Period 
9.2.2. Clinical Laboratory Tests 
9.2.4. Echocardiography 
9.2.6. Hepatitis B Virus DNA 
9.2.8.3. Alanine Aminotransferase, 
Aspartate Aminotransferase, and Bilirubin 
Elevations 
11.9. Data Review Committee 
Minor clarifications, grammatical and formatting changes were 
made. 
9.2.3. Electrocardiogram 
Minor errors were corrected. 
 
Amendment 1 (07 November 2016) 
The overall reason for the amendment: Change in design of the Phase 2a study with a staggered treatment fashion 
to start cohort 2 (chronic hepatitis C with compensated cirrhosis) after confirmation of tolerability in cohort 1 
(chronic hepatitis C without cirrhosis), other clarification and minor updates. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Following Health Authority feedback, the sponsor has decided to start dosing in cohort 2 according to a 
DRC’s decision after reviewing all available relevant safety data with 6 subjects until Week 4 visit in cohort 1, in 
light of securing subjects' safety. Dosing in cohort 2 will only be started when no new or unexpected signs or signals 
of hepatic toxicity, which are considered as a clinically significant issue, are detected. DRC may require further data 
to review before the decision about start of dosing in cohort 2, if any of potential concerns are detected with the data 
of 6 subjects until Week 4 visit in cohort 1. 
In addition, start of dosing in cohort 2 will be notified to investigators and be opened via an interactive web 
response system (IWRS) by the sponsor. 
Synopsis  
Overview Of Study Design 
Data Review Committee 
9.1.1. Overview 
11.9. Data Review Committee 
Added description about DRC review for decision to start dosing in 
cohort 2, notification of start of dosing in cohort 2. 
3.1. Overview of Study Design  
Added description about DRC review for decision to start dosing in 
cohort 2. 
Updated Figure 1 (Schematic Overview of the Study) to show the 
updated study design visually. 
Rationale: Description related to anticipated events were removed as they will not be identified for Japanese Health 
Authority. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
11 
Approved, Date: 27 July 2017  
Applicable Section(s) 
Description of Change(s) 
Synopsis  
Overview Of Study Design 
Data Review Committee 
1.3.3. Overall Benefit/Risk Assessment 
3.1. Overview of Study Design 
9.1.3. Open-label Treatment Period 
9.2. Safety Evaluations 
11.9. Data Review Committee 
12.3.1. All Adverse Events 
Attachment 4: Anticipated Events 
Description related to anticipated events were removed. 
Rationale: Requirement for dosage and administration of study drugs were clarified for each subgroup, sparse PK 
and rich PK substudies. 
6. Dosage And Administration 
7. Treatment Compliance 
Clarified the requirement for each subgroup. 
Rationale: Clarified the required period for use of birth control. 
4.1. Inclusion Criteria 
Clarified the required period for use of birth control under inclusion 
criteria #9 and 12. 
Rationale: Added new definition of term, Late viral relapse. 
Definitions Of Terms 
Added new definition of term, Late viral relapse. 
Rationale: Minor errors and inconsistencies were noted and corrected and clarifications were added where required.
Synopsis  
Time And Events Schedule 
1.3.3. Overall Benefit/Risk Assessment 
3.1. Overview of Study Design 
6. Dosage And Administration 
9.1.2. Screening Period 
9.3.3. Pharmacokinetic Parameters 
Minor grammatical and formatting changes were made. 
4.1. Inclusion Criteria, #11 
9.1.1. Overview 
9.2.2. Clinical Laboratory Tests 
9.2.8.1. Rash (Including Photosensitivity 
Conditions) 
9.3.1. Evaluations 
9.5.1. HCV RNA Levels 
Minor errors were corrected. 
 
 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
12 
Approved, Date: 27 July 2017  
SYNOPSIS 
A Phase 2a, Multicenter, Open-label Study to Investigate the Safety, Pharmacokinetics, and Efficacy of 
Combination Treatment of AL-335, Odalasvir, and Simeprevir in Japanese Subjects With Chronic 
Hepatitis C Genotype 1 or 2 Virus Infection, With or Without Compensated Cirrhosis who are Direct-
acting Antiviral Treatment-naïve  
AL-335 (also known as JNJ-64146212) is a uridine-based nucleoside monophosphate prodrug (or 
nucleotide analog) targeting the hepatitis C virus (HCV) nonstructural protein (NS)5B polymerase, being 
developed for the treatment of chronic HCV infection. 
Odalasvir (ODV, JNJ-64289901, also known as ACH-0143102 and ACH-3102) is an inhibitor of the 
HCV NS5A complex, being developed for the treatment of chronic HCV infection. 
Simeprevir (SMV, also known as TMC435) is an HCV NS3/4A protease inhibitor approved for the 
treatment of chronic HCV genotype 1 and 4 infections. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS 
Objectives 
Primary Objectives 
 
To evaluate the safety and tolerability of a combination treatment of AL-335, ODV, and SMV for 
8 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 chronic HCV infection without 
cirrhosis and for 12 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 chronic HCV 
infection with compensated cirrhosis. 
Secondary Objectives 
 
To evaluate the pharmacokinetics (PK) of AL-335 (and its 2 metabolites ALS-022399 and 
ALS-022227; AL-335, the metabolites ALS-022399 and ALS-022227 are hereafter referred to as 
AL-335 [and metabolites]), ODV, and SMV in plasma in Japanese subjects with genotype 1 or 2 
chronic HCV infection with or without compensated cirrhosis who are DAA-naïve. 
 
To evaluate the efficacy, ie, sustained virologic response (SVR) at 4, 12, and 24 weeks after the 
end-of-treatment (EOT) (SVR4, SVR12, and SVR24), of a combination treatment with AL-335, 
ODV, and SMV for 8 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 chronic HCV 
infection without cirrhosis and for 12 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 
chronic HCV infection with compensated cirrhosis. 
 
To evaluate on-treatment viral kinetics in an 8 or 12-week treatment regimen containing AL-335, 
ODV, and SMV in subjects who are DAA- naïve. 
 
To evaluate the incidence of on-treatment failure during an 8 or 12-week treatment regimen 
containing AL-335, ODV, and SMV in subjects who are DAA-naïve. 
 
To evaluate the incidence of viral relapse after an 8 or 12-week treatment regimen containing 
AL-335, ODV, and SMV in subjects who are DAA-naïve. 
Exploratory Objectives 
 
To explore relationships of exposure of AL-335 (and metabolites), ODV, and SMV with SVR and 
safety. 
 
To evaluate the impact of the patient and disease characteristics at baseline on SVR, including but 
not limited to prior treatment history, interleukin-28B (IL28B) genotype, presence of cirrhosis, HCV 
RNA level, and HCV geno/subtype. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
13 
Approved, Date: 27 July 2017  
 
To evaluate the impact of the presence of HCV NS3/4A, NS5A, and/or NS5B polymorphisms at 
baseline on treatment outcome. 
 
To assess the emergence of resistant variants in subjects not achieving SVR. 
Endpoints 
Primary Endpoint 
 
Safety data, including but not limited to adverse events (AEs), physical examination, vital signs, 
12-lead electrocardiograms (ECGs), echocardiograms, and clinical laboratory results (including 
chemistry, hematology, and urine) 
Secondary Endpoints 
 
PK parameters for AL-335 (and metabolites), ODV, and SMV in plasma 
 
The proportion of subjects who have an SVR4, SVR12, and SVR24 
 
The proportion of subjects with viral relapse 
 
The proportion of subjects with on-treatment failure 
 
The proportion of subjects with on-treatment virologic response: 
 
HCV RNA not detected 
 
HCV RNA <lower limit of quantification (LLOQ) 
 
Time to achieve HCV RNA not detected or HCV RNA <LLOQ 
Exploratory Endpoints 
 
The effect of the presence or absence at baseline of HCV NS5A, NS5B, and/or NS3/4A 
polymorphisms on treatment outcome 
 
The changes in the HCV NS3/4A, NS5A and/or NS5B sequences in subjects not achieving SVR 
 
Impact of baseline condition on SVR (including but not limited to prior treatment history, IL28B 
genotype, presence of cirrhosis, HCV RNA level, and HCV geno/subtype) 
Hypothesis 
The study is hypothesis-generating. No formal hypothesis will be tested. 
OVERVIEW OF STUDY DESIGN 
This is a Phase 2a, multicenter, open-label study to investigate the safety, efficacy, and PK of an 8 or 
12-week treatment regimen with AL-335, ODV, and SMV in Japanese subjects with genotype 1 or 2 
chronic HCV infection with or without compensated cirrhosis who are DAA-naïve, followed by a 
24-week posttreatment follow-up. 
The study will include a Screening Period of maximum 6 weeks starting from the time of the first 
screening assessment. In exceptional cases, the Screening Period can be extended if discussed with and 
approved (documented) by the sponsor. Thereafter, if eligible, subjects will be assigned to 1 of the 
2 treatment cohorts to receive AL-335, ODV, and SMV combination treatment for 8 or 12 weeks based 
on the absence or presence of compensated cirrhosis. A posttreatment follow-up until 24 weeks after the 
actual EOT is included to assess SVR4, SVR12, and SVR24. The total study duration for each subject 
will be approximately 38 or 42 weeks (including the 6-week Screening Period, the 8 or 12-week 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
14 
Approved, Date: 27 July 2017  
Treatment Period, and the 24-week Posttreatment Follow-up Period). The study will be considered to be 
completed with the last visit of the last subject participating in the study. 
Approximately 20 DAA-naïve chronic HCV genotype 1 or 2-infected subjects without cirrhosis will be 
assigned to Cohort 1, and approximately 20 DAA-naïve HCV genotype 1 or 2-infected subjects with 
compensated cirrhosis will be assigned to Cohort 2. 
 
Cohort 1 (N=20, chronic hepatitis C without cirrhosis): AL-335 800 mg once daily (qd) + 
ODV 25 mg qd + SMV 75 mg qd for 8 weeks 
 
Cohort 2 (N=20, chronic hepatitis C with compensated cirrhosis): AL-335 800 mg qd + 
ODV 25 mg qd + SMV 75 mg qd for 12 weeks 
Subjects volunteering to participate, having signed the informed consent form (ICF), and found eligible 
for the study at screening, will be required to discontinue specified disallowed medication. 
The primary objective of this study is to assess safety and tolerability of the 3 DAA combination in 
Japanese patients with and without compensated liver cirrhosis. Compared to subjects with chronic 
hepatitis C without cirrhosis (enrolled in cohort 1), subjects with chronic hepatitis C with compensated 
cirrhosis (enrolled in cohort 2) are considered to potentially have a higher safety risk. To conduct this 
study carefully in light of securing subjects' safety, dosing of cohort 2 with patients with compensated 
cirrhosis will only start after a Data Review Committee (DRC) has reviewed all available relevant safety 
data when the first 6 subjects in cohort 1 completed the Week 4 visit, (including but not limited to AE, 
Serious AE [SAE], clinical laboratory test) and no new or unexpected events, which are considered 
clinically significant, are detected. DRC may require to review data of further patients before deciding 
about the start of dosing in cohort 2. 
If study drug is discontinued prematurely, for reasons other than withdrawal of consent, a Treatment 
Withdrawal Visit should be scheduled as soon as possible after the EOT. The subjects will be followed up 
for 24 weeks after EOT. If a subject discontinues treatment due to withdrawal of consent, the subject will 
be offered an optional Treatment Withdrawal Visit to be scheduled as soon as possible after withdrawal 
and/or a safety Follow-up Visit, which needs to be scheduled 4 weeks after EOT. At the safety Follow-up 
Visit safety assessments of the Week 4 Follow-up Visit need to be performed. 
Subjects will discontinue study drugs if a virologic stopping rule is met to limit the risk of developing 
drug resistance and to reduce unnecessary exposure to study drugs for subjects with no chance or only a 
small chance of treatment success. All study drugs will be discontinued for subjects with viral 
breakthrough, defined as a confirmed increase of >1.0 log10 IU/mL in HCV RNA from nadir or confirmed 
HCV RNA >2.0 log10 IU/mL in subjects who had previously achieved HCV RNA <LLOQ (detected or 
not detected) while on treatment. 
DRC will be established to monitor data with focus on the safety and on the general conduct of the study. 
The DRC is a committee within the sponsor’s organization that is independent of the sponsor’s study 
team. Details will be specified in a separate charter. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
15 
Approved, Date: 27 July 2017  
SUBJECT POPULATION 
Key Inclusion Criteria 
Description 
Age and sex 
Man or woman, 20 to 75 years of age, inclusive. 
Body Mass Index 
Body mass index of 18.0 to 35.0 kg/m2, inclusive. 
HCV genotype 
All subjects must have HCV genotype 1 or 2 infection, determined 
at screening. 
Plasma HCV RNA  
≥10,000 IU/mL (determined at screening). 
HCV treatment history 
Subjects must be DAA-naïve, defined as not having received 
treatment with any approved or investigational DAA for chronic 
HCV infection. Prior HCV therapy consisting of interferon (IFN)
(pegylated or nonpegylated) with or without ribavirin (RBV) is 
allowed. 
Presence or absence of cirrhosis 
Subjects without cirrhosis (absence of cirrhosis), defined as any of 
the following: 
 
Fibroscan with a result of ≤12.5 kPa within 6 months of 
baseline/Day 1, OR 
 
Liver biopsy within 6 months of baseline/Day 1 showing 
absence of cirrhosis (METAVIR score of F0-F3 or 
Ishak score <5). 
Subjects with compensated cirrhosis (not meeting the criterion for 
hepatic decompensation described in the Exclusion Criteria), 
defined as any of the following: 
 
Fibroscan (prior report or during Screening Period) with a 
result of >12.5 kPA, OR 
 
Liver biopsy (prior report or during Screening Period) 
showing 
cirrhosis 
(eg, METAVIR 
score 
of 
F4 
or 
Ishak score ≥5). 
Key Exclusion Criteria 
Description  
Infection/coinfection 
HCV coinfection with multiple genotypes. 
Human immunodeficiency virus (HIV) coinfection. 
HCV genotype 3, 4, 5, or 6 infection. 
Exposure to a DAA 
Prior exposure to an HCV DAA, either in combination with 
pegylated interferon (PegIFN) or IFN-free. 
Liver disease of nonHCV etiology 
Any evidence of liver disease of nonHCV etiology. This includes, 
but 
is 
not 
limited 
to, 
acute 
hepatitis A 
infection 
(immunoglobulin M), hepatitis B infection (hepatitis B surface 
antigen [HBsAg] positive), drug- or alcohol-related liver disease, 
autoimmune 
hepatitis, 
hemochromatosis, 
Wilson’s disease, 
alpha-1 antitrypsin deficiency, primary biliary cirrhosis, or any 
other nonHCV liver disease that is considered clinically significant 
by the investigator. 
Hepatic decompensation 
Evidence of hepatic decompensation (history or current clinical 
evidence of ascites, bleeding varices, or hepatic encephalopathy). 
Organ transplant 
Subjects who were recipients of an organ transplant (other than 
cornea, hair transplant, or skin graft). 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
16 
Approved, Date: 27 July 2017  
Cardiac-related medical history 
History or other clinical evidence of significant cardiac findings or 
conditions such as: 
 
cardiac disease (eg, angina, congestive heart failure, 
myocardial infarction, diastolic dysfunction, significant 
arrhythmia, coronary heart disease, moderate or severe 
valvular disease, or uncontrolled hypertension) at screening 
 
screening echocardiogram left ventricular ejection fraction 
(LVEF) <55.0% or any other echocardiogram finding 
suggestive of clinically relevant cardiomyopathy 
 
abnormal ECG findings such as: significantly abnormal PR 
[PR interval >200 msec], QRS intervals or corrected QT 
interval [QTc] >450 msec for male subjects and >470 msec
for female subjects (based on the average of the ECGs) 
 
evidence of any heart block 
 
evidence of right bundle branch block or left bundle branch 
block 
 
history or family history of prolonged QT syndrome (eg, 
torsade de pointes) or sudden cardiac death 
Key laboratory values 
Any of the following laboratory abnormalities at screening: 
 
platelet count <75×10³/µL or <75×109/L 
 
hemoglobin <11 g/dL or <6.83 mmol/L for male subjects, 
<10 g/dL or <6.21 mmol/L for female subjects 
 
absolute neutrophil count <1.00×10³/µL 
 
alanine 
aminotransferase 
(ALT) 
and/or 
aspartate 
aminotransferase (AST) >10×upper limit of normal (ULN) 
 
total serum bilirubin >1.5×ULN 
 
albumin <3.5 g/dL or <35 g/L 
 
estimated 
glomerular 
filtration 
rate 
(eGFR) 
of 
<50 mL/min/1.73m2 
 
hypo-/hyperkalemia (Grade 2 or higher) 
Hepatocellular carcinoma 
Subjects who have a history of hepatocellular carcinoma 
regardless of period before screening; or currently, have findings 
suggestive of hepatocellular carcinoma. 
 
DOSAGE AND ADMINISTRATION 
All subjects will receive AL-335 800 mg qd, ODV 25 mg qd, and SMV 75 mg qd. The treatment duration 
is 8 weeks for subjects without cirrhosis (cohort 1) and 12 weeks for subjects with compensated cirrhosis 
(cohort 2). 
All study drugs should be taken together in the morning at approximately the same time with food (ie, 
during or within 15 minutes after completion of a meal). 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
17 
Approved, Date: 27 July 2017  
SAFETY EVALUATIONS 
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards until the 
subject’s last study visit. The evaluations of safety and tolerability will include monitoring of AEs, 
clinical laboratory tests, ECGs, echocardiograms, vital sign measurements, and physical examinations at 
predefined time points. 
All AEs, whether serious or nonserious as well as pregnancies, will be reported from the time a signed 
ICF is obtained until the subject’s last study visit. 
Specific toxicity management plans in line with the known pharmacologic profile of the study drugs (and 
the drug class) evaluated in this study are incorporated in this protocol. 
PHARMACOKINETIC EVALUATIONS 
Sparse PK Sampling 
Sparse PK sampling for the measurement of plasma concentrations of AL-335 (and metabolites), ODV, 
and SMV will be performed in all subjects. Sparse PK sample will be taken at predose, between 2-to 
4-hours postdose, and between 4- to 6-hours postdose at Weeks 2, 4, 6 and at the EOT (Week 8) Visit 
(Cohort 1), or Weeks 2, 4, 6, 8 and at the EOT (Week 12) Visit (Cohort 2). At Week 4, no sparse PK 
sample will be taken for subjects participating in the rich serial PK substudy. At the Week 12 Follow-up 
Visit, sparse PK sample will be taken at any time for the measurement of plasma concentrations of ODV. 
Study drugs should be taken on site at the time points in the Time and Events Schedule. 
Rich Serial PK Sampling for Noncompartmental PK Analysis in the PK Subgroups 
In the rich serial PK substudy, rich serial PK blood sampling for the measurement of plasma 
concentrations of AL-335 (and metabolites), ODV, and SMV will be performed in approximately more 
than 6 subjects in each cohort. Subjects participating in the rich serial PK substudy will undergo rich 
serial PK sampling at their Week 4 Visit, at 10 different time points within the dosing interval. For the 
intensive PK samples of the rich PK substudy, noncompartmental PK analysis of AL-335 (and 
metabolites), ODV, and SMV will be performed using actual sampling time points and plasma 
concentrations obtained from rich serial PK blood sampling at Week 4. 
EFFICACY EVALUATIONS 
HCV RNA Levels 
Blood samples for the determination of HCV RNA levels will be taken at all scheduled visits and 
processed in real time. The results will be communicated to the sponsor and the investigator throughout 
the study. 
Resistance Determinations 
Sequencing of the HCV NS3/4A, NS5A, and NS5B regions will be performed to identify preexisting 
sequence polymorphisms and characterize emerging HCV variants. The HCV NS3/4A, NS5A, and NS5B 
regions will be sequenced pretreatment (at baseline) by default in all subjects and postbaseline in subjects 
not achieving SVR. Sequencing of additional samples may be triggered by the sponsor's virologist. 
PHARMACOGENOMIC EVALUATIONS 
One mandatory blood sample for host IL28B genotyping will be collected at the Baseline Visit, providing 
the opportunity to explore the influence of a genetic polymorphism upstream of the IL28B gene 
(rs12979860) on treatment outcome to the drug regimen assessed in this study. No other analysis will be 
performed with this sample. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
18 
Approved, Date: 27 July 2017  
Determination of the subject’s IL28 genotype will be performed on human genomic deoxyribonucleic 
acid (DNA) by techniques allowing amplification of the DNA and identification of the polymorphism. 
STATISTICAL METHODS 
Sample Size Determination 
Since this is an exploratory study, no formal sample size calculation has been performed. 
With a total sample size of 40 subjects, the probability to observe an AE with an incidence of 10.0% is 
99.0%. The probability to observe an AE with an incidence of 1.0%, 2.5%, and 5.0% is 33.0%, 64.0%, 
and 87.0%, respectively. With 20 subjects per cohort, the probability to observe an AE with an incidence 
of 10.0% is 88.0%. The probability to observe an AE with an incidence of 1.0%, 2.5%, and 5.0% is 
18.0%, 40.0%, and 64.0%, respectively in a cohort. 
With an expected SVR rate of 90.0%, and 40 subjects in 2 cohorts combined, the corresponding 95%, 
2-sided confidence interval (CI) is 76.3% to 97.2%. With 95.0% SVR, the corresponding 95% CI ranges 
from 83.1% to 99.4%. With an expected SVR rate of 90.0%, and 20 subjects per cohort, the 
corresponding 95%, 2-sided CI is 68.3% to 98.8%. With 95.0% SVR, the corresponding 95% CI ranges 
from 75.1% to 99.9% in a cohort. 
Therefore, a total sample size of approximately 40 subjects is considered sufficient to explore the safety 
and efficacy of the combination regimen consisting of AL-335, ODV, and SMV in this study from a 
clinical point of view. 
Interim Analysis 
No formal interim analysis will be performed; however, a DRC will be commissioned to regularly 
monitor the safety in interim data review. 
Safety Analyses 
The incidence of AEs will be summarized by body system and preferred term for each cohort and total. 
Changes from baseline in clinical laboratory values, vital signs, and ECG parameters will be presented 
descriptively. The percentage of subjects with abnormal clinical laboratory, vital signs, and ECG 
parameter values will be presented. 
The safety analyses will be done separately for each study period (screening, treatment, and follow-up). 
Pharmacokinetic Analyses 
Population PK Analysis for all Subjects 
Population PK (PopPK) analysis of plasma concentration-time data of AL-335 (and metabolites), ODV, 
and SMV from all subjects will be performed using nonlinear mixed-effects modeling. PopPK modeling 
will be used to describe the concentration-time profiles and estimate the exposure parameters (AUC24h 
and C0h) of AL-335 (and metabolites), ODV, and SMV. Available baseline subject characteristics 
(demographics, body weight, laboratory variables, genotype, etc) may be explored as potential covariates 
affecting PK parameters. Details will be given in a popPK analysis plan and the results of the popPK 
analysis will be presented in a separate popPK report. 
Data will be listed for all subjects with available plasma concentrations. For each cohort, descriptive 
statistics, including arithmetic mean, standard deviation (SD), coefficient of variation, median, minimum, 
maximum, and geometric mean will be performed for all individually estimated exposure parameters 
(AUC24h and C0h) of AL-335 (and metabolites), ODV, and SMV. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
19 
Approved, Date: 27 July 2017  
Rich Serial PK Sampling for Noncompartmental PK Analysis in the PK Subgroups 
For each cohort, descriptive statistics will be provided for the plasma concentrations at each sampling 
time point and the PK parameters derived. 
All individual concentrations at each sampling time point and all individual PK parameters will be listed. 
For each subject, plasma concentration-time data will be graphically presented. Similarly, graphs of the 
mean plasma concentration-time profiles and overlay graphs with combined individual plasma 
concentration-time profiles will be produced. PK parameters will be subjected to an exploratory graphical 
analysis. Additional analyses may be performed if deemed warranted. 
Pharmacokinetic/Pharmacodynamic Analyses 
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure parameters 
(AUC24h and C0h) with SVR4, SVR12, and SVR24 and with safety endpoints may be explored. These 
relationships will be presented in a graphical display. 
Efficacy Analyses 
The primary analyses will be performed when all subjects have reached the SVR12 time point (Week 12 
Follow-up Visit) or discontinued earlier. The final analysis (as secondary analysis) will be performed 
when all subjects have completed the last study-related visit (SVR24 time point; Week 24 Follow-up 
Visit) or discontinued earlier. 
The efficacy analyses will be performed on the full analysis set (FAS), defined as all subjects who 
received at least 1 dose of the study drug (AL-335, ODV, or SMV) and have at least 1 postbaseline 
efficacy measurement in the current study. Additional sensitivity analyses on efficacy may be performed 
after excluding subjects with early treatment discontinuation due to nonvirologic reasons or missing data 
at SVR4, SVR12, or SVR24 time points, as well as on the per-protocol set (PPS), defined as the FAS 
subjects without a prespecified major protocol deviation. 
The potential association between treatment outcome and baseline subject and disease characteristics such 
as prior treatment history, IL28B genotype (rs12979860), presence of cirrhosis, HCV RNA level, and 
HCV geno/subtype will be explored. 
Criteria for Endpoints 
HCV RNA levels will be used to determine the response to HCV treatment: virologic response and failure 
(on-treatment failure and viral relapse). Refer to the DEFINITIONS OF TERMS for more details. 
Resistance Determination Analyses 
Pretreatment polymorphisms in the HCV NS3/4A, NS5A, and NS5B regions in all subjects and relevant 
changes in the HCV NS3/4A, NS5A, and NS5B regions in subjects not achieving SVR will be tabulated 
and described. The effect of pretreatment HCV NS3/4A, NS5A, and NS5B polymorphisms on treatment 
outcome will be explored. 
Pharmacogenomic Analyses 
Baseline IL28B genotyping data will be tabulated. Subgroup analyses will be done to explore the effect of 
the IL28B genotype (rs12979860) on efficacy by means of descriptive statistics and frequency tabulations. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
20 
Approved, Date: 27 July 2017  
Data Review Committee 
A DRC will be established to monitor data with focus on the safety and generally on the conduct of the 
study. Emerging safety data from this study will be reviewed at predetermined intervals.  
To conduct this study carefully in light of securing subjects' safety, dosing of cohort 2 with patients with 
compensated cirrhosis will only start after a DRC has reviewed all available relevant safety data when the 
first 6 subjects in cohort 1 completed the Week 4 visit, (including but not limited to AE, SAE, clinical 
laboratory test) and no new or unexpected events, which are considered clinically significant, are detected. 
DRC may require to review data of further patients before deciding about the start of dosing in cohort 2. 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
21 
Approved, Date: 27 July 2017  
TIME AND EVENTS SCHEDULE 
Period 
Screening 
Perioda 
Treatment Periodc 
Posttreatment 
Follow-up Period 
Week/Day 
W-6 
Baselineb
D1 
D2
D3 W1 W2 W3 W4
W6
W8ff
W10ff 
EOT 
(W8 or 
12)gg 
Treatment 
Withdrawal 
Visitd 
W4 
FU
W8 
FU
W12 
FU
W18 
FU 
W24 
FUe
Study Procedures 
Screening/Administrative 
Informed consent formf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prestudy therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant diseases 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C virus geno-
/subtyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroscan/biopsyh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver ultrasonography, CT, 
or MRIaa 
(subjects with cirrhosis) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiographyi  
X 
 
 
 
 
 
 
X
 
 
 
X 
X 
X 
 
 
 
 
Triplicate ECGi 
X 
X 
X
X
X
X
X
X
X
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy testj 
X 
X 
 
 
 
 
 
X
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Follicle-stimulating 
hormone (FSH)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis A, B, and C 
serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Human immunodeficiency 
virus (HIV) 
Type 1 and 2 serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
Provision of study drugs for 
daily use at home 
 
X 
 
 
 
 
 
Xee
 
Xee 
 
 
 
 
 
 
 
 
Study drugs to be taken on-
site 
 
X 
 
 
 
X
 
X
X
X 
 
X 
 
 
 
 
 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
22 
Approved, Date: 27 July 2017  
Period 
Screening 
Perioda 
Treatment Periodc 
Posttreatment 
Follow-up Period 
Week/Day 
W-6 
Baselineb
D1 
D2
D3 W1 W2 W3 W4
W6
W8ff
W10ff 
EOT 
(W8 or 
12)gg 
Treatment 
Withdrawal 
Visitd 
W4 
FU
W8 
FU
W12 
FU
W18 
FU 
W24 
FUe
Study Procedures 
Provision and explanation 
of medication diary 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection and review of 
medication diary, and 
review of used or unused 
study drugs 
 
 
X
X
X
X
X
X
X
X 
X 
X 
X 
 
 
 
 
 
Adherence counseling 
 
X 
X
X
X
X
X
X
X
X 
X 
X 
 
 
 
 
 
 
Efficacy Assessments 
HCV RNA determinationm 
X 
Xl 
X
X
X
X
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral sequencingn 
 
X 
 
 
X
X
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
Sparse PK - plasma 
concentrations of AL-335 
(and metabolites), ODV and 
SMVo 
 
 
 
 
 
Xp,s
 
Xp,r,
s 
Xp,s
Xp,s 
 
Xp,s 
 
 
 
Xq
 
 
Rich PK substudy - plasma 
concentrations of AL-335 
(and metabolites), ODV, 
and SMV 
 
 
 
 
See TIME AND EVENTS SCHEDULE: Rich serial PK Assessments 
Safety Assessments 
Physical examinationt 
X 
X 
 
 
X
X
 
X
 
X 
 
X 
X 
X 
 
 
 
X 
Vital signsu 
X 
X 
X
X
X
X
X
X
X 
X 
X 
X 
X 
X 
 
 
 
X 
Clinical Laboratory Assessments 
Hematology, biochemistry  
Xx 
Xv,w,bb  
 
 
X
Xv,bb
 
X
v,bb
Xbb
Xbb 
Xbb 
Xv,w,x,bb
Xx 
Xv,bb
Xdd
Xv,w
Xdd
X 
Urinalysis 
Xy 
X 
 
 
X
X
 
X
 
X 
 
X 
X 
X 
 
X 
 
X 
HBV DNAcc 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
Pharmacogenomics (blood sample) 
Host interleukin-28B 
(IL28B) genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
Period 
Screening 
Perioda 
Treatment Periodc 
Posttreatment 
Follow-up Period 
Week/Day 
W-6 
Baselineb
D1 
D2
D3 W1 W2 W3 W4
W6
W8ff
W10ff 
EOT 
(W8 or 
12)gg 
Treatment 
Withdrawal 
Visitd 
W4 
FU
W8 
FU
W12 
FU
W18 
FU 
W24 
FUe
Study Procedures 
Ongoing Subject Review 
Concomitant therapy 
X 
X 
X
X
X
X
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsz 
X 
X 
X
X
X
X
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Key: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CT=computed tomography; BNP=B-type natriuretic peptide; D=day(s); DNA=deoxyribonucleic 
nucleic acid; ECG=electrocardiogram; EOT=end-of-treatment; ICF=informed consent form; LLOQ=lower limit of quantification; HBV=hepatitis B virus; 
antiHBc=hepatitis B core antibody; HCV=hepatitis C virus; FU: follow-up; MRI= magnetic resonance imaging; ODV=odalasvir; PK=pharmacokinetic; 
RNA=ribonucleic acid; SMV=simeprevir; TSH= thyroid stimulating hormone; W=week 
 
a. 
The first screening assessment has to be performed within 6 weeks prior to the Baseline Visit. Retesting of values (eg, safety laboratory or HCV RNA) that lead to 
exclusion will be allowed once during the Screening Period to assess eligibility. Any potential delays in the Screening Period will be discussed with the sponsor 
and evaluated on a case-by-case basis. 
b. 
All baseline assessments need to be performed before study drug intake. 
c. 
Subjects should ensure intake of study drugs up to 8 weeks (56 ± 1 days) or 12 weeks (84 ± 1 days) of treatment, in order to complete the indicated treatment 
duration. A Data Review Committee (DRC) will be established in this study to perform reviews with focus on the safety. 
d. 
If study drug is discontinued prematurely, for reasons other than withdrawal of consent, a Treatment Withdrawal Visit should be scheduled as soon as possible 
after the EOT. The subjects will be followed up for 24 weeks after EOT, with visits as indicated in the TIME AND EVENTS SCHEDULE. If a subject 
discontinues treatment due to withdrawal of consent, the subject will be offered an optional Treatment Withdrawal Visit, to be scheduled as soon as possible after 
withdrawal and/or a safety Follow-up Visit, which needs to be scheduled 4 weeks after EOT. At the safety Follow-up Visit safety assessments of the W4 FU Visit 
need to be performed. 
e. 
Any subject who withdraws consent during the Follow-up Period and/or notifies the site that he or she will not return for study visits, will be invited to do a 
Follow-up Visit at the time of withdrawal to complete the full set of protocol procedures as scheduled for the Week 24 Follow-up Visit. However, all possible 
efforts should be made to ensure that subjects complete the study. 
f. 
Signing of the ICF can be done before the Screening Visit but needs to be done before the first study-related activity. 
g. 
Investigator to confirm eligibility based on the overall clinical picture. 
h. 
In subjects with cirrhosis, cirrhosis confirmed by a fibroscan or liver biopsy performed prior to or during the Screening Period. For subjects without cirrhosis, 
absence of cirrhosis confirmed by fibroscan performed or liver biopsy within 6 months of baseline (Day 1). 
i. 
Additional ECG or echocardiography may be done at any time during the study if clinically indicated in the opinion of the investigator. The subject will be 
instructed to rest in the supine position for 5 minutes before having an ECG assessment performed. If blood sampling or vital signs are scheduled at the same time 
point as the ECG recording, the procedures should preferably be performed in the following order: ECG, vital signs, and blood draw. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
j. 
For women of childbearing potential, a serum pregnancy test will be performed at screening and a urine pregnancy test is to be performed on-site on Day 1 and 
every 4 or 6 weeks up to the W24 FU Visit. 
k. 
Follicle-stimulating hormone will be tested for female subjects who are postmenopausal for less than 2 years. 
l. 
A blood sample needs to be taken at predose. The timing of the predose blood sample, as well as the timing of the dosing at baseline should be recorded. 
m. 
During follow-up, suspected relapse, ie, HCV RNA ≥LLOQ after previous <LLOQ, needs to be confirmed preferably within 2 weeks after the result has become 
available, and this retest may require an unscheduled visit which should be scheduled by the investigator. 
n. 
Viral sequencing will be performed at baseline by default in all subjects and at postbaseline in subjects not achieving sustained virologic response (SVR). 
Sequencing of additional samples may be triggered by the sponsor virologist. 
o. 
Sparse PK sampling for AL-335 (and metabolites), ODV, and SMV will be performed in all subjects. 
p. 
Sparse PK sample will be taken at predose, between 2 to 4-hours postdose, and between 4- to 6-hours postdose. Study drugs should be taken on site. 
q. 
Sparse PK sample will be taken any time during the visit for ODV only. 
r. 
No sparse PK sample will be taken for subjects participating in the rich serial PK substudy. 
s. 
Intake of study drugs should take place on site when predose PK sampling is performed. 
t. 
Complete physical examination (including height, body weight, and body systems) will be performed at screening (does not include breast, genitals, or rectal 
examination unless considered necessary by the investigator based on the subject’s past and present medical history). At all other time points, a targeted physical 
examination based on the medical history and overall clinical presentation (including body weight) will be performed. 
u. 
Systolic and diastolic blood pressure and pulse rate need to be taken supine after at least 5 minutes of rest. 
v. 
Biochemistry samples must be taken after fasting for at least 8 hours at these visits as the lipid profile is also assessed. 
w. 
An additional blood sample for biochemistry should be taken for assessment of insulin and glucose after fasting for at least 8 hours. 
x. 
Thyroid stimulating hormone (TSH) is to be assessed at screening and EOT or early withdrawal. 
y. 
Includes a urine drug screening test. 
z. 
All adverse events (AEs), whether serious or nonserious, and pregnancies will be reported from the time a signed ICF is obtained until the subject’s last study visit. 
aa. 
Subjects with cirrhosis have to receive an ultrasound scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) within 3 months prior to 
baseline/Day 1. 
bb. 
Includes assessment of B-type natriuretic peptide (BNP). 
cc. 
HBV DNA will be evaluated at the EOT Visit, or Treatment Withdrawal Visit, and may be evaluated at any time when there is a significant increase in the AST or 
ALT levels. This only refers to subjects with antiHBc and/or HBs antibody [antiHBs] positive status at screening and not to subjects who have received HBV 
vaccine and are only antiHBs positive. 
dd. 
Serum chemistry panel only, excluding TSH, BNP, glucose, insulin, and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. 
ee. 
Provision of study drug at Week 4 (all subjects) and 8 (Cohort 2 only) in principal. 
ff. 
Only for subjects enrolled in Cohort 2. 
gg. 
Week 8 (D56) for subjects enrolled in Cohort 1, and Week 12 (D84) for subjects enrolled in Cohort 2. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
TIME AND EVENTS SCHEDULE: WEEK/DAY AND TIME WINDOWS 
Period 
Screening 
Period 
Treatment Period 
Posttreatment 
Follow-up Period 
Week/ 
Day 
Cohort 1 
W-6 
Baseline 
D1 
D2 D3
W1
(D7)
W2
(D14)
W3
(D21)
W4
(D28)
W6
(D42)
- 
- 
EOT 
(D56) 
Treatment 
Withdrawal 
Visit 
W4 FU
(D84)
W8 FU
(D112) 
W12 
FU 
(D140) 
W18 
FU 
(D182)
W24 
FU 
(D224)
(D-42 to D0) 
-1 to + 1D 
(D6 to D8) 
-2 to + 2D 
(D12 to D16) 
-2 to + 2D 
(D19 to D23) 
-2 to + 2D 
(D26 to D30) 
-2 to + 2D 
(D40 to D44) 
- 
- 
-1 to + 1D 
(D55 to D57) 
-3 to + 3D 
(D81 to D87) 
-7 to + 7D 
(D105 to D119) 
-7 to + 7D 
(D133 to D147) 
-7 to + 7D 
(D175 to D189) 
-7 to + 7D 
(D217 to D231) 
Cohort 2 
W-6 
Baseline 
D1 
D2 D3
W1
(D7)
W2
(D14)
W3
(D21)
W4
(D28)
W6
(D42)
W8
(D56)
W10 
(D70)  
EOT 
(D84) 
Treatment 
Withdrawal 
Visit 
W4 FU
(D112)
W8 FU
(D140) 
W12 
FU 
(D168) 
W18 
FU 
(D210)
W24 
FU 
(D252)
(D-42 to D0) 
-1 to + 1D 
(D6 to D8) 
-2 to + 2D 
(D12 to D16) 
-2 to + 2D 
(D19 to D23) 
-2 to + 2D 
(D26 to D30) 
-2 to + 2D 
(D40 to D44) 
-2 to + 2D 
(D54 to D58) 
-2 to + 2D 
(D68 to D72) 
-1 to + 1D 
(D83 to D85) 
-3 to + 3D 
(D109 to D115) 
-7 to + 7D 
(D133 to D147) 
-7 to + 7D 
(D161 to D175) 
-7 to + 7D 
(D203 to D217) 
-7 to + 7D 
(D245 to D259) 
TIME AND EVENTS SCHEDULE: RICH SERIAL PK ASSESSMENTS 
Rich Serial PK Substudya (Approximately More Than 6 Subjects in Each Cohortb) 
Time of Visit 
Sampling Time (hours) 
 
Predose 
Dosing 
1 h 
2 h 
3 h 
4 h 
6 h 
8 h 
10 h 
12 h 
24 h 
Week 4c 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
Key: h=hour(s); ODV=odalasvir; PK=pharmacokinetic; SMV=simeprevir 
 
a. 
This may require an overnight stay in the hospital. 
b. 
Rich PK sampling for AL-335 (and metabolites), ODV, and SMV will be performed in approximately more than 12 subjects (Cohorts 1 and 2 combined). 
c. 
Study drugs should be taken on site. 
d. 
The predose sample should be collected before study drug intake (within 0.5 hour before). 
e. 
The 24 hour PK sample must be taken before study drug intake on the morning following the overnight stay. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
antiHBc 
hepatitis B core antibody 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC24h 
AUC from time 0 to 24 hours 
AV 
atrioventricular 
C0h 
predose plasma concentration 
CI 
confidence interval 
CK 
creatine kinase 
CK-MB 
creatine kinase muscle-brain 
Cmax 
maximum drug concentration 
Cmin 
minimum plasma concentration 
CT 
computed tomography 
CYP 
cytochrome P450 
DAA 
direct-acting antiviral 
DCV 
daclatasvir 
DDI 
drug-drug interaction 
DNA 
deoxyribonucleic acid 
DRC 
Data Review Committee 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDC 
electronic data capture 
EF 
ejection fraction 
eGFR 
estimated glomerular filtration rate 
EOT 
end-of-treatment 
FAS 
full analysis set 
FC 
fold change 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IL 
interleukin 
IWRS 
interactive web response system 
IRB 
Institutional Review Board 
IUS 
intrauterine hormone-releasing system 
LFC 
liquid-filled capsule 
LLOQ 
lower limit of quantification 
LVEF 
left ventricular ejection fraction 
MAD 
multiple ascending dose 
MRI 
magnetic resonance imaging 
MRP 
multidrug resistance-associated protein 
NS 
nonstructural protein 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
ODV 
odalasvir 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
27 
Approved, Date: 27 July 2017  
PD 
pharmacodynamic 
PegIFN 
pegylated interferon 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
popPK 
population PK 
PQC 
product quality complaint 
qd 
once daily 
qod 
once every other day 
QTc 
corrected QT interval 
QTcF 
QT corrected according to Fredericia's formula 
RAV 
resistance-associated variants 
RBC 
red blood cell 
RBV 
ribavirin 
RGT 
response-guided therapy 
RNA 
ribonucleic acid 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMV 
simeprevir 
SOF 
sofosbuvir 
SUSAR 
suspected unexpected serious adverse reaction 
SVR 
sustained virologic response 
t1/2,term 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach the maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
DEFINITIONS OF TERMS 
Study drugs: 
AL-335, odalasvir (ODV), and simeprevir (SMV) 
 
End-of-treatment (EOT) 
Completion of dosing or premature discontinuation of treatment, whichever is 
earlier 
On-treatment Virologic 
Response 
Subjects with hepatitis C virus (HCV) RNA not detected or HCV RNA <lower 
limit of quantification (LLOQ) (detected or not detected) at specified time points 
during treatment. 
 
Sustained Virologic 
Response (SVRX) 
Subjects achieve SVRX if HCV RNA <LLOQ (detected or not detected) X weeks 
after the actual EOT. 
 
Failure (no SVR12) 
Subjects who do not achieve SVR12, including: 
on-treatment failure (see below) 
posttreatment failure, including subjects with: 
- viral relapse (see below) 
- missing HCV RNA at time point of SVR12 
 
On-treatment Failure 
Subjects who do not achieve SVR12, with confirmed HCV RNA ≥LLOQ at the 
actual EOT. Includes subjects with: 
- viral breakthrough, defined as a confirmed increase of >1.0 log10 IU/mL in 
HCV RNA from nadir or confirmed HCV RNA >2.0 log10 IU/mL in 
subjects who had previously achieved HCV RNA <LLOQ (detected or not 
detected) while on treatment. 
- other with confirmed HCV RNA ≥LLOQ at the actual EOT (eg, completed 
study drug treatment, discontinued due to AEs, withdrawal of consent). 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
Viral Relapse 
Subjects who did not achieve SVR12, with HCV RNA <LLOQ at the EOT and 
confirmed HCV RNA ≥LLOQ during follow-up. 
Late viral relapse 
Subjects who achieved SVR12 but have confirmed HCV RNA ≥LLOQ afterwards 
during follow-up (after W12 FU, and before or at W24 FU visit). 
1. 
INTRODUCTION 
AL-335 (also known as JNJ-64146212) is a uridine-based nucleoside monophosphate prodrug 
(or nucleotide analog) targeting the hepatitis C virus (HCV) nonstructural protein (NS)5B 
polymerase, being developed for the treatment of chronic HCV infection. 
Odalasvir (ODV, JNJ-64289901, also known as ACH-0143102 and ACH-3102) is an inhibitor of 
the HCV NS5A complex, being developed for the treatment of chronic HCV infection. 
Simeprevir (SMV, also known as TMC435) is an HCV NS3/4A protease inhibitor approved for 
the treatment of chronic HCV genotype 1 and 4 infections. 
For the most comprehensive nonclinical and clinical information regarding AL-335, ODV, and 
SMV, refer to the latest version of the Investigator's Brochure (IB) and addenda, for AL-335,16,18 
ODV,19,20 and SMV.21,22 
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document. 
1.1. 
Background 
1.1.1. 
HCV Infection 
Hepatitis C virus infection is a leading cause of liver disease worldwide. An estimated 130 to 
150 million people (about 2.0% of the global population) are currently infected with HCV,36 with 
an incidence of 3 to 4 million new infections per year.37 Between 70.0% and 90.0% of acute 
HCV infections become chronic and may lead to liver cirrhosis, chronic liver failure, 
hepatocellular carcinoma, liver transplantation, and death.8,25,37 Complications of HCV infection 
are currently the most common indication for liver transplantation. In the US alone, it is 
estimated that currently 3 to 4 million people are chronically infected with HCV; it is projected 
that by the year 2020, about 1 million of those will have cirrhosis.7 The risk of hepatic 
decompensation in subjects with cirrhosis is approximately 5.0% per year and the 5-year survival 
rate after decompensation is around 50.0%.4 
Hepatitis C virus has been classified into at least 6 major genotypes (designated 1 to 6) and many 
subtypes (a, b, c, etc).7 Epidemiology studies have shown marked differences in genotype 
distribution of HCV by geographic region and patient population. A recent study reported that 
genotype 1 is estimated to account for more HCV cases globally than any other genotype 
(46.0%), followed by genotype 3 (30.0%), genotype 2 (9.0%), genotype 4 (8.0%), genotype 6 
(5.0%), and genotype 5 (<1.0%).27 Genotype 1b is the most common subtype, accounting for 
22.0% of all infections. Infections in North America, Latin America, and Europe are 
predominantly of genotype 1. North Africa and the Middle East were found to have a large 
genotype 4 population (71.0%), which is related to the high prevalence of genotype 4 in Egypt. 
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Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
Asia has predominantly genotype 3 (39.0%), largely driven by the HCV infections in India and 
Pakistan, followed by genotype 1 (36.0%).12 
In Japan, the number of patients with chronic Hepatitis C viremia is estimated to be 1.5 to 
2 million. The distribution of HCV genotype 1b, 2a, and 2b was reported as 70%, 20%, and 10%, 
respectively. Almost all of HCV genotype 1 in Japan is of the 1b subtype.30 
1.1.2. 
Treatment of HCV Infection 
Until 2011, standard-of-care treatment for chronic HCV infection consisted of the combination 
of pegylated interferon (PegIFN) and ribavirin (RBV). In 2011, telaprevir and boceprevir, in 
combination with PegIFN/RBV, were the first approved direct-acting antivirals (DAAs) for the 
treatment of chronic HCV infection. SMV and sofosbuvir (SOF) were the first DAAs approved 
as part of an interferon (IFN)-free regimen for the treatment of chronic HCV infection as 
specified in their prescribing information.28,29,32 Since 2014, additional DAAs, including 
daclatasvir (DCV) (Daklinza®),6 dasabuvir (Exviera®)9 and the fixed-dose combinations 
SOF/ledipasvir 
(Harvoni®)13 
and 
ombitasvir/paritaprevir/ritonavir 
(Viekirax®)35 
and 
Technivie®),34 have been approved for use in the United States, European Union, and/or in other 
regions. 
In Japan, telaprevir (Telavic®) in combination with PegIFN/RBV, were the first approved DAAs 
for the treatment of chronic HCV infection in 2011. In November 2013, SMV (Sovriad®),33 a 
protease inhibitor was approved for patients with genotype 1 and high HCV RNA levels, and in 
July 2014, the combination of asunaprevir (ASV) (Sunvepra®) and DCV (Daklinza) was 
approved for patients with genotype 1 This first IFN-free treatment combination allowed the 
treatment of IFN-ineligible patients and improved outcome in patients with prior nonresponse to 
IFN-based treatment. Since 2014, the fixed dose combinations SOF/LDV (Harvoni) and 
combination therapy with paritaprevir/ombitasvir/ritonavir (Viekirax) were approved for 
genotype 1. For IFN-free treatment of genotype 2, the combination of SOF (Sovaldi) with RBV 
was approved in March 2015.2 
The removal of PegIFN and RBV from HCV treatment combinations leads to improved safety 
and tolerability, with a significant decrease in associated adverse events (AEs). In addition, 
combinations of DAAs may overcome nonresponsiveness to PegIFN by increasing antiviral 
activity and reducing the risk of developing resistance-associated variants (RAVs). Furthermore, 
an all oral, 1-tablet, fixed-dose-combination treatment without the AEs associated with IFN may 
facilitate treatment adherence and improve the chance of achieving sustained virologic response 
(SVR). All-oral treatment regimens consisting of 2 (eg, SMV/SOF; Harvoni, Zepatier, Epclusa, 
Viekirax/Technivie) or 3 (eg, Viekirax+Exviera/Viekira Pak) DAAs within the classes of 
HCV NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors have been 
approved in several countries, and high SVR rates have been demonstrated for such regimens. 
New all-oral IFN- and RBV-free regimens are currently under investigation. An optimal 
IFN-free regimen for treatment of chronic HCV infection requires a combination of agents with 
different mechanisms of action. Available data suggest that addition of a third antiHCV agent to 
a 2-DAA regimen may increase the robustness of the regimen to allow for a shorter treatment 
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AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
duration compared to currently available treatment regimens while maintaining high efficacy, 
particularly when considering more difficult-to-cure patients.24 
The current open-label Phase 2a study is designed to investigate the safety, efficacy, and 
pharmacokinetics (PK) of an 8 or 12-week combination regimen of AL-335, ODV, and SMV in 
DAA-naïve Japanese subjects with genotype 1 or 2 chronic HCV infection with or without 
compensated cirrhosis. 
1.1.3. 
Background of AL-335 
AL-335 is a uridine-based nucleoside monophosphate prodrug (or nucleotide analog) being 
developed in combination with ODV and SMV as an orally administered antiHCV therapeutic. 
A summary of in vitro, nonclinical and clinical data for AL-335 is provided below; more details 
can be found in the IB and its addenda.16,17,18 
In Vitro/Nonclinical Data 
AL-335 is a potent and highly selective inhibitor of NS5B-directed HCV ribonucleic acid (RNA) 
replication in vitro, with similar potency across HCV replicons containing NS5B coding 
sequence derived from genotypes 1a, 1b, 2b, 3a, 4a, 5a, and 6a. In a stable HCV genotype 1b 
replicon, AL-335 demonstrated a 50% effective concentration (EC50) of 0.075 µM. The EC50 of 
AL-335 against chimeric replicons harboring the NS5B from genotypes 2b, 3a, 4a, 5a, and 6a 
strains was 0.04, 0.06, 0.06, 0.07, and 0.07 µM, respectively. AL-335 retains potent antiviral 
activity against HCV replicons that show resistance to DAAs with other mechanisms of action. 
AL-335 (prodrug) is well absorbed in rats and dogs. Both in vitro and in vivo, AL-335 is 
efficiently and rapidly metabolized to form the active nucleoside 5’-triphosphate (ALS-022235). 
AL-335 is efficiently converted to ALS-022235 in human hepatocytes. After single oral 
administration of 14C-AL-335 to rats and dogs, 15.0% and 36.0% of the administered 
radioactivity was recovered in urine. Oral administration of (nonlabeled) AL-335 revealed that 
AL-335 was recovered mainly as the metabolites in urine with only 0.0006% to 0.17% of 
AL-335 excreted in urine in rats and dogs. In contrast, 0.02% to 2.0% of ALS-022399 
(metabolite) and 4.0% to 18.0% of ALS-022227 (metabolite) is excreted in urine in rats and dogs, 
respectively. 
AL-335 (and its 2 metabolites ALS-022227 and ALS-022399; AL-335, the metabolites 
ALS-022399 and ALS-022227 are hereafter referred to as AL-335 [and metabolites]) are not 
expected to cause drug-drug interactions (DDIs) with other drugs that are metabolized by 
cytochrome P450 (CYP) enzymes. AL-335 is metabolized by esterases and is not a substrate of 
any CYP enzymes. AL-335 (and metabolites) has demonstrated a very low inhibition potential to 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A. AL-335 is a 
substrate for P-glycoprotein (P-gp) but does not inhibit P-gp. ALS-022399 and ALS-022227 are 
neither substrates nor inhibitors of P-gp, organic anion transporting polypeptide (OATP) 1B1, 
OATP1B3, organic anion transporter (OAT) 1, OAT3, or organic cation transporter (OCT) 2 
transport. 
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AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
AL-335 was well tolerated in all toxicology studies; following 91 days of repeated dosing, the 
target organs for toxicity were not identified even when dosed up to the maximum recommended 
doses of 1,000 mg/kg/day in both rats and dogs. In the dog cardiovascular study, emesis and 
slight increases in heart rate (~10.0%) and body temperature (<1°C) were observed at the 
1,000 mg/kg dose. All of these findings were monitorable and reversible, and all were considered 
nonadverse. 
In vitro inhibition of human deoxyribonucleic acid (DNA) polymerase alpha, beta, and gamma 
and of human RNA polymerase II was insignificant under the conditions used. In addition, 
ALS-022235 was not a substrate for the human mitochondrial RNA polymerase and AL-335 did 
not inhibit mitochondrial protein synthesis in HepG2 cells. Taken together, the data suggest a 
high degree of selectivity of AL-335 for inhibition of the HCV NS5B polymerase. 
Clinical Experience 
Up to 28 August 2015, 40 healthy subjects had received single doses up to 1,200 mg (single 
ascending dose [SAD]) or multiple ascending doses (MADs) of AL-335 of 400 mg and 800 mg 
for 7 days (AL-335-601). This study also evaluated the monotherapy of AL-335 in HCV 
genotype 1, 2, 3, and 4-6-infected subjects. In the cohorts completed at the time of the initial 
protocol writing, subjects had received AL-335 400 mg (genotype 1 only) or 800 mg (genotype 1 
to 4) for 7 days. 
In addition, safety data from a DDI study with AL-335, ODV, and SMV (AL-335-602) in 
healthy subjects are available. 
A Phase 2a study (AL-335-604) is ongoing, with AL-335, ODV, and SMV in HCV genotype-1 
and 3-infected treatment-naïve subjects. Preliminary data from this ongoing study are available. 
More information on the studies including AL-335+ODV±SMV is provided in Section 1.2. 
Pharmacokinetics 
In the SAD/MAD study (AL-335-601), after single oral ascending doses of 100 to 1,200 mg of 
AL-335, AL-335 (prodrug) was rapidly absorbed (median time to reach the maximum plasma 
concentration [tmax] 30 to 45 minutes) and converted to ALS-022399. The terminal elimination 
half-life (t1/2,term) of AL-335 was 30 to 60 minutes. In healthy subjects, both the maximum 
plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of 
AL-335 increased in a dose-proportional manner except at higher doses (ie, 800 and 1,200 mg) 
for Cmax, which appeared less than dose proportional. Food had a moderate effect on AUC, 
increasing AL-335 exposure by 61% with no effect on Cmax. Bioavailability of the oral 
suspension was lower than the tablets (44% and 42% decrease in Cmax and AUC, respectively). 
Upon multiple dosing up to 800 mg, AL-335 Cmax and AUC appeared dose proportional between 
400 mg and 800 mg; there was no accumulation of AL-335 between Day 1 and 7. 
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Efficacy and Safety 
In the 40 healthy subjects of Study AL-335-601, there were no serious adverse events (SAEs), 
and no clinically relevant laboratory, electrocardiogram (ECG), Holter, vital sign, or physical 
examination safety signals have been identified. Three subjects reported 4 AEs, 1 of which 
emerged prior to dose administration. For the treatment-emergent AEs (TEAEs), 1 subject 
experienced mild intermittent palpitations 72 hours after dosing. The event did not require 
concomitant medication or other intervention, was not associated with objective evidence of 
tachycardia, and was deemed unlikely to be related to the study drug. The second TEAE, 
moderate dental pain (2 events), occurred 9 hours postdose and again 6 days after dosing. These 
events were assessed as unrelated to the study drug. 
In the same Phase 1b study, multiple ascending doses of AL-335 (400 or 800 mg) over 7 days 
were evaluated in 20, 10, and 10 subjects with genotype 1, 2, or 3 chronic HCV infection, 
respectively. Thirty-two subjects received active study drug (400 or 800 mg AL-335 
[genotype 1], or 800 mg only [genotypes 2 and 3]) and 8 received placebo. In Study AL-335-601, 
monotherapy with AL-335 800 mg once daily (qd) for 7 days resulted in a mean maximum 
decline in HCV RNA from baseline of 4.00 log10 IU/mL in HCV genotype 1 and of 
4.46 log10 IU/mL and 4.72 log10 IU/mL in HCV genotypes 2 and 3, respectively. In all genotypes 
tested, HCV RNA returned to baseline levels around 14 days after the last dose (see Section 1.2). 
No SAEs and a total of 26 AEs have been reported after initiation of dosing. The most 
commonly reported AEs (≥2 events reported) were headache (8 events), increased creatine 
kinase (CK; 2 events), elevated alanine aminotransferase (ALT; 2 events) and elevated aspartate 
aminotransferase (AST; 2 events). The ALT and AST elevations each occurred in 2 subjects 
≥10 days after the conclusion of dosing and were similar in magnitude to baseline (predose) 
levels. Three AEs occurred 1 time each: fatigue, common cold, and increased bilirubin. All AEs 
were mild (8 events) or moderate (8 events) in severity with the exception of 1 event of elevated 
CK, which was considered severe but not serious. This subject was asymptomatic and had a 
history of elevated CK levels related to body building activities. His CK levels peaked at Day 3 
of dosing and then declined despite continuing dosing through study completion (Day 7). 
Including the laboratory-based AEs described above, no clinically relevant laboratory, ECG, 
Holter, vital sign, or physical examination safety signals have been identified to date. 
1.1.4. 
Background of ODV 
ODV is an HCV NS5A inhibitor being developed in combination with AL-335 and SMV as an 
orally administered antiHCV therapeutic. 
A summary of in vitro, nonclinical, and clinical data for ODV is provided below; more details 
can be found in the IB and its addendum.19,20 
For details on the clinical studies including ODV, see Section 1.2. 
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In Vitro/Nonclinical Data 
ODV is a highly potent HCV NS5A inhibitor with a mean EC50 of 5.3 pM and 26 pM against 
genotypes 1b and 1a HCV replicons, respectively, and 6.4 to 27 pM and 9.0 to 20 pM against 
chimeric replicons carrying NS5A from genotypes 1b and 1a clinical isolates, respectively. The 
EC50 values of ODV against chimeric replicons carrying the N-terminus of NS5A from 
representative strains of genotypes 2a, 2b, 3a, 4a, 5a, and 6a are 25, 215, 48, 8, 15, and 58 pM, 
respectively. ODV has demonstrated potent antiviral activity against most HCV replicons that 
show resistance to other HCV NS5A inhibitors. 
ODV has a long t1/2,term in plasma (rat: up to 55 hours; dog: up to 114 hours; monkey: 65.8 hours). 
The plasma half-life after oral administration was long and was a consequence of slow 
elimination from tissues and low plasma clearance. A 2- to 5-fold accumulation occurred with 
multiple dose administration. Plasma protein binding of ODV was 97.0% or greater in rat, dog, 
and human plasma. 
Preclinical data indicate that 91.0% to 98.0% of the administered oral dose of ODV is recovered 
in excreta by 168 hours postdose and excretion of drug-derived radioactivity was primarily 
through biliary and/or gastrointestinal secretion. Drug-derived radioactivity was preferentially 
distributed into kidneys, brown fat, liver, pancreas, small intestine, thyroid, and spleen. 
In nonclinical studies, ODV has demonstrated a low inhibition potential for CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A. ODV is primarily cleared by biliary 
secretion, is not significantly metabolized, and is not expected to be involved with clinically 
significant DDIs associated with the CYP enzyme system. ODV is not an inhibitor of OATP1B1, 
OATP1B3, and is neither a substrate nor an inhibitor of transporters such as breast cancer 
resistance protein, multidrug resistance-associated protein (MRP)2, MRP3, and bile salt export 
pump. ODV is a low-affinity substrate of OATP1B1. ODV is not a substrate but is an inhibitor 
of P-gp. 
The toxicology profile for ODV has been established in single- and repeated-dose toxicology 
studies, reproductive toxicity studies, and genotoxicity studies. ODV was, in general, well 
tolerated in all toxicology studies. 
The heart is a target organ of ODV toxicity, based on the findings in repeat-dose toxicity studies 
in rats and dogs up to 26 weeks duration. While ODV did not have any effect on human 
ether-a-go-go-related gene (hERG) channel current in vitro or in single-dose dog cardiovascular 
studies, repeated dosing of ODV in dogs leading to exposure levels 14 times higher as compared 
to the target exposure in the current study was associated with ECG changes (prolonged PR 
and/or 1st degree atrioventricular [AV] block, prolonged QRS, QT, and corrected QT interval 
[QTc] intervals, and decreased heart rate), and echocardiography findings (progressive left 
ventricular dilatation, eccentric hypertrophy). Increased heart weights were noted following 
repeated dosing in rats and dogs. All those findings were partially to fully reversible. For more 
information, see Section 1.3.2.2. 
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Clinical Protocol 64294178HPC2003 Amendment 5 
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Clinical Experience 
As of 9 April 2015, more than 500 healthy volunteers and HCV-infected subjects have 
participated in clinical studies including SAD, MAD, single dose proof-of-concept, DDI studies, 
and clinical studies of up to 12 weeks in duration. A total of 440 subjects have received ODV. Of 
the subjects dosed with ODV, 365 were healthy subjects and 75 were HCV-infected subjects. 
Since 9 April 2015, 2 additional studies, conducted under the responsibility of Alios BioPharma 
Inc, were initiated, ie, Study AL-335-602 and Study AL-335-604. Safety data from the DDI 
Study AL-335-602 with AL-335, ODV, and SMV in healthy subjects are available. Preliminary 
data from the ongoing Study AL-335-604 with AL-335, ODV, and SMV in HCV genotype 1 and 
3-infected treatment-naïve subjects are available. More information on these studies including 
AL-335+ODV±SMV is provided in Section 1.2. 
Pharmacokinetics 
ODV has a t1/2,term of about 250 hours as determined from single-dose data in healthy volunteers. 
In general, the biphasic decline in plasma concentrations from Cmax may be characterized by a 
rapid phase, followed by a more prolonged, slower phase of decline. In the rapid phase, plasma 
concentrations generally decline to 10.0% of Cmax values by 4 to 5 days after dose administration. 
The PK behavior of ODV is comparable between healthy volunteers and HCV-infected subjects. 
After chronic dosing, the plasma half-life for washout of ODV in HCV infected subjects is 
approximately 4 to 5 weeks. Plasma sampling beyond a 12-week Dose Period suggested that it 
would take approximately 20 to 24 weeks after the end of dosing to achieve effective clearance 
of the drug. 
No clinically significant DDIs were observed between ODV and sovaprevir, montelukast, 
atazanavir/ritonavir, efavirenz/emtricitabine/tenofovir disoproxil fumarate, darunavir/ritonavir, 
or raltegravir. 
Efficacy and Safety 
Efficacy data on different DAA combinations including ODV are described in Section 1.2. 
In the completed clinical studies of ODV, including administration of single ODV doses as high 
as 1,000 mg, and multiple qd doses as high as 100 mg for 14 days in healthy volunteers, and 
75 mg for 12 weeks in chronic HCV infected subjects, ODV has been well tolerated. In some 
studies, the ODV dose regimens included a loading dose on Day 1, but ODV in combination 
with SOF has been used successfully without a loading dose in a recent Phase 2a study, 
ACH102-017. ODV has been studied in combination with other antiviral agents such as RBV, 
sovaprevir, and SOF, and has been well-tolerated in each of these settings as well. 
Cardiac monitoring in these studies with ODV in HCV-infected subjects did not identify any 
clinically significant trends. One SAE of asymptomatic second-degree Mobitz type 1 AV block 
was reported in a subject in Study AL-335-604 with a borderline elevated PR interval at 
screening. The event led to discontinuation of the study drugs (AL-335, ODV, and SMV) and 
was considered probably related to ODV by the investigator. Echocardiography remained normal 
and the event was considered a benign conduction disorder which appeared to have settled 
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Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
4 days after study drug discontinuation, and no further investigations were considered needed. In 
Study ACH102-005, a treatment-emergent PR prolongation was observed until treatment 
Week 12; this event evolved to a transient Type 1 2nd degree AV block. The cardiologist 
assessed the subject's 2nd degree AV block to be of undetermined etiology but unlikely due to 
study drug. The subject completed the full course of 12 weeks therapy with ODV and RBV. 
Based on the currently available data, the cardiac safety profile of ODV is acceptable to conduct 
the present study. 
1.1.5. 
Background of SMV 
SMV is an HCV NS3/4A protease inhibitor approved in 2013 in the US, Canada, and Japan for 
the treatment of patients with chronic HCV genotype 1 infection. Since that time, SMV has been 
approved in the European Union and other countries, and regions globally for the treatment of 
chronic HCV genotypes 1 and 4 infection with and without human immunodeficiency virus 
(HIV) coinfection. Additional registration procedures are ongoing worldwide. The marketed 
SMV formulation is an oral capsule. Each hard capsule contains SMV sodium equivalent to 
150 mg (globally except Japan) or 100 mg (Japan only). The estimated cumulative 
postauthorization exposure to SMV is over 95,000 treatment courses (from launch to 
31 May 2015). 
A summary of in vitro nonclinical and clinical data for SMV relevant to the present study is 
provided below; more details can be found in the IB and its addendum.21,22 For details on 
IFN-free studies including SMV, see Section 1.2. 
In vitro/Nonclinical Data 
SMV is highly protein-bound in plasma (>99.9%) at pharmacologically relevant concentrations. 
The median SMV EC50 and 90% effective concentration (EC90) against an HCV genotype 1b 
replicon were 9.4 nM (7.05 ng/mL) and 19 nM (14.25 ng/mL), respectively. Chimeric replicons 
carrying NS3 sequences derived from HCV protease inhibitor treatment naïve genotype 1a and 
genotype 1b patients displayed median fold change (FC) in EC50 values of 1.4 (N=78) and 
0.4 (N=59) compared to reference genotype 1b replicon, respectively. Genotypes 1a and 1b 
isolates with a baseline Q80K polymorphism resulted in median FC in SMV EC50 of 11 (N=33) 
and 8.4 (N=2), respectively. Median SMV FC values against genotype 2 and genotype 3 baseline 
isolates tested were 25 (N=4) and 1,014 (N=2). Median SMV FC values against genotypes 4a, 4d, 
and 4 other baseline isolates tested were 0.5 (N=38), 0.4 (N=24), and 0.8 (N=29), respectively. 
Clinical Experience 
Clinical data for SMV in combination with RBV/PegIFN are available from 9 global Phase 3, 
2 Phase 2b, and 2 Phase 2a clinical studies. During these studies 2,649 HCV-infected subjects 
were exposed to SMV. Of these, 1,808 HCV-infected subjects were treated with 
SMV 150 mg qd for 12 weeks. Data from SMV IFN-free clinical studies are available from 
2 Phase 3 and 2 Phase 2 studies. In these studies, 580 HCV-infected subjects received SMV in 
combination with SOF with or without RBV and 168 HCV-infected subjects received SMV in 
combination with DCV with or without RBV. Other SMV-containing IFN-free studies are 
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Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
ongoing. In addition, data are available from 30 Phase 1 studies, during which 
1,027 nonHCV-infected subjects were exposed to SMV and 8 studies conducted in Japan 
(4 Phase 3, 1 Phase 2 and 3 Phase 1 studies) including 434 HCV-infected treatment-naïve and 
treatment-experienced subjects who received SMV. 
Pharmacokinetics 
The blood to plasma ratio of SMV is approximately 0.66, indicating that SMV is largely 
contained in the plasma rather than the cellular components of the blood. 
SMV formulated as an oral capsule, was readily absorbed. In healthy subjects, tmax was 4 to 
6 hours. 
In chronic HCV genotype 1-infected subjects, the exposure was generally greater than observed 
in healthy subjects. In subjects with chronic hepatitis C, t1/2,term was approximately 41 hours, a 
profile that supports a qd dosing regimen. Renal clearance plays an insignificant role in the 
elimination of SMV and its metabolites. 
Compared to intake without food, administration of SMV with food to healthy subjects increased 
the AUC by 61.0% after a high fat, high caloric breakfast (928 kcal) and by 69.0% after a normal 
caloric breakfast (533 kcal), and delayed the absorption by 1 hour and 1.5 hours, respectively. 
SMV should be taken with food. 
A number of Phase 1 PK and DDI studies have been conducted with SMV and are summarized 
in the IB including the following: the methadone interaction Study C110, which demonstrated no 
interaction between SMV and methadone. 
CYP3A enzymes are mainly involved in the metabolism of SMV. 
SMV is a mild inhibitor of intestinal (but not hepatic) CYP3A activity and a mild inhibitor of 
CYP1A2. In addition, DDI studies with transporter substrates suggest that SMV likely inhibits 
P-gp and OATP1B1 in vivo. 
Efficacy and Safety 
SMV at a dose of 150 mg qd in combination with PegIFN/RBV has demonstrated statistically 
significantly higher efficacy compared to PegIFN/RBV alone and a favorable safety/tolerability 
profile in HCV treatment-naïve and treatment-experienced subjects with chronic HCV 
genotype 1 with or without HIV-type 1 (HIV-1) coinfection and in subjects with chronic HCV 
genotype 4 infection, with no clinically relevant additional toxicity.28,29 
SVR rates of SMV in combination with PegIFN/RBV were reduced in subjects with hepatitis C 
genotype 1a with NS3 Q80K polymorphism compared to subjects without Q80K polymorphism. 
In the Phase 2a Study TMC435350-TiDP16-C202, treatment-naïve subjects with HCV 
genotypes 2, 3, 4, 5, and 6 infections were treated with SMV 200 mg qd monotherapy for 7 days. 
Monotherapy with oral SMV 200 mg qd for 7 days showed potent antiviral activity against HCV 
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Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
genotypes 2, 4, 5, and 6. For the primary endpoint at Day 8, the mean (±standard error) change in 
plasma HCV RNA (log10 IU/mL) from baseline was the greatest for genotypes 6 (-4.35±0.29) 
and 4 (-3.52±0.43), followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39). No clear antiviral 
activity with SMV monotherapy was observed against HCV genotype 3. The efficacy in HCV 
genotype 4-infected subjects was confirmed in the Phase 3 Study TMC435HPC3011 
(RESTORE). 
In Phase 2 Studies TMC435HPC2002 and TMC435HPC2014 (COSMOS and OSIRIS, 
respectively) and Phase 3 Studies TMC435HPC3017 (OPTIMIST-1), TMC435HPC3018 
(OPTIMIST-2), and TMC435HPC3021 (PLUTO), high SVR at 12 weeks after the 
end-of-treatment 
(EOT) 
(SVR12) 
rates 
were 
observed 
in 
treatment-naïve 
and 
treatment-experienced HCV genotype 1- or genotype 4-infected subjects with and without 
cirrhosis treated with SMV and SOF; for more details on SMV in an all-oral combination 
regimen, refer to Section 1.2. 
1.2. 
Background to All-oral DAA Combination Regimens 
A summary of available data for AL-335, ODV, and SMV containing all-oral regimens in 
HCV-infected subjects is provided below. 
Combination of an NS3/4A Protease Inhibitor and a Nucleotide NS5B Polymerase 
Inhibitor: SMV/SOF 
HCV genotype 1-infected subjects 
In the Phase 2 Study TMC435HPC2002, in HCV genotype 1-infected treatment-naïve subjects 
and null responders to prior PegIFN/RBV therapy who were treated with SMV 150 mg qd for 
12 or 24 weeks in combination with SOF 400 mg qd with or without RBV, high SVR12 rates 
(≥90.0%) were observed irrespective of treatment duration, treatment with or without RBV, and 
prior treatment history. The overall SVR12 rate in subjects receiving 12 weeks of SMV in 
combination with SOF with or without RBV was 94.0%. Similar SVR12 rates were observed for 
HCV genotype 1a-infected subjects with and without baseline Q80K polymorphism. 
In Phase 3 Studies TMC435HPC3017 and TMC435HPC3018, treatment-naïve and 
treatment-experienced (to prior IFN-based treatment with or without RBV) subjects with chronic 
HCV genotype 1 infection, without and with cirrhosis, respectively, were treated with SMV 
150 mg qd in combination with SOF 400 mg qd for 12 or 8 weeks. 
 
The SVR12 rate of 96.8% in chronic HCV genotype 1-infected treatment-naïve or 
treatment-experienced subjects without cirrhosis treated with a 12-week SMV+SOF regimen 
was superior versus the historical control SVR12 rate of 87.0% (composite of approved 
DAA/PegIFN/RBV regimens). High SVR12 rates were observed for the 12-week regimen, 
regardless of the subgroup analyzed. 
 
The SVR12 rate of 82.6% in subjects treated with an 8-week SMV+SOF regimen in the 
TMC435HPC3017 study was not superior versus the historical control SVR12 rate of 83.0%. 
Higher SVR12 rates were observed among those subjects with more favorable demographic 
and baseline disease characteristics. 
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 
The SVR12 rate of 83.5% in chronic HCV genotype-1 infected treatment-naïve or 
treatment-experienced subjects with cirrhosis treated with a 12-week SMV+SOF regimen in 
the TMC435HPC3018 study was superior versus the historical control SVR12 rate of 70%. 
Pooled data from Studies TMC435HPC2002, TMC435HPC3017, and TMC435HPC3018, 
indicated that treatment of HCV genotype 1-infected subjects who are treatment-experienced or 
treatment-naïve (with or without cirrhosis) with SMV 150 mg qd and SOF 400 mg qd was 
generally safe and well tolerated irrespective of the treatment duration (8, 12, or 24 weeks of 
SMV+SOF). No new confirmed safety issues were identified other than those observed with 
SMV in combination with PegIFN and RBV. 
Serious adverse events and AEs leading to discontinuation of study drugs were rare in these 
studies. 
Although there was a trend for a higher incidence of AEs in subjects receiving 24 weeks of 
treatment, no clinically relevant differences were observed in the incidence of Grade 3 or 4 AEs, 
SAEs, or AEs leading to discontinuation of study drugs between the 8-, 12-, and 24-week 
treatment duration groups. No clinically relevant differences in safety were observed between the 
subgroup of patients with cirrhosis as compared to those without cirrhosis, despite a trend 
towards more rash AEs (AE of clinical interest) in subjects with cirrhosis. 
HCV genotype 4-infected subjects 
In the Phase 2a Study TMC435HPC2014, in HCV genotype 4-infected treatment-naïve and 
treatment-experienced (to prior IFN-based treatment with RBV) subjects who were treated with 
SMV 150 mg qd for 8 or 12 weeks in combination with SOF 400 mg qd, high SVR12 rates were 
observed. An SVR12 rate of 100% was observed after treatment for 12 weeks in subjects with 
and without cirrhosis and regardless of prior treatment history. An SVR12 rate of 75% was 
observed in subjects without cirrhosis who were treated for 8 weeks. 
In Phase 3 Study TMC435HPC3021, HCV genotype 4-infected treatment-naïve and 
treatment-experienced (to prior IFN-based treatment with or without RBV) subjects were treated 
with SMV 150 mg qd for 12 weeks in combination with SOF 400 mg qd. Regardless of prior 
treatment history, 100.0% of subjects with and without cirrhosis achieved SVR12 and SVR 
24 weeks after the EOT (SVR24). 
Data from Studies TMC435HPC2014 and TMC435HPC3021 indicated that treatment of HCV 
genotype 4-infected subjects who are treatment-experienced or treatment-naïve (with or without 
cirrhosis) with SMV 150 mg qd and SOF 400 mg qd was generally safe and well tolerated. 
Combination of an NS3/4A Protease Inhibitor and an NS5A Inhibitor 
SMV/DCV 
The AI444-062 Phase 2 study, performed by Bristol-Myers Squibb, evaluated the use of 
SMV 150 mg qd in combination with DCV 30 mg qd, with and without RBV, for 12 or 24 weeks 
in subjects with chronic HCV genotype 1 infection who were HCV treatment-naïve (N=116) or 
null responders to prior PegIFN/RBV therapy (N=52).38 SVR12 was achieved in 74.5% and 
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84.9% of HCV genotype 1b-infected treatment-naïve subjects treated with and without RBV, 
respectively, and in 65.2% and 95.0% of HCV genotype 1b-infected prior null responders treated 
without and with RBV, respectively. Subjects with genotype 1a infection all received SMV and 
DCV with RBV and SVR12 rates for treatment-naïve subjects were 66.7%; viral breakthrough 
occurred frequently in the prior null responders (7 of 9 subjects). 
Treatment with SMV 150 mg qd and DCV 30 mg qd with or without RBV was generally safe 
and well tolerated. Most AEs were Grade 1 or 2. Grade 3 or 4 AEs were reported in 10.0% (9/92) 
and 5.0% (4/76) of subjects treated with SMV and DCV with and without RBV, respectively. 
One death during treatment was reported (trauma-associated intracranial hematoma, unrelated to 
the study drug). Serious adverse events occurred in 4.0% (4/92) and 9.0% (7/76) of subjects 
treated with SMV and DCV with and without RBV, respectively. Serious adverse events were 
related to study drug in 2 subjects (neurotoxicity, liver disorder). Adverse events leading to early 
discontinuation were reported in 2.0% (2/92) and 3.0% (2/76) of subjects treated with SMV and 
DCV with and without RBV, respectively. Three subjects had treatment-related AEs leading to 
early discontinuation (constipation, neurotoxicity, and insomnia/sleep terror). Grade 3 or 4 
hyperbilirubinemia occurred in 15.0% (14/92) and 4.0% (3/76) of subjects treated with SMV and 
DCV with and without RBV, respectively. 
ODV/sovaprevir 
ACH102-007 was a placebo-controlled Phase 2 study to evaluate the safety, tolerability, and 
efficacy of ODV and sovaprevir in combination with RBV for 12 weeks in chronic 
HCV genotype 1-infected subjects. A total of 30 subjects were enrolled, of whom 20 received 
active treatment, and 10 received placebo. For active subjects, the ODV dosing regimen was a 
150-mg loading dose on Day 1, followed by a 50-mg daily dose for the remainder of the 
treatment duration; sovaprevir was administered as either a 200-mg (Group 1) or 400-mg 
(Group 2) daily dose; and RBV dosing was weight-based as per the label. All doses were to be 
taken with food. For both Groups 1 and 2, administration of sovaprevir, ODV, and RBV was 
associated with rapid and sustained reductions in HCV RNA, while placebo subjects had little or 
no change in viral load. Viral clearance occurred by Week 2 in all active subjects who received 
at least 2 weeks of study drugs. There have been 3 viral breakthroughs in Groups 1 and 2 each, 
and 1 viral relapse in Group 1, all occurring in subjects infected with the HCV genotype 1a. In 
contrast, no subjects with HCV genotype 1b infection have had viral breakthrough or relapse. 
Both combination dosing regimens were well tolerated with no drug-related SAEs and no 
discontinuations for safety. Trough concentrations of ODV were similar in Group 1 
(200 mg sovaprevir) and Group 2 (400 mg sovaprevir), suggesting no effect of sovaprevir dose 
on ODV concentrations. 
Combination of a Nucleotide NS5B Polymerase Inhibitor and a NS5A Inhibitor: 
ODV/SOF1,15 
ACH102-017 was a Phase 2 study to evaluate the safety, tolerability, and efficacy of ODV in 
combination with SOF (a nucleotide analog HCV inhibitor) for 6 or 8 weeks in chronic 
HCV genotype 1-infected subjects. The dosing regimen was 50-mg liquid-filled capsule (LFC) 
formulation of ODV given in the fasted condition without a loading dose plus 400 mg of SOF for 
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either 8 weeks (Group 1; N=18, ie, 12 on active treatment and 6 observational subjects) or 
6 weeks (Group 2; N=12, the 6 observational subjects from Group 1+6 additional subjects). 
Pharmacokinetic results suggest that ODV and SOF concentrations in this study are similar to 
those expected based on historical data. Group 1 included 10 subjects with HCV genotype 1a; 
median HCV RNA in Group 1 was 7.15 log10 IU/mL (range: 5.5-7.8 log10 IU/mL). Group 2 
included 6 subjects with HCV genotype 1a; median HCV RNA at baseline in Group 2 was 
6.95 log10 IU/mL (range: 6.2-8.0 log10 IU/mL). All 12 (100.0%) subjects in Group 1 and all 
12 (100.0%) subjects in Group 2 achieved SVR12 and subsequently SVR24. Six additional 
rollover 
subjects 
(Group 3) 
also 
received 
6 weeks 
of 
treatment 
consisting 
of 
ODV 50 mg+SOF 400 mg qd. Five out of the 6 were HCV genotype 1a-infected subjects, 4 out 
of 6 subjects had interleukin-28B (IL28B) genotype nonCC (2 subjects with IL28B 
genotype TT) 
and 
median 
baseline 
HCV 
RNA 
was 
6.32 log10 IU/mL 
(range: 
6.0-7.3 log10 IU/mL). All 6 (100.0%) subjects achieved SVR12 and subsequently SVR24. 
The dosing regimen was well tolerated in both groups with no SAEs or discontinuations for 
safety. No significant ECG findings or laboratory abnormalities were observed during treatment. 
3-DAA Combination of an NS3/4A Protease Inhibitor, an NS5A Inhibitor, and a 
Nucleotide NS5B Polymerase Inhibitor: SMV/DCV/SOF, SMV/ODV/AL-335 
At the time of the initial protocol writing, interim results from the Phase 2 IMPACT 
(TMC435HPC2010) study, investigating SMV 150 mg qd+DCV 60 mg qd+SOF 400 mg qd for 
12 weeks in treatment-naïve and treatment-experienced subjects with chronic HCV genotype 1 
or 4 infection and decompensated liver disease were available. The combination of 
SMV/DCV/SOF resulted in high on-treatment virologic response and 100% SVR12 rates in 
HCV genotype-1 or 4-infected subjects with compensated liver disease. All subjects (100.0%) 
with available data in both the Child-Pugh A (N=19) with evidence of portal hypertension and 
Child-Pugh B (N=9) groups achieved SVR4. SMV exposures in Child-Pugh B subjects were 
within the range observed for Child-Pugh A. The combination was generally safe and well 
tolerated; AEs were Grade 1 or Grade 2 in severity with no AE-related treatment 
discontinuations. 
Since the writing of the initial protocol, a DDI study, AL-335-602, involving 32 subjects over 
2 groups, evaluating varying combinations of daily dosing over 23 days with AL-335 (800 mg), 
ODV (150 mg loading dose followed by 50 mg maintenance doses), and SMV (150 mg) was 
completed. Pharmacokinetic data indicated that AL-335 had no impact on either SMV or ODV 
exposures (AUC). ODV increased SMV exposures (AUC0-24h) by approximately 1.8-fold. 
SMV increased ODV exposure (AUC0-24h) by 1.5-fold. Coadministration of all 3 drugs resulted 
in significant increase in AL-335 (prodrug) exposures (6.9- to 8.2-fold) and metabolite 
ALS-022399 (2.6- to 2.8-fold), with no effect on metabolite ALS-022227 (1- to 1.1-fold).  
In Study AL-335-602, repeated daily administration of oral ODV (150-mg loading dose followed 
by 50-mg maintenance doses) as monotherapy or as combination with AL-335 (800 mg) and/or 
SMV (150 mg) for 23 days, was well tolerated. All TEAEs (N=20) were assessed as mild 
(N=14) or moderate (N=6; oropharyngeal pain, tooth abscess, ALT increase, and fatigue 
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[3 events]), in severity by the investigator. The most commonly reported TEAEs (≥2 events) 
were fatigue (8 events) and diarrhea/soft feces (3 events), neither of which was considered 
clinically concerning or suggestive of a safety signal which would preclude dosing with any 
combination of the study drugs. No SAEs and no medically significant events were reported. 
One AE, tooth abscess, led a subject to prematurely discontinue study drugs. One subject 
experienced increased ALT (Grade 3)/AST (Grade 2) levels which were attributed to new onset 
cytomegalovirus infection. The increased ALT/AST values returned to within the normal range 
by the end of the study. With the exception of the subject with increased ALT/AST, no clinically 
significant abnormalities with respect to laboratories, vital signs, physical examinations, or ECGs 
were identified. 
A Phase 2a, open-label study (AL-335-604) to evaluate the safety, PK, and efficacy of the 
combination of AL-335+ODV±SMV in HCV genotype 1 and 3 infected treatment-naïve subjects 
has been initiated under the responsibility of Alios BioPharma Inc. Preliminary data from 
7 cohorts were available from an analysis with a cut-off date of 22 June 2016, which was based 
on a snapshot database (no official database lock and cleaning was performed). Additional 
preliminary key HCV RNA and safety data obtained since 22 June through 03 August 2016 are 
provided below. Subjects in Cohorts 1, 1b, 2, 3, and 4 were infected with HCV genotype 1 and 
had no cirrhosis. Subjects enrolled in Cohort 5 were infected with HCV genotype 3 without 
cirrhosis and subjects enrolled in Cohort 6 were infected with HCV genotype 1 and had 
Child-Pugh A cirrhosis. 
In Cohort 1 (AL-335 400 mg qd, ODV 50 mg qd, and SMV 100 mg qd for 8 weeks), Cohort 2 
(AL-335 800 mg qd, ODV 50 mg once every other day [qod], and SMV 75 mg qd for 8 weeks) 
and Cohort 3 (AL-335 800 mg qd, ODV 50 mg qod, and SMV 75 mg qd for 6 weeks), all 
subjects received the 3-DAA regimen. As of 22 June 2016, in Cohort 1 all subjects (20/20) had 
HCV RNA not detected or <lower limit of quantification (LLOQ) at the follow-up Week 12 and 
follow-up Week 24 time points (100% SVR12 and 100% SVR24). All subjects in Cohort 2 
(20/20) had HCV RNA not detected or <LLOQ at the follow-up Week 12 time point (100% 
SVR12; SVR24 data not yet available). In Cohort 3 all subjects (20/20) had HCV RNA not 
detected or <LLOQ at the follow-up Week 4 time point (100% SVR4) and all 14 subjects with 
data available from the follow-up Week 8 visit had HCV RNA not detected or <LLOQ at this 
time point (100% SVR8, SVR12 data not yet available). 
No subjects in Cohort 5 (HCV genotype-3 infected subjects treated with AL-335 800 mg qd, 
ODV 50 mg qod, and SMV 75 mg qd for 8 weeks) or Cohort 6 (HCV genotype-1 infected 
subjects with compensated cirrhosis treated with AL-335 800 mg qd, ODV 50 mg qod, and SMV 
75 mg qd for 8 weeks) had completed dosing. No cases of viral breakthrough or viral relapse 
were known to have occurred in any cohorts including 3-DAA treatment as of the 
03 August 2016 data cut-off. 
In Cohort 1b, HCV genotype-1a infected subjects without cirrhosis received the 2-DAA regimen 
of AL-335 and ODV (AL-335 800 mg qd+ODV 50 mg qod without SMV for 8 weeks). In this 
cohort, at the SVR12 visit, 18/20 (90%) subjects had HCV RNA not detected or <LLOQ. Two 
subjects (10%) experienced viral relapse between the follow-up Week 8 and follow-up Week 12 
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visits and follow-up Week 4 and follow-up Week 12 assessments (follow-up Week 8 visit was 
not completed), respectively. No ODV or AL-335 RAVs were observed at baseline in the 
2 subjects with viral relapse, both infected with HCV genotype 1a. At the time of viral relapse, 
both subjects had emerging ODV RAVs at NS5A amino acid positions 28 or 93 (M28T in 
combination with T64A in 1 subject and Y93H in combination with T21A in the other subject) 
and no emerging AL-335 RAVs. Of the 5 subjects in Cohort 4 (AL-335 800 mg qd+ODV 50 mg 
qod without SMV for 8 weeks) that had completed treatment and reached the follow-up Week 4 
visit as of the 3 August 2016 cut-off, 1 subject infected with HCV genotype 1a was known to 
have experienced viral relapse. This viral relapse was identified on 02 August 2016 and viral 
sequencing was pending. No other cases of viral relapse or viral breakthrough were known to 
have occurred in any cohorts including 2-DAA treatment as of the 03 August 2016 data cut-off. 
Taken together, the available safety data from Study AL-335-604 up to 22 June 2016 indicate 
that dosing with AL-335 in combination with ODV±SMV at several dose combinations was 
generally safe and well tolerated. No clear safety signals have been identified in terms of TEAEs, 
laboratory abnormalities, ECGs, and echocardiograms. 
In this study, up to 22 June 2016, 97 subjects received at least 1 dose of study medication. 
Overall (Cohorts 1, 1b, 2, 3, 4, 5, and 6 combined), as of 22 June 2016, 173 TEAEs had been 
reported. All TEAEs were mild (N=162 events) or moderate (N=11 events) in severity; no severe 
or life-threatening AEs were reported. The most commonly reported TEAEs (≥5% of the 
subjects) were headache (17 subjects; 17.5%), fatigue (13 subjects; 13.4%), upper respiratory 
tract infection (10 subjects, 10.3%), contusion (8 subjects 8.2%), insomnia (6 subjects; 6.2%) 
and diarrhea, cough and accidental overdose of study medication (5 subjects each; 5.2%). The 
reported overdoses generally involved subjects who took ODV qd instead of qod (Cohorts 1b-3) 
or misunderstood dosing instructions or both. None of these overdose events involved ingestion 
of clinically important excesses of study drug, none were associated with any symptomatology, 
and none were intentional. All subjects that experienced these overdoses were reeducated about 
dosing instructions and subsequently completed their treatment course. None of the reported 
TEAEs were considered suggestive of a safety signal. 
Two treatment-emergent SAEs were reported in the study. One event occurred in a subject in 
Cohort 1b who was diagnosed with a transitional cell carcinoma of the urethra. This event was 
identified during treatment when the subject was worked up for an approximately 5-month 
history of recurrent urinary tract infections and macroscopic hematuria. This disease was likely 
present at baseline, but unrecognized, and was considered unrelated to study drug by the 
investigator. The other treatment-emergent SAE occurred in a subject in Cohort 1 who 
experienced a progressive increase in PR interval from baseline to Mobitz Type 1 2nd degree AV 
block (Wenckebach, toxicity Grade 2) at Week 5 of treatment. More information on this SAE is 
provided in Section 1.3.2.2. 
Two subjects prematurely discontinued 1 or more study drugs. The first subject discontinued all 
3 study drugs after experiencing Mobitz Type 1 2nd degree AV block (SAE) described above. 
The second subject had an elevated PR interval (mean: 234 msec) at baseline, which did not 
change significantly postbaseline (maximum mean: 257 msec). This was not considered a TEAE; 
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however, in light of the 2nd degree AV block described above, ODV was discontinued in this 
subject as a precaution at treatment Week 5. The subject continued AL-335 and SMV through 
Week 8. 
Between 22 June and 03 August 2016, no additional treatment-emergent SAEs, serious/life 
threatening TEAEs, or TEAEs leading to study drug discontinuation were reported in this study. 
No subjects had Grade 3 or 4 hematology laboratory abnormalities and there were no Grade 3 or 
4 urinalysis abnormalities.  
Several subjects experienced treatment-emergent chemistry laboratory abnormalities of 
Grade ≥3; Grade 3 elevation of CK in 1 subject, Grade 3 increase in cholesterol in 1 subject, and 
3 subjects experienced Grade 3 (2 subjects) or Grade 4 (1 subject) lipase levels. None of the 
abnormalities were considered clinically significant by the investigator or resulted in premature 
discontinuation of the study drugs.  
Apart from the subject in Cohort 1, who was identified as developing 2nd degree AV block type 
Wenckebach, which resulted in study drug discontinuation, no other postbaseline ECGs were 
considered to have an overall interpretation which was clinically concerning or suggestive of a 
safety signal. 
No echocardiogram was interpreted by the central reader to be clinically significantly abnormal 
and no echocardiogram finding was associated with symptoms or resulted in study drug 
discontinuation. 
The doses of the study drugs in the current study were selected based on review of the 
on-treatment responses and the evaluation of the safety and PK data from Phase 1 and Phase 2a 
studies.  
1.3. 
Risk/Benefit Section 
1.3.1. 
Known Benefits and Risks 
Known Benefits and Risks for AL-335 
AL-335 is a potent and highly selective inhibitor of NS5B-directed HCV RNA replication in 
vitro, including replication of replicons containing NS5B sequences derived from isolates of 
genotypes 1a, 1b, 2b, 3a, 4a, 5a, and 6a. 
A formal adverse drug reaction analysis has not yet been conducted for AL-335. 
Please see Section 1.1.3 and Section 1.2 for further details. 
Known Benefits and Risks for ODV 
ODV is an inhibitor of the HCV NS5A protein with potent in vitro activity against genotype 1 
replicons and against chimeric replicons containing the N-terminus of NS5A of genotypes 2 to 6. 
For the majority of mutations associated with resistance to first generation NS5A inhibitors, the 
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effect on the in vitro activity of ODV is substantially lower than for first generation NS5A 
inhibitors, in particular in genotype 1b. In a proof-of-concept study in HCV genotype 1-infected 
subjects, ODV has shown potent antiviral activity after a single dose for all dose groups tested. 
In a Phase 2a study (ACH102-017), ODV in a 2-DAA combination with SOF with treatment 
duration of 6 weeks has shown an efficacy of 100% SVR12 in treatment-naïve 
HCV genotype 1-infected subjects without cirrhosis. 
In a placebo-controlled Phase 2 study in HCV genotype 1-infected subjects, administration of 
sovaprevir (an HCV NS3 inhibitor), ODV, and RBV for short durations of 12 weeks in 
treatment-naïve genotype 1-HCV infected subjects was associated with rapid reductions in 
HCV RNA but the viral failure rate was high in patients infected with genotype 1a. 
A formal adverse drug reaction analysis has not yet been conducted for ODV. However, an 
internal assessment of all preclinical and clinical information available at the time of the protocol 
writing has identified the effect of ODV on PR interval prolongation as a potential risk. Details 
are discussed in Section 1.3.2 
Please see Section 1.1.4 and Section 1.2 for further details. 
Known Benefits and Risks for SMV 
SMV is an inhibitor of the HCV NS3/4A protease which is essential for viral replication. In a 
biochemical assay, SMV inhibited the proteolytic activity of recombinant genotypes 1a and 1b 
HCV NS3/4A proteases, with median kinetic inhibition constant values of 0.5 nM and 1.4 nM, 
respectively. 
In HCV genotype 1-treatment-naïve and treatment-experienced subjects, SMV 150 mg qd 
administered for 12 weeks with PegIFNα-2a/RBV or PegIFNα-2b/RBV for response-guided 
24 or 48 weeks was superior (based on the primary endpoint, SVR12) to placebo with 
PegIFN/RBV alone for 48 weeks. SMV in combination with PegIFN/RBV has also been shown 
to be efficacious in HCV genotype 4 and HIV/HCV genotype 1-infected subjects.  
SMV at a dose of 100 mg qd in combination with PegIFN/RBV has demonstrated a favorable 
safety/tolerability profile in Japanese and white HCV genotype 1 treatment-naïve and treatment-
experienced subjects. 
The Japan Phase 2/3 clinical data package included 1 Phase 2b and 4 Phase 3 studies 
(1 placebo-controlled and 3 open-label studies), including data for SMV 50 mg qd 
(TMC435-TiDP16-C215 only, N=40) and 100 mg qd (TMC435-TiDP16-C215: N=37, 
TMC435HPC3003: N=123, TMC435HPC3004: N=106, TMC435HPC3008: N=49, and 
TMC435HPC3010: N=79), all in combination with PegIFN/RBV. Data presented below focus 
on the SMV 100 mg data, the marketed SMV dose in Japan. 
After administration of SMV 100 mg qd for 12 weeks in combination with PegIFNα-2a/RBV for 
24 or 48 weeks in the Phase 3 studies conducted in Japan, including subjects with chronic HCV 
genotype 1 infection with a high viral load, SVR12 was achieved in 88.6% in treatment-naïve 
subjects (TMC435HPC3003), 95.9% in prior relapsers (TMC435HPC3008), and 52.8% in prior 
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nonresponders (TMC435HPC3004). For treatment-naïve subjects, the proportion of subjects 
achieving SVR12 was significantly higher in the SMV group compared to the placebo group 
(treatment with PegIFNα-2a/RBV alone) (61.7%). For both prior relapsers and prior 
nonresponders, the SVR12 rate in subjects who received SMV in combination with 
PegIFNα-2a/RBV was significantly higher than the SVR24 rates defined in the null hypothesis in 
subjects who received PegIFN/RBV (based on historical data). Similar efficacy data were 
obtained for SMV in combination with PegIFNα-2b/RBV. 
Subgroup analyses based on age, baseline platelet count, and IL28B genotype showed high 
efficacy in all subgroups and no clear differences were noted across the subgroups. 
PegIFN/RBV therapy could be shortened to 24 weeks in a high proportion of subjects based on 
response-guided therapy (RGT). In total, 91.9% of the SMV-treated treatment-naïve subjects 
(TMC435HPC3003) met the RGT criteria and completed the study treatment at Week 24, of 
whom 92.0% achieved SVR12. The majority of prior relapsers (TMC435HPC3008) and prior 
nonresponders (TMC435HPC3004) met the RGT criteria and could therefore, complete the study 
treatment at Week 24 (95.9% and 73.6%, respectively). The SVR12 rate was high (95.7%) in the 
prior relapsers and was 48.7% to 60.5% in prior nonresponders. 
The TIGER study (TMC435HPC3005), a Phase 3 study, which included treatment-naïve chronic 
HCV genotype 1-infected Asian subjects from China and South Korea, demonstrated superiority 
of both SMV 100 mg (p=0.003) and SMV 150 mg (p≤0.001) both for 12 weeks in combination 
with response-guided PegIFN/RBV (24 or 48 weeks) over PegIFN/RBV for 48 weeks in terms of 
SVR12 (88.9% in the SMV 100 mg arm, 90.8% in the SMV 150 mg arm and 75.7% in the 
placebo arm). 
The observed safety profile of SMV 150 mg/PegIFN/RBV in Asian subjects from China and 
South Korea was similar to the known safety profile of SMV 150 mg in white subjects despite 
the 2.1-fold higher exposure (mean AUC from time 0 to 24 hours after dosing [AUC24h]). The 
overall incidence of AEs was similar in all the treatment arms, with no relevant differences in the 
safety profile of the SMV arms, except for events of increased bilirubin. The majority of these 
events were Grade 1 or 2, in general not associated with increases in liver transaminases, and 
reversible on completion of SMV/placebo. 
SMV 150 mg qd in combination with SOF 400 mg qd for 12 weeks in HCV genotype 1-infected 
subjects without cirrhosis achieved high SVR12 (>92.0%) irrespective of baseline characteristics 
and was safe and well tolerated. SMV 150 mg qd in combination with SOF 400 mg qd for 
12 weeks in HCV genotype 1-infected subjects with cirrhosis achieved SVR12 rates of 83.5%. 
Although superiority of the SMV+SOF treatment over a composite historical control could be 
concluded (95% confidence interval [CI]: 75.8%-91.1%; lower limit of the 95% CI was higher 
than the SVR12 historical control rate [70.0%]), it is recommended that HCV 
genotype 1-infected patients with cirrhosis are treated with SMV/SOF for 24 weeks. 
SMV 150 mg qd in combination with SOF 400 mg qd for 8 weeks or 12 weeks in HCV 
genotype 4-infected subjects resulted in high SVR12 rates: an SVR12 rate of 100% was observed 
after treatment for 12 weeks in subjects with and without cirrhosis and regardless of prior 
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treatment history. An SVR12 rate of 75.0% was observed in subjects without cirrhosis who were 
treated for 8 weeks. 
SVR rates of SMV in combination with PegIFN/RBV were reduced in subjects with HCV 
genotype 1a with NS3 Q80K polymorphism compared to subjects without Q80K polymorphism. 
In HCV genotype 1a-infected subjects without cirrhosis, efficacy of SMV in combination with 
SOF at the recommended 12-week treatment duration was not impacted by the presence of 
NS3 Q80K polymorphism. 
Adverse reactions of SMV 
SMV 150 mg qd was generally safe and well tolerated when administered for a duration of 
12 weeks in combination with PegIFN/RBV to adults with compensated liver disease with or 
without HIV coinfection. 
The grouped terms identified as SMV adverse reactions are constipation, blood bilirubin 
increased, photosensitivity reaction, pruritus, and rash. 
In the pooled data set from the three placebo-controlled Phase 3 studies (TMC435-TiDP16-C208, 
TMC435-TiDP16-C216, and TMC435HPC3007 [PROMISE]) of SMV in combination with 
PegIFN/RBV, at least one SMV adverse reaction was reported in 44.7% of SMV-treated subjects 
and in 31.2% of subjects on placebo, during the first 12-week Phase. Adverse reactions reported 
in SMV-treated subjects and placebo-treated subjects were pruritus (21.9% versus 14.6%), rash 
(21.8% versus 16.6%), blood bilirubin increased (7.4% versus 2.8%), photosensitivity reaction 
(4.7% versus 0.8%), and constipation (2.6% versus 2.5%). With exception of constipation, 
incidences were higher in the SMV-treated subjects, but the differences between the treatment 
groups became smaller when considering the entire Treatment Phase. For constipation, the time 
to onset was shorter in the SMV group than in the placebo group. 
In the development of SMV in combination with PegIFN/RBV, the pooled analysis for the 
5 Phase 2b/3 studies conducted in Japan (TMC435-TiDP16-C215, TMC435HPC3003, 
TMC435HPC3004, TMC435HPC3008, and TMC435HPC3010) indicated that SMV in 
combination with PegIFN/RBV was generally safe and well tolerated in subjects with chronic 
hepatitis C. In the pooled analysis, increased bilirubin-related events, which were defined as 
special interest for its potential as a signal for liver toxicity were observed in SMV 100 mg 
12-week treatment group (31.5%, 104/330 subjects) and placebo group (8.2%, 6/73 subjects). 
However, the majority of the increased bilirubin-related events in SMV 100 mg 12-week 
treatment group were Grade 1 (18.5%, 61/330 subjects) or 2 (11.2%, 37/330 subjects) and 
transient and not associated with ALT or AST increases. The incidences of Grade 3 increased 
bilirubin-related events in SMV 100 mg 12-week treatment group were low (1.8%, 6/330), and 
no Grade 4 increased bilirubin-related events were reported. The incidences of Grade 3 rash 
events, serious events, and events that led to the discontinuation of all study drugs were low. The 
overall incidence of all rash-related events in the SMV group was lower than in the PegIFN/RBV 
group and the incidence of grade 3 rash related events and rash-related events leading to 
discontinuation of all study drugs were similar to those reported in the PegIFN/RBV group. 
Serious anemia-related events, grade 3 anemia-related events, and anemia related events leading 
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to discontinuation of all study drugs were reported only in the SMV group, but the incidences 
were low for all cases. The overall incidence of all anemia related events was similar to that 
reported in the PegIFN/RBV group. Additionally, the proportion of subjects who experienced 
temporary interruption or dose reduction of RBV due to anemia or hemoglobin decreased was 
similar between the treatment groups. No new clinically relevant safety concerns as compared to 
the global development program were identified. 
Most adverse reactions were Grade 1 or 2 in severity. During the first 12 weeks of treatment 
(SMV+PegIFN/RBV), the incidence of Grade 3 or 4 adverse reactions (2.8% in SMV-treated 
subjects and 0.5% [2 subjects] in subjects on placebo), serious adverse reactions 
(0.3% [2 subjects] vs 0.0% [none]), and adverse reactions leading to SMV/placebo 
discontinuation (0.9% [7 subjects] vs 0.3% [1 subject]) was low. 
No safety issues other than the known adverse reactions could be identified in Japanese subjects 
or Asian subjects from China and South Korea. 
A formal adverse reaction identification process was conducted on the pooled clinical safety data 
of TMC435HPC2002, TMC435HPC3017, and TMC435HPC3018 (SMV+SOF) studies. No new 
adverse reactions of SMV could be identified. 
In total, during the Treatment Phase, adverse reactions were reported in 19.9% of the subjects. 
The majority of the adverse reactions were Grade 1 or 2 in severity. The overall incidence of 
adverse reactions was similar for all studied treatment durations (8, 12, or 24 weeks), except for 
events of rash (grouped term), for which there was a slight trend towards a higher proportion of 
subjects with events in the 24-week treatment group than in the 8-week or the 12-week treatment 
group (4.5% of subjects in the 8-week treatment group, 8.0% of subjects in the 12-week 
treatment group, and 12.9% in the 24-week treatment group). Most rash events were Grade 1 or 
2 in severity and 1 case, reported in the 12-week treatment group, led to discontinuation of study 
drugs, as mandated by the protocol. 
None of the above-mentioned adverse reactions require monitoring beyond the guidance per the 
product information of the coadministered HCV medication, if applicable. As specified in the 
SMV product information, patients must use appropriate sun protective measures during 
treatment with SMV. Excess exposure to sun and use of tanning devices during treatment with 
SMV should be avoided (see Section 4.3). 
Please see Section 1.1.5 and Section 1.2 for further details. 
1.3.2. 
Potential Benefits and Risks 
1.3.2.1. 
Potential Benefits 
For the subjects in this study, the status of their HCV infection and general health will be closely 
monitored. It is possible that by participating in this study the subject’s general health and HCV 
disease status will improve. The use of a 3-DAA combination in this study (including agents 
with a high genetic barrier) may increase the robustness of the regimen allowing for shorter 
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treatment durations compared to currently available treatment regimens to achieve cure for all 
infected patients irrespective of genotype or any other baseline factor, all without compromising 
patient compliance and safety. 
1.3.2.2. 
Potential Risks 
Potential Risks for AL-335 
 
Nonclinical Safety Evaluations: 
 
The toxicology profile for AL-335 has been established in multiple in vitro and in vivo 
studies. AL-335 was well tolerated in all toxicology studies; following 14 days of 
repeated dosing, the target organs for toxicity were not identified even when dosed up 
to the maximum recommended doses of 1,000 mg/kg/day in both rats and dogs. 
 
Because nucleosides, as a class, have a known risk of mitochondrial toxicity, which is 
often manifested as muscle injury, this study will systematically assess study subjects 
for laboratory abnormalities which might be present after muscle injury. Specifically, 
CK is checked throughout the study Treatment Period. The potential risk of developing 
any of these abnormalities is considered to be very low as AL-335 did not exhibit 
mitochondrial toxicity in in vitro or in vivo toxicology studies. In addition, a toxicity 
management plan for mitochondrial toxicity is included in the protocol (see 
Section 9.2.8.6). 
Potential Risks for ODV 
The heart is a target organ of ODV toxicity based on the findings in repeat-dose toxicity studies 
in rats and dogs up to 26 weeks duration. In vitro, ODV has shown to have no effect on hERG 
channel currents at the maximal feasible concentration (5 µM) tested, which was at least 
500 times the target clinical mean plasma concentration of unbound ODV, indicating a large 
safety margin with regards to QT prolongation. Additional information about a potential QT 
effect in humans will be collected in a planned modified thorough QT study. ODV did not have 
any effect in single-dose dog cardiovascular safety pharmacology studies. Additional 
information about a potential QT effect in humans will be collected in a planned modified 
thorough QT study. 
Summary of Cardiac Safety in Animal Studies 
In vivo, no cardiac effects occurred at exposure levels (Cmax and AUC) about 6 times the target 
clinical exposure of ODV (when administered at a dose of 25 mg qd in combination with 
SMV 75 mg qd and AL-335 800 mg qd). 
After repeated dosing of ODV in rats and dogs with exposure levels (Cmax and AUC) 14 times 
the target clinical exposure, increased heart weights were noted. In repeated dose studies in the 
dog, administration of ODV, at similar exposure levels, was associated with ECG changes 
(prolonged PR intervals and/or 1st degree AV block, prolonged QRS and QT intervals, and 
decreased heart rate). Echocardiography was performed in the 26-week toxicity study in the dog 
and revealed progressive left ventricular dilatation, eccentric hypertrophy, and minor reduction 
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in ejection fraction (the latter within normal reference range) associated with increased stroke 
volume, while the cardiac index was not affected. 
All cardiac findings were found to be reversible or partially reversible. 
Preliminary data from an 8-week repeat-dose (70 mg/kg/day orally) mechanistic study in the 
telemetered dog showed a decrease in cardiac contractility, resulting in a decrease in ejection 
fraction and systolic and diastolic blood pressure. The increase of PR/PQ interval preceded an 
increase in ventricular mass. QT interval increased later in the study. In this study, ODV was 
administered at a dose approximately 200 times higher than the dose planned for the current 
Study 64294178HPC2003. As information of exposure levels achieved with this dose is not 
available yet, a complete assessment of the clinical relevance of these findings is not yet possible. 
Importantly, analysis of all available echocardiography assessments from clinical studies in 
humans does not show any safety trends or signals (see below).  
For more information refer to the Investigator’s Brochure and its addendum.19,20 
Summary of Cardiac Safety in Humans 
A total of 440 subjects, of whom 75 were HCV-infected subjects and 365 were healthy subjects 
(ie, nonHCV infected subjects) had initiated treatment with ODV alone or in combination with 
DAAs other than AL-335 and SMV. These included therapeutic Phase 2 studies of up to 
12 weeks in duration where ECG and echocardiography were performed for cardiac safety 
monitoring. No notable effects on mean PR, QRS, or QT interval corrected for heart rate 
according to Fredericia (QTcF)10 values over time were noted and there were no clinically 
significant findings identified in the echocardiograms. 
In addition, data are available from 2 studies evaluating ODV in combination with AL-335 with 
or without SMV (completed DDI Study AL-335-602 in healthy volunteers and ongoing Phase 2a 
Study AL-335-604 in HCV-infected subjects). In Study AL-335-602, 32 healthy subjects 
received AL-335+ODV±SMV. As of 22 June 2016, 97 subjects in Study AL-335-604 had 
enrolled and had received at least 1 dose of study drug (AL-335+ODV±SMV). The cardiac 
monitoring in these studies did not identify any clinically significant trends. 
One SAE of asymptomatic 2nd degree Mobitz Type 1 AV block was reported (Week 5 of 
treatment) in a subject in Study AL-335-604 with a borderline elevated PR interval at screening. 
The subject received study treatment with AL-335 400 mg qd+ODV 50 mg qd+SMV 150 mg qd. 
The event led to discontinuation of the study drugs (AL-335, ODV, and SMV) and was 
considered probably related to ODV by the investigator. Echocardiography remained normal and 
the event was considered a benign conduction disorder which appeared to have settled 4 days 
after study drug discontinuation, and no further investigations were considered needed. In 
Study AL-335-604, an additional subject had an elevated PR interval (mean: 234 msec) at 
baseline which did not change significantly post baseline (maximum mean: 257 msec). This was 
not considered TEAE; however, in light of the Wenckebach SAE described above, ODV was 
discontinued in this subject as a precaution at study Week 5. The subject continued AL-335 and 
SMV through Week 8. 
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In Study ACH102-005, a treatment-emergent PR prolongation was observed; this event evolved 
to a transient Type 1 2nd degree AV block. The cardiologist assessed the subject's 2nd degree AV 
block to be of undetermined etiology but unlikely due to study drug. The subject completed the 
full course of 12-week therapy with ODV and RBV. Based on the currently available data, the 
cardiac safety profile of ODV is acceptable to conduct the present study. 
Continued surveillance for this potential risk will be done in this Phase 2 study via assessments 
of AEs and ECGs and regular echocardiograms, which will be obtained at specified time points 
during the treatment and Follow-up Period (see the TIME AND EVENTS SCHEDULE). In 
addition, a toxicity management plan for cardiac events (see Section 9.2.8.7) and study wide 
treatment stopping rules (see Section 6.4) taking into account cardiac safety data of all ongoing 
studies including ODV dosing are included in the protocol. Finally concomitant medications 
with a potential to prolong QT interval (eg, digoxin as well as ion channel blockers) are 
disallowed from screening until the end of the study (see Section 8). 
Potential Risks for SMV 
 
Hepatic Decompensation and Hepatic Failure 
 
Hepatic decompensation and hepatic failure, including fatal cases, have been reported 
postmarketing in patients treated with SMV in combination with PegIFN/RBV and in 
combination with SOF. Most cases were reported in patients with advanced and/or 
decompensated cirrhosis who are at increased risk for hepatic decompensation or 
hepatic failure. Because these events have been reported voluntarily during clinical 
practice, estimates of frequency cannot be made and a causal relationship between 
treatment with SMV and these events has not been established. In clinical studies of 
SMV, modest increases in bilirubin levels were observed related to the inhibition by 
SMV of bilirubin transporters (OATP) without impacting hepatic function and were 
generally not associated with elevations in liver transaminases. 
Potential Risks for AL-335, ODV, and SMV 
The following potential risks will be carefully monitored during the study and are specified in 
this protocol: 
 
Reproductive Risks and Pregnancy 
 
No studies have been performed with AL-335, ODV, and SMV in pregnant women. 
 
The effect of AL-335 on reproduction and development is not known. Participation in 
clinical studies including AL-335, requires a subject and his or her partner to, between 
them, use 2 effective methods of birth control. 
 
There was no maternal toxicity and no effects on embryo/fetal survival, growth, or 
external fetal morphology in rat at any ODV dose level up to the highest dose tested 
(150 mg/kg/day) and in rabbits at any dose level up to the highest dose tested 
(300 mg/kg/day). 
 
In animal studies, SMV had no effect on fertility and early embryonic and fetal 
development in rats up to doses of 500 mg/kg corresponding to an exposure of 
221 μg.h/mL in plasma. No human data on the effect of SMV on fertility are available. 
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Therefore, pregnancy and breastfeeding have been exclusion criteria for all clinical 
studies with SMV conducted to date. Women of childbearing potential and men 
included in studies with SMV have been required to use effective methods of birth 
control. 
 
In this study, female subjects of childbearing potential and their male partners must 
agree to follow the contraceptive requirements as described in Section 4.1. Female 
subjects’ study treatment will be discontinued if they become pregnant (see 
Section 12.3.3). Female partners of male subjects are not allowed to be pregnant or plan 
on becoming pregnant (during treatment and up to 6 months after the EOT). 
 
Drug-drug Interactions 
 
An overview of disallowed concomitant medication is presented in Section 8, Prestudy 
and Concomitant Therapy. 
 
Based on in vitro data, AL-335 is predicted to have a low potential for 
CYP450-mediated DDI. Despite a low risk for DDIs, as a precaution, subjects should 
not receive any medication known to be a strong inducer or inhibitor of CYP3A within 
2 weeks prior to receiving AL-335 until completing AL-335 treatment. 
 
The Phase 1 DDI study (AL-335-602) to evaluate the effect of SMV (150 mg qd) and 
ODV (loading dose of 150 mg followed by 50 mg qd) on AL-335 (800 mg qd) PK in 
healthy volunteers indicated that coadministration of all 3 study drugs (SMV, ODV, and 
AL-335) resulted in a 7- to 9-fold, 2.5- to 2.7-fold, and 1- to 1.5-fold increase in 
AL-335, ALS-022399, and ALS-022227 plasma exposure, respectively, compared to 
administration of AL-335 alone. A 2-fold increase of SMV plasma exposure and a 
1.7-fold increase of ODV exposure were observed when the 3 study drugs were 
coadministered compared to SMV administered alone or ODV administered alone, 
respectively. 
 
No clinically significant DDI was observed between ODV and sovaprevir, montelukast, 
atazanavir/ritonavir, efavirenz/emtricitabine/tenofovir disoproxil fumarate, darunavir/ 
ritonavir, or raltegravir. ODV is a low-affinity substrate of OATP1B1 and an inhibitor 
of P-gp. 
 
SMV is mainly metabolized by CYP3A enzymes. Coadministration of SMV and drugs 
that induce CYP3A enzymes may decrease SMV plasma concentrations and reduce its 
therapeutic effect. Conversely, coadministration of SMV and drugs that inhibit CYP3A 
enzymes may increase SMV plasma concentrations and increase or prolong its 
therapeutic and adverse effects. 
 
The impact of SMV on drug-metabolizing enzymes is limited to mild inhibition of 
intestinal (not hepatic) CYP3A and mild inhibition of CYP1A2. In addition, interaction 
potential with P-gp and OATP1B1 substrates has been identified. 
 
Development of Drug Resistance 
 
The persistence of emergent AL-335-, ODV-, and/or SMV-RAVs could potentially 
impair a subject’s future treatment options with respect to retreatment due to potential 
cross-resistance within the respective DAA class. 
 
AL-335: 
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o 
In the MAD part of Study AL-335-601, 16 HCV genotype 1-, 8 HCV genotype 2-, 
and 8 HCV genotype 3-infected subjects received AL-335 (400 or 800 mg) for 
7 days and 4 HCV genotype 1, 2 HCV genotype 2, and 2 HCV genotype 3 subjects 
received placebo for 7 days. Population sequencing of the HCV NS5B region was 
performed for 20 HCV genotype-1 infected subjects before, during, and after 
treatment in samples with HCV RNA levels above the limit of detection of the 
sequencing assay (1,000 IU/mL). The NS5B amino acid change S282T, previously 
identified in vitro to be associated with AL-335 resistance, was not observed by 
population sequencing in the HCV genotype-1 infected subjects at any time point 
during the study. No other potential AL-335 RAVs were observed in these subjects. 
o 
In the ongoing Study AL-335-604, 2 subjects (10%) in Cohort 1b, HCV 
genotype-1a infected subjects receiving the 2-DAA regimen of AL-335 and ODV 
(AL-335 800 mg qd+ODV 50 mg qod without SMV for 8 weeks) experienced viral 
relapse. At the time of viral relapse both subjects had emerging ODV RAVs at 
NS5A amino acid positions 28 or 93 (M28T in combination with T64A in 1 subject 
and Y93H in combination with T21A in the other subject) and no emerging 
AL-335 RAVs. Further, 1 HCV genotype-1a infected subject in Cohort 4, receiving 
AL-335 800 mg qd+ODV 50 mg qod without SMV for 8 weeks experienced viral 
relapse. Viral sequencing data of this subject at the time of viral relapse was 
pending. 
 
ODV: 
o 
In the Phase 2 Study ACH102-005, evaluating ODV+RBV for 12 weeks in 
8 treatment-naïve 
subjects 
with 
HCV 
genotype 1b 
infection 
and 
IL28B genotype CC, there were no instances of viral breakthrough despite the 
presence of preexisting mutations associated with NS5A inhibitor resistance. In 
2 subjects, a slower rate of viral load decline during treatment was observed and 
HCV RNA remained above the limit of quantification at EOT. In these 2 subjects, 
multiple NS5A amino acid substitutions (3 up to 6) were detected at baseline. 
Three out of 6 subjects who achieved HCV RNA levels less than the LLOQ at EOT, 
relapsed. In the subjects who experienced viral relapse, emerging mutations 
observed at time of failure conferred high level resistance to ODV (L28M+Y93H 
[n=1], L28M+Y93N [n=1], P29 deletion [n=1]) and these required at least 
2 nucleotide changes. 
o 
In the Phase 2a Study ACH102-007, evaluating ODV in combination with 
sovaprevir and RBV for 12 weeks in HCV genotype 1-infected subjects (N=30; 
20 active/10 placebo) virologic failure was seen only in subjects with HCV 
genotype 1a, with a total of 6 viral breakthroughs and 1 relapse out of 12 genotype 
1a subjects. Highly resistant mutations were detected around the time when viral 
breakthrough or relapse occurred in both target genes (NS3 protease and NS5A) in 
all subjects, with emerging NS5A mutations observed by population sequencing at 
NS5A positions 28, 30, 58, and/or 93. The emerging mutations in NS5A persisted 
through the last follow-up time point, ie, EOT+52 weeks. 
o 
In the ongoing Study AL-335-604, 2 subjects (10%) in Cohort 1b, HCV 
genotype-1a infected subjects receiving the 2-DAA regimen of AL-335 and ODV 
(AL-335 800 mg qd+ODV 50 mg qod without SMV for 8 weeks) experienced viral 
relapse. At the time of viral relapse both subjects had emerging ODV RAVs at 
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NS5A amino acid positions 28 or 93 (M28T in combination with T64A in 1 subject 
and Y93H in combination with T21A in the other subject) and no emerging 
AL-335 RAVs. Further, 1 HCV genotype-1a infected subject in Cohort 4, receiving 
AL-335 800 mg qd+ODV 50 mg qod without SMV for 8 weeks experienced viral 
relapse. Viral sequencing data of this subject at the time of viral relapse was 
pending. 
 
SMV: 
o 
In a pooled analysis of subjects with HCV genotype 1 infection, treated with 
SMV 150 mg qd in combination with PegIFN/RBV, who did not achieve SVR in 
the placebo-controlled Phase 2b and Phase 3 Studies TMC435-TiDP16-C205, 
TMC435-TiDP16-C206, TMC435-TiDP16-C208, TMC435-TiDP16-C216, and 
TMC435HPC3007, emerging mutations at NS3 positions 80, 122, 155 and/or 168 
were observed in 180 of 197 (91.0%) subjects. Mutation R155K alone or in 
combination with other mutations at positions 80, 122, and/or 168 emerged most 
frequently in HCV genotype 1a-infected subjects and mutation D168V emerged 
most frequently in HCV genotype 1b-infected subjects. Emerging mutations 
generally conferred high level resistance to SMV in vitro. 
o 
Follow-up of the subjects with emerging mutations at time of failure within the 
Phase 2b and Phase 3 studies showed that emerging RAVs were no longer 
detectable by standard population sequencing in 90 of 180 (50.0%) subjects within 
the study period (median follow-up time 28 weeks; range: 0 to 70 weeks). 
o 
In the TMC435HPC3011 study in HCV genotype 4-infected subjects, 28 of 
32 (88.0%) subjects who did not achieve SVR had emerging mutations at NS3 
positions 80, 122, 155, 156, and/or 168 (mainly mutations at position 168; 24 of 
32 [75.0%] subjects), 
similar 
to 
the 
emerging 
mutations 
observed 
in 
HCV genotype 1-infected subjects. 
o 
In the TIGER study, paired baseline and failure NS3 sequencing information was 
available for 13 of the 32 subjects with treatment failure in the SMV arms 
(6 subjects 
in 
the 
SMV100/PegIFN/RBV 
arm 
and 
7 subjects 
in 
the 
SMV150/PegIFN/RBV arm), all of whom were infected with HCV genotype 1b. 
The majority of subjects with treatment failure and sequencing data available had 
emerging mutations at NS3 position 80 and/or 168 (10 of 13 [76.9%] subjects). 
Nine out of the 10 subjects with emerging mutations had emerging D168V. 
o 
In the Japan Phase 3 studies (SMV 100 mg qd), the NS3 sequencing data showed 
that most subjects with treatment failure (75.0% to 92.9% depending on prior 
treatment history) had emerging resistance mutations (R155K in subjects with 
HCV genotype 1a and primarily D168V in subjects with HCV genotype 1b) in the 
NS3 protease domain. In many subjects, these mutations detected at the time of 
treatment failure were not detected anymore by the end of the study. 
o 
The majority of HCV genotype 1-infected subjects treated with SMV and SOF 
(with or without RBV) for 12 or 24 weeks who did not achieve SVR12 and with 
sequencing data available had emerging NS3 mutations at position 168 and/or an 
emerging R155K mutation: 5 of the 6 subjects in Study TMC435HPC2002, 1 of the 
3 subjects in Study TMC435HPC3017, and 11 of the 13 subjects in 
Study TMC435HPC3018. The emerging NS3 amino acid substitutions were similar 
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Clinical Protocol 64294178HPC2003 Amendment 5 
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to those observed in subjects who did not achieve SVR following treatment with 
SMV in combination with PegIFN/RBV. 
o 
In contrast, the majority of subjects experiencing viral relapse following 8 weeks of 
treatment with SMV and SOF in Study TMC435HPC3017 had no emerging NS3 
mutations reducing SMV activity in vitro at the time of failure. 
o 
The long-term clinical impact of the emergence of SMV-resistance associated 
mutations is unknown. 
1.3.3. 
Overall Benefit/Risk Assessment 
Based on the available data and proposed safety measures, the overall risk/benefit assessment for 
this clinical study is acceptable for the following reasons: 
 
The toxicology profile for AL-335, established in multiple in vitro and in vivo studies. Data 
from a Phase 1 study in healthy volunteers and HCV-infected subjects with AL-335 800 mg 
qd for 7 days, as well as a Phase 1 study (AL-335-602) in healthy volunteers and an ongoing 
Phase 2a study (AL-335-604) in HCV-infected subjects provide evidence that AL-335 has 
an acceptable safety profile. 
 
ODV safety results from the completed and ongoing clinical studies, along with results from 
the nonclinical toxicology studies provide preliminary evidence that ODV is generally safe 
and well tolerated. Given the available nonclinical and clinical data, cardiac monitoring is 
conducted 
through 
ECGs 
and 
regular 
echocardiograms 
(see 
the 
TIME AND EVENTS SCHEDULE). In addition, a toxicity management plan for cardiac 
events is included in the protocol (see Section 9.2.8.7) and all concomitant medications with 
a potential to prolong QT interval (eg, digoxin as well as ion channel blockers) are 
disallowed from screening until the end of the study (see Section 8). 
 
SMV safety data from Phase 1, 2, and 3 studies showed that SMV was generally safe and 
well tolerated in healthy and HCV infected adults at all doses tested. Phase 2 and 3 studies 
showed that dosing with SMV 100 mg and 150 mg qd for 12 weeks in combination with 
PegIFN/RBV for 24 or 48 weeks and SMV in combination with SOF with or without RBV 
was safe and well tolerated in HCV-infected subjects. 
 
Data from the Phase 2a Study AL-335-604 in HCV infected subjects, including interim PK 
and safety data were reviewed and guided the selection of the AL-335 dose in the present 
study (see Sections 1.2 and 3.2 for details). The target doses for the individual study drugs 
are 800 mg qd for AL-335, 25 mg qd for ODV, and 75 mg qd for SMV. 
 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria (as 
specified in Section 4) will be allowed to participate in this study. The selection criteria 
include adequate provisions to minimize the risk and protect the well-being of subjects in 
the study. 
 
Safety will be closely monitored throughout the study. Safety and tolerability assessments 
(including vital signs, physical examination, ECGs, and clinical laboratory tests) will be 
performed at scheduled visits throughout the study until the Follow-up Visit, 24 weeks after 
the actual EOT. Adverse events will be collected from signing of the informed consent form 
(ICF) until the subject’s last study visit. All collected AEs and SAEs will be followed until 
satisfactory resolution (eg, value returns to baseline value) or stabilization (to be agreed 
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Clinical Protocol 64294178HPC2003 Amendment 5 
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upon in collaboration with the sponsor). Pregnancies will be reported until the subject’s last 
study visit. 
 
DRC will be established to monitor data with focus on the safety and on the general conduct 
of the study. The DRC is a committee within the sponsor’s organization that is independent 
of the sponsor’s study team.  
 
Several safety measures have been proposed to minimize potential risk to subjects, 
including: 
o The safety monitoring and toxicity management plan in this study (see Section 9.2.8), 
which takes into account AEs based on toxicities of AL-335, ODV, and SMV, 
clinical safety data of ODV and SMV, target organs identified in nonclinical studies, 
and toxicities reported for nucleotide analogs. 
o Individual subject treatment stopping rules for viral breakthrough and specific 
toxicities (see Section 6.3 and Section 10.2 respectively) 
o Study treatment stopping rules that terminate further enrollment and dosing of all 
subjects in the study based on pre-specified cardiac safety information from any 
ongoing study using ODV (see Section 6.4) 
o Prohibitions and restrictions related to pregnancy and photosensitivity (see 
Section 4.3). 
o Predefined safety-related criteria detailed in Section 10.2 require subjects to 
discontinue all study drugs (AL-335, ODV, and SMV). 
If a subject withdraws from the study (ie, withdrawal of consent), he/she maintains the option to 
participate in the safety follow-up procedures. 
1.4. 
Overall Rationale for the Study 
While DAA combination treatment has led to high SVR rates with a good safety profile, there 
remains an unmet medical need for alternative effective, safe, shorter, and simpler treatment 
regimens that can be used in all HCV-infected patient subgroups, regardless of genotype or 
baseline prognostic factors. This study is designed to investigate the safety, efficacy, and PK of 
administration of an 8 or 12-week regimen of AL-335 (HCV NS5B inhibitor), ODV (a second 
generation HCV NS5A inhibitor), and SMV (HCV NS3/A4 inhibitor) directed at 3 different 
targets in the HCV life cycle, respectively, in Japanese subjects with chronic 
hepatitis C genotype 1 or 2 virus infection with or without compensated cirrhosis who are DAA 
treatment-naïve (DAA-naïve, defined as not having received treatment with any approved or 
investigational DAA for chronic HCV infection; prior HCV therapy consisting of IFN [pegylated 
or nonpegylated] with or without RBV is allowed). It is anticipated that an all-oral, qd, 3-DAA 
combination of AL-335, ODV, and SMV may allow shortening of HCV treatment duration 
compared to currently available treatment regimens. In Japan, SMV is not approved for patients 
with cirrhosis; therefore, subjects with compensated cirrhosis will be enrolled in a separate 
cohort and will be monitored closely for safety and tolerability. 
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2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS 
2.1. 
Objectives and Endpoints 
2.1.1. 
Objectives 
Primary Objectives 
 
To evaluate the safety and tolerability of a combination treatment of AL-335, ODV, and 
SMV for 8 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 chronic HCV 
infection without cirrhosis and for 12 weeks in DAA-naïve Japanese subjects with 
genotype 1 or 2 chronic HCV infection with compensated cirrhosis. 
Secondary Objectives 
 
To evaluate the PK of AL-335 (and metabolites), ODV, and SMV in plasma in Japanese 
subjects with genotype 1 or 2 chronic HCV infection with or without compensated cirrhosis 
who are DAA-naïve. 
 
To evaluate the efficacy, ie, SVR4, SVR12, and SVR24, of a combination treatment with 
AL-335, ODV, and SMV for 8 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 
chronic HCV infection without cirrhosis and for 12 weeks in DAA-naïve Japanese subjects 
with genotype 1 or 2 chronic HCV infection with compensated cirrhosis. 
 
To evaluate on-treatment viral kinetics in an 8 or 12-week treatment regimen containing 
AL-335, ODV, and SMV in subjects who are DAA- naïve. 
 
To evaluate the incidence of on-treatment failure during an 8 or 12-week treatment regimen 
containing AL-335, ODV, and SMV in subjects who are DAA-naïve. 
 
To evaluate the incidence of viral relapse after an 8 or 12-week treatment regimen 
containing AL-335, ODV, and SMV in subjects who are DAA-naïve. 
Exploratory Objectives 
 
To explore relationships of exposure of AL-335 (and metabolites), ODV, and SMV with 
SVR and safety. 
 
To evaluate the impact of the patient and disease characteristics at baseline on SVR, 
including but not limited to prior treatment history, IL28B genotype, presence of cirrhosis, 
HCV RNA level, and HCV geno/subtype. 
 
To evaluate the impact of the presence of HCV NS3/4A, NS5A, and/or NS5B 
polymorphisms at baseline on treatment outcome. 
 
To assess the emergence of resistant variants in subjects not achieving SVR. 
2.1.2. 
Endpoints 
Primary Endpoint 
 
Safety data, including but not limited to AEs, physical examination, vital signs, 12-lead 
ECGs, echocardiograms, and clinical laboratory results (including chemistry, hematology, 
and urine) 
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Secondary Endpoints 
 
PK parameters for AL-335 (and metabolites), ODV, and SMV in plasma 
 
The proportion of subjects who have an SVR4, SVR12, and SVR24 
 
The proportion of subjects with viral relapse 
 
The proportion of subjects with on-treatment failure 
 
The proportion of subjects with on-treatment virologic response: 
 
HCV RNA not detected 
 
HCV RNA <LLOQ 
 
Time to achieve HCV RNA not detected or HCV RNA <LLOQ 
Exploratory Endpoints 
 
The effect of the presence or absence at baseline of HCV NS5A, NS5B, and/or NS3/4A 
polymorphisms on treatment outcome 
 
The changes in the HCV NS3/4A, NS5A and/or NS5B sequences in subjects not achieving 
SVR 
 
Impact of baseline condition on SVR (including but not limited to prior treatment history, 
IL28B genotype, presence of cirrhosis, HCV RNA level, and HCV geno/subtype) 
Refer to Section 9, Study Evaluations for evaluations related to endpoints. 
2.2. 
Hypothesis 
The study is hypothesis-generating. No formal hypothesis will be tested. 
3. 
STUDY DESIGN AND RATIONALE 
3.1. 
Overview of Study Design 
This is a Phase 2a, multicenter, open-label study to investigate the safety, efficacy, and PK of an 
8 or 12-week treatment regimen with AL-335, ODV, and SMV in Japanese subjects with 
genotype 1 or 2 chronic HCV infection with or without compensated cirrhosis who are 
DAA-naïve, followed by a 24-week posttreatment follow-up. 
The study will include a Screening Period of maximum 6 weeks starting from the time of the 
first screening assessment. In exceptional cases, the Screening Period can be extended if 
discussed with and approved (documented) by the sponsor. Thereafter, if eligible, subjects will 
be assigned to 1 of the 2 treatment cohorts to receive AL-335, ODV, and SMV combination 
treatment for 8 or 12 weeks based on the absence or presence of compensated cirrhosis. A 
posttreatment follow-up until 24 weeks after the actual EOT is included to assess SVR4, SVR12, 
and SVR24. The total study duration for each subject will be approximately 38 or 42 weeks 
(including the 6-week Screening Period, the 8 or 12-week Treatment Period, and the 24-week 
Posttreatment Follow-up Period). The study will be considered to be completed with the last visit 
of the last subject participating in the study. 
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Approximately 20 DAA-naïve chronic HCV genotype 1 or 2-infected subjects without cirrhosis 
will be assigned to Cohort 1, and approximately 20 DAA-naïve HCV genotype 1 or 2-infected 
subjects with compensated cirrhosis will be assigned to Cohort 2. 
 
Cohort 
1 
(N=20, 
chronic 
hepatitis 
C 
without 
cirrhosis): 
AL-335 800 mg qd+ODV 25 mg qd+SMV 75 mg qd for 8 weeks 
 
Cohort 
2 
(N=20, 
chronic 
hepatitis 
C 
with 
compensated 
cirrhosis): 
AL-335 800 mg qd+ODV 25 mg qd+SMV 75 mg qd for 12 weeks 
Subjects volunteering to participate, having signed the ICF, and found eligible for the study at 
screening, will be required to discontinue specified disallowed medication (as specified in the list 
of disallowed medication; see Section 8). 
If study drug is discontinued prematurely, for reasons other than withdrawal of consent, a 
Treatment Withdrawal Visit should be scheduled as soon as possible after the EOT. The subjects 
will be followed up for 24 weeks after EOT, with visits as indicated in the 
TIME AND EVENTS SCHEDULE. If a subject discontinues treatment due to withdrawal of 
consent, the subject will be offered an optional Treatment Withdrawal Visit to be scheduled as 
soon as possible after withdrawal and/or a safety Follow-up Visit, which needs to be scheduled 
4 weeks after EOT. At the safety Follow-up Visit safety assessments of the Week 4 Follow-up 
Visit need to be performed. 
Subjects will discontinue study drugs if the stopping rule is met to limit the risk of developing 
drug resistance and to reduce unnecessary exposure to study drugs for subjects with no chance or 
only a small chance of treatment success. All study drugs will be discontinued for subjects with 
viral breakthrough, defined as a confirmed increase of >1.0 log10 IU/mL in HCV RNA from 
nadir or confirmed HCV RNA >2.0 log10 IU/mL in subjects who had previously achieved 
HCV RNA <LLOQ (detected or not detected) while on treatment. 
A DRC will be established to monitor data with focus on the safety and on the general conduct of 
the study. The DRC is a committee within the sponsor’s organization that is independent of the 
sponsor’s study team. Details will be specified in a separate charter. 
The primary objective of this study is to assess safety and tolerability of the 3 DAA combination 
in Japanese patients with and without compensated liver cirrhosis. Compared to subjects with 
chronic hepatitis C without cirrhosis (enrolled in cohort 1), subjects with chronic hepatitis C with 
compensated cirrhosis (enrolled in cohort 2) are considered to potentially have a higher safety 
risk. To conduct this study carefully in light of securing subjects' safety, dosing of cohort 2 with 
patients with compensated cirrhosis will only start after a DRC has reviewed all available 
relevant safety data when the first 6 subjects in cohort 1 completed the Week 4 visit (including 
but not limited to AE, SAE, clinical laboratory test) and no new or unexpected events, which are 
considered clinically significant, are detected. DRC may require to review data of further 
patients before deciding about the start of dosing in cohort 2. Enrollment in cohort 1 will be kept 
ongoing during the data review process. 
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All study drugs (AL-335, ODV, and SMV) should be taken together in the morning at 
approximately the same time with food (ie, during or within 15 minutes after completion of a 
meal). Intake of study drugs should take place on site during visits when biochemistry samples 
are to be taken after fasting for at least 8 hours, and when predose PK sampling (sparse and rich 
sampling) is performed. For more information on the dose selection, see Section 3.2. 
A diagram of the study design is provided in Figure 1. 
Figure 1: 
Schematic Overview of the Study 
 
Cohort 1 
(N =20) 
F0-F3 
Screening Period 
Within 6 weeks 
Treatment Period 
AL-335 800 mg qd + 
ODV 25 mg qd +  
SMV 75 mg qd  
for 8 weeks 
Follow-up Period 
24 weeks 
 
 
 
Dosing in cohort 2 will be started according to  
decision of DRC. 
 
Cohort 2 
(N =20) 
F4 (compensated) 
Screening Period 
Within 6 weeks 
Treatment Period 
AL-335 800 mg qd +  
ODV 25 mg qd +  
SMV 75 mg qd  
for 12 weeks 
Follow-up Period 
24 weeks 
 
Key: ODV=odalasvir; qd=once daily; SMV=simeprevir 
Assessments 
The Baseline Visit (Day 1) may be scheduled as soon as the results of all screening assessments 
are known (but should occur within 6 weeks from the first screening assessment) and show that 
the subject is eligible for inclusion. Study drug intake will start on Day 1 after the completion of 
the baseline assessments. 
Efficacy of the regimen will be assessed by means of HCV RNA levels at all scheduled visits 
(see Section 9.5.1). HCV RNA levels will be processed in real time, and results will be 
communicated to the sponsor and the investigator throughout the study. For resistance 
determination, blood samples will be collected throughout the study (see Section 9.5.2). 
Blood samples will be collected to assess the PK in the rich serial PK substudy at Week 4 Visit, 
at 10 different time points within the dosing interval, for the measurement of plasma 
concentrations of AL-335 (and metabolites), ODV, and SMV, in approximately more than 
12 subjects (approximately more than 6 subjects from Cohort 1 and Cohort 2, each). Sparse PK 
sampling for AL-335 (and metabolites), ODV, and SMV will be performed in all subjects 
including subjects participating in the rich serial PK substudy. Sparse PK sample will be taken at 
predose, between 2-to 4-hours postdose, and between 4-to 6-hours postdose at Weeks 2, 4, 6, and 
at the EOT (Week 8) Visit (Cohort 1), or Weeks 2, 4, 6, 8 and at the EOT (Week 12) Visit 
(Cohort 2). At Week 4, no sparse PK sample will be taken for subjects participating in the rich 
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serial PK substudy. At the Week 12 Follow-up Visit, sparse PK sample will be taken at any time 
for the measurement of plasma concentrations of ODV. Intake of study drugs should take place 
on site when predose PK sampling (sparse and rich sampling) is performed. At the EOT Visit, 
intake of study drugs should take place on site when predose PK sampling (sparse and rich 
sampling) is performed. (see Section 9.3) 
One mandatory pharmacogenomic blood sample will be collected at baseline to allow for the 
determination of the subject’s IL28B genotype (rs12979860) (see Section 9.6). 
The safety evaluations will include monitoring of AEs, clinical laboratory tests, ECGs, 
echocardiograms, vital sign measurements, and physical examinations. Specific toxicity 
management plans in line with the known pharmacologic profile of the study drugs (and the drug 
class) evaluated in this study will be implemented (see Section 9.2). 
Subjects will complete all above mentioned assessments during study-related visits as specified 
in the TIME AND EVENTS SCHEDULE. 
3.2. 
Study Design Rationale 
Dose and Treatment Duration 
The present study will evaluate a 3-DAA regimen of AL-335 800 mg qd, ODV 25 mg qd, and 
SMV 75 mg qd, coadministered with food (as individual tablets/capsules) for 8 weeks in 
DAA-naïve Japanese subjects without cirrhosis or 12 weeks in DAA-naïve Japanese subjects 
with compensated cirrhosis. 
An optimal IFN-free regimen for treatment of chronic HCV infection requires a combination of 
agents with different mechanisms of action. Available data suggest that addition of a third 
antiHCV agent to a 2-DAA regimen may increase the robustness of the regimen to allow for a 
shorter treatment duration compared to currently available treatment regimens while maintaining 
high efficacy, particularly when considering more difficult-to-cure patients. 
The study population will include chronic HCV genotype 1 or 2-infected Japanese subjects who 
are DAA-naïve. 
Selection of Doses for AL-335, ODV, and SMV 
AL-335 dose selection 
Pharmacokinetic data from the Phase 1 DDI study AL-335-602 with SMV (150 mg qd), ODV 
(loading dose of 150 mg followed by 50 mg qd) and AL-335 (800 mg qd) in healthy volunteers 
suggested SMV and ODV individually and combined increase AL-335 (prodrug) exposure 
(AL-335 AUC increased 3- to 4-fold with SMV or ODV and 7- to 8-fold with SMV+ODV). 
Modest increases in plasma exposure (AUC) are also observed in the AL-335 prodrug metabolite 
ALS-0022399 (2.6- to 2.8-fold), with little to no effect on the AL-335 parent nucleoside 
metabolite ALS-0022227 when AL-335 is combined with SMV and/or ODV. The parent 
nucleoside is the major circulating drug-related moiety. 
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The objective of the ongoing Phase 2a Study AL-335-604, is to enable the selection of a dose 
and regimen with optimal risk/benefit profile for the Phase 2b study. In each cohort, the PK, 
safety, and efficacy of the orally administered combinations of AL-335 and ODV with or 
without SMV are being evaluated in 20 treatment-naïve subjects with chronic HCV infection 
without cirrhosis. Based on the DDI study in healthy volunteers (AL-335-602), the first cohort 
was dosed with SMV 100 mg qd, ODV 50 mg qd and AL-335 400 mg qd for 8 weeks. The PK 
data from this first cohort of Study AL-335-604 indicated that, at the 400 mg dose of AL-335, 
plasma levels of the parent nucleoside metabolite were similar to that observed in the 
monotherapy study AL-335-601 at the 400 mg dose and the increase in prodrug AL-335 in the 
presence of ODV and SMV (AL-335-602) did not translate into increases of the parent 
nucleoside of AL-335. In the AL-335-601 study, 7 days of AL-335 monotherapy in HCV 
genotype 1-infected subjects, showed a greater magnitude of HCV RNA decline from baseline at 
800 mg qd compared to that observed with 400 mg qd (mean maximum decrease in HCV RNA 
from baseline of 4.00 log10 IU/mL for the 800 mg dose compared to 2.76 log10 IU/mL for the 
400 mg dose). In addition, 7 days of monotherapy with AL-335 at 800 mg qd in HCV 
genotypes 2- and 3-infected subjects showed potent suppression of viral replication with a mean 
maximum decrease in HCV RNA from baseline of 4.46 log10 IU/mL and 4.72 log10 IU/mL for 
genotypes 2 and 3, respectively. Therefore, the selected dose of AL-335 for subsequent cohorts 
in the Phase 2a Study AL-335-604, and for use in the current Phase 2a study is 800 mg qd. 
AL-335 was generally well tolerated at single doses up to 1,200 mg by healthy volunteers and 
for multiple doses of 400 mg and 800 mg administered as monotherapy in HCV infected subjects 
for 7 days (Study AL-335-601). No treatment-related SAEs, and no clinically relevant laboratory, 
ECG, Holter, vital signs, or physical examination safety signals were identified when AL-335 
was administered as monotherapy. Preliminary safety evaluation of the first 80 subjects who 
were dosed for 6 or 8 weeks with AL-335 and ODV with or without SMV in the ongoing 
Phase 2a Study AL-335-604, revealed no safety signals in AEs, laboratory tests, ECGs, 
echocardiograms, vital signs, or physical examinations. One cardiac-related SAE was reported in 
a subject with progressive prolongation of PR interval and development of Type 1 2nd degree AV 
block (Wenckebach) (see Section 1.3.2.2 for details). 
ODV dose selection 
In the proof-of-concept Phase 1b study evaluating a single dose of ODV at 25 mg, 50 mg, 
150 mg, or 300 mg in genotype 1-infected subjects, potent antiviral activity was demonstrated 
for all doses. 
Preliminary data from both the DDI study, AL-335-602 and the ongoing Phase 2a 
Study AL-335-604, indicated that multiple doses of the new tablet formulation used in these 
studies resulted in higher exposure levels of ODV than those observed with the LFC formulation 
that was used in previous ODV studies. In the Study ACH102-017, ODV Cmax and trough 
plasma concentration (Ctrough) at steady state after a 50-mg qd dose (LFC formulation, no loading 
dose; administered in fasted state) was 182 and 108 ng/mL and 214 and 132 ng/mL, respectively, 
in Groups 1 and 2. In Study AL-335-602, the Cmax and minimum plasma concentration (Cmin) for 
ODV 50 mg (tablet formulation, 150 mg loading dose; administered in fed state [standard meal]) 
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qd alone after 10 days of dosing was 582 ng/mL and 235 ng/mL, respectively. In order to match 
the exposures to the exposures observed in Study ACH102-017, the ODV dose was lowered to 
25 mg/day (50 mg every other day) in the cohorts of Phase 2a Study AL-335-604, and in the 
current Phase 2a study. 
SMV dose selection 
Although SMV exposure was increased by 1.6-fold when administered in combination with 
ODV compared to SMV administered alone in the DDI study, AL-335-602 in healthy volunteers, 
results from the Phase 2a Study AL-335-604, indicated that there is no significant interaction 
when these compounds are administered to HCV subjects. In the Phase 2b Study C205, of SMV 
in combination with PegIFN/RBV, SMV doses of 75 mg and 150 mg were evaluated in 
treatment-naïve HCV infected subjects; no significant difference in SVR rates was observed 
between 75 mg and 150 mg doses of SMV and only a trend for higher SVR was observed with 
the SMV 150-mg dose in some difficult-to-cure subpopulations. However, in the context of an 
IFN-free 3-DAA regimen in which SMV is administered in combination with 2 other potent 
DAAs, it is hypothesized that 75 mg will provide optimal efficacy when administered together 
with AL-335 and ODV. In addition, SMV at a lower 75 mg dose is expected to be associated 
with a lower frequency of events such as increases in bilirubin, rash, and photosensitivity, which 
are known to correlate with SMV exposure. In addition, the potential risk of higher exposures of 
ODV due to drug interactions with SMV is anticipated to be lower when SMV is administered at 
a dose of 75 mg. 
Taking into account the dose selection rationale described above, the doses for AL-335, ODV, 
and SMV in the current study will be 800 mg qd, 25 mg qd, and 75 mg qd, respectively. 
Selection of treatment duration  
In the current study, an 8 and 12-week treatment course of AL-335, ODV, and SMV will be 
investigated in treatment-naïve Japanese subjects with chronic HCV genotype 1 or 2 infection 
with or without compensated cirrhosis. 
In subjects with chronic HCV infection and compensated liver disease, 12-week treatment with 
2 DAAs has been demonstrated to lead to high SVR rates (see also Section 1.2, Background to 
All-oral IFN-free DAA Combination Regimens). Combination regimens consisting of 3 DAAs 
have been shown to increase the speed with which HCV RNA declines to undetectable levels,23 
suggesting a more robust inhibition of HCV replication. 
It is anticipated that combinations of 3 DAAs with different mechanisms of action will provide a 
higher antiviral pressure on HCV in patients with decompensated liver disease leading to higher 
SVR rates compared to less robust regimens. 
ODV in a 2-DAA combination with SOF demonstrated an efficacy of 100% SVR in 
treatment-naïve HCV genotype-1 infected subjects without cirrhosis (Study ACH102-017) with 
treatment duration of 8 weeks (12 subjects) and 6 weeks (18 subjects). Given the high SVR rates 
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achieved with the 2-DAA combination, with a treatment duration of 8 weeks and 6 weeks, it is 
anticipated that the addition of a 3rd DAA, resulting in a regimen including 3-DAAs with a 
different mechanism of action, will provide a robust HCV treatment regimen, also at short 
treatment durations, ie, 6 or 8 weeks of total treatment. In the ongoing Study AL-335-604, to 
date, no cases of viral failure or relapse have been observed in 3-DAA arms, whereas, 3 cases of 
viral relapse were observed in Cohorts 1b and 4 in which AL-335 and ODV were dosed without 
SMV; therefore, it is anticipated that addition of a third DAA will yield in higher SVR rates. In 
Study AL-335-604, the SVR24 rate in treatment-naïve, HCV genotype-1 infected subjects 
without cirrhosis treated with AL-335 400 mg qd, ODV 50 mg qd, and SMV 100 mg qd for 
8 weeks, was 100% (20/20 subjects). Of the 40 subjects in Cohort 2 and Cohort 3 dosed with 
AL-335 800 mg qd, ODV 50 mg qod, and SMV 75 mg qd for 8 or 6 weeks, respectively, all 
subjects achieved SVR12 and SVR4, respectively. 
In patients with compensated cirrhosis, based on preliminary data from Phase 2 study 
AL-335-604, suggesting further benefit, treatment durations of 8 and 12 weeks are studied in 
additional cohorts (Phase 2b). The outcome of this study will inform the duration evaluated in 
Phase 3 for patients with compensated cirrhosis. To assess safety, PK and efficacy of the 
potentially longest treatment duration in Japanese subjects with compensated cirrhosis before 
going to Phase 3, the Sponsor decided to extend the treatment duration of the cirrhotic cohort 2 
in this study from 8 to 12 weeks. 
Pharmacogenomic (DNA) Evaluations 
A genetic polymorphism upstream of the IL28B gene (single nucleotide polymorphism 
rs12979860) has been associated with viral clearance in response to PegIFN/RBV treatment.11 
Analyses of pooled data from 2 Phase 3 studies, in which SMV and PegIFN/RBV were 
combined, also showed lower SVR12 rates in subjects with IL28B genotype TT versus CT and 
CC. The role of this polymorphism in novel treatment regimens for HCV consisting of DAAs 
without PegIFN/RBV has not been established. The present study will assess the influence of 
this polymorphic genetic marker on the treatment response to the drug regimen investigated in 
this study (see Section 9.6, Pharmacogenomic Evaluations). 
Study Population 
A number of IFN-free DAA combination regimens have been approved mainly for the treatment 
of HCV genotypes 1 and 4-infected patients, and recently also for HCV genotypes 2-, 3-, 5-, and 
6-infected patients. Availability of multiple agents that can interrupt several steps of the HCV 
lifecycle affords providers and patients with options that can be combined and individually 
tailored to each patient's unique needs to obtain high rates of SVR. In Japan, IFN-free DAA 
combination regimens have been approved only for the treatment of HCV genotype 1. 
The pan-genotypic activity of both the NS5A-inhibitor ODV and the nucleotide NS5B inhibitor 
AL-335, as observed from the in vitro data (see Sections 1.1.4 and 1.1.3, respectively), is 
expected to provide in combination with SMV, an effective treatment for HCV genotypes 1 to 
6-infected patients. 
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In Japan, approximately 70% of HCV-infected patients have genotype 1 infection and 
approximately 30% have genotype 2 infection. Based on this epidemiology data, this study will 
include treatment-naïve Japanese subjects with HCV genotype 1 or 2 infection. Subjects will be 
assigned to 2 separate cohorts (Cohort 1 or Cohort 2) based on the absence or presence of 
compensated cirrhosis. This study aims to include 40 subjects (20 subjects per cohort). 
4. 
SUBJECT POPULATION 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination. 
4.1. 
Inclusion Criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study:  
1. 
Man or woman, 20 to 75 years of age, inclusive. 
2. 
Body mass index; weight in kg divided by the square of height in meters) of 18.0 
to 35.0 kg/m2, inclusive. 
3. 
Documented chronic HCV infection: diagnosis of HCV infection >6 months 
before the first screening assessment, either by detectable HCV RNA, an HCV 
positive antibody test, or presence of histological changes consistent with chronic 
hepatitis in a liver biopsy. 
4. 
All subjects must have HCV genotype 1 or 2 infection, determined at screening. 
Note: genotype and HCV RNA plasma levels will be determined by the central 
laboratory at screening. In case of discrepancy between previously documented 
geno/subtype and the geno/subtype determined at screening, the screening results 
will be used. 
5. 
HCV RNA plasma levels ≥10,000 IU/mL, determined at screening. 
6. 
DAA-naïve subjects, defined as not having received treatment with any approved 
or investigational DAA drug for chronic HCV infection; prior HCV therapy 
consisting of IFN (pegylated or nonpegylated) with or without RBV is allowed. 
7. 
Subjects with chronic Hepatitis C without cirrhosis defined as any of the 
following: 
 
Fibroscan with a result of ≤12.5 kPa within 6 months of baseline/Day 1, OR 
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 
Liver biopsy within 6 months of baseline/Day 1, showing absence of cirrhosis 
(METAVIR score of F0-F3 or Ishak score <5) 
Subjects with chronic Hepatitis C with compensated cirrhosis (not meeting the 
criterion for hepatic decompensation described in the Exclusion Criteria #6 
[Section 4.2]), defined as any of the following: 
 
Fibroscan (prior report or during Screening Period) with a result of 
>12.5 kPA, OR 
 
Liver biopsy (prior report or during Screening Period) showing cirrhosis 
(eg, METAVIR score of F4 or Ishak score ≥5). 
8. 
A woman of childbearing potential must have a negative highly sensitive serum 
pregnancy test (-human chorionic gonadotropin [-hCG]) at screening. 
9. 
Contraceptive use by women should be consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical studies, if 
these are stricter than what is proposed in these inclusion criteria. 
Before enrollment, a woman must be either: 
a. 
not of childbearing potential defined as: 
o 
postmenopausal (ie, 2 years of amenorrhea without an alternative 
medical cause) and a serum follicle stimulating hormone (FSH) level 
in the postmenopausal range (>40 IU/mL), OR 
o 
be surgically sterile (have had a total hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation/bilateral tubal clips without 
reversal operation), or otherwise be incapable of pregnancy 
OR 
b. of childbearing potential and 
 
not heterosexually active (eg, abstinence) from at least 14 days prior to 
Day 1 until 12 weeks after the EOT (or longer, if dictated by local 
regulations), OR 
o 
have a vasectomized partner (confirmed sterile per verbal account of 
the subject), OR 
o 
if heterosexually active, be practicing an acceptable method of birth 
control from at least 14 days prior to Day 1, and agree to continue to 
use the same method of contraception throughout the study and for at 
least 12 weeks after the EOT (or longer, if dictated by local 
regulations. Oral hormone-based contraceptives are not allowed from 
14 days before baseline until the Week 4 Follow-up Visit. An 
intrauterine device, being either hormonal (ie, intrauterine hormone-
releasing system (IUS)* or nonhormonal, is considered highly 
effective and reliable, therefore, subjects are not required to use 
additional contraceptive methods (no double-barrier method 
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required). Other nonoral hormone based contraception methods (eg, 
injectable, implants, transdermal system, vaginal ring)** may be 
continued, but as the interaction of the study drug with hormone-
based contraception is unknown, these methods are not considered to 
be reliable, and therefore, subjects should use a double-barrier 
method (eg, male condom+either diaphragm or cervical cap with or 
without spermicide)**. Subjects having a vasectomized partner 
(confirmed sterile per verbal account of the subject) are not required 
to use additional contraceptive methods. 
*An IUS does not rely on systemic plasma concentrations, and is 
therefore, not expected to be impacted by a potential DDI. 
**Non-oral hormone based contraception methods (eg, injectable, 
implants, transdermal system, vaginal ring), cervical cap and diaphragm 
with spermicide are not approved in Japan. 
Note 1: Sexual abstinence is considered a highly effective method, only if defined 
as refraining from heterosexual intercourse during the entire period of risk 
associated with the study drug. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the subject. 
Note 2: A male and female condom should not be used together due to risk of 
breakage or damage caused by latex friction. 
10. 
Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for a period of 12 weeks after the EOT. 
11. 
Women must have a negative highly sensitive urine pregnancy test at Day 1. 
12. 
Contraceptive use by men should be consistent with local regulations regarding the 
use of contraceptive methods for subjects participating in clinical studies, if these 
are stricter than what is proposed in these inclusion criteria. 
Before enrollment, a man must either: 
a. 
be surgically sterile (had a vasectomy), or otherwise incapable of 
fathering a child 
OR 
b. 
not be heterosexually active (eg, abstinence) from at least 14 days prior to 
Day 1 until at least 12 weeks after the EOT, OR 
c. 
if heterosexually active, have a partner who is postmenopausal (2 years 
amenorrhea), surgically sterile (has had a total hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation/bilateral tubal clips without 
reversal operation), or otherwise incapable of becoming pregnant, OR 
d. if heterosexually active with a woman of childbearing potential, be 
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practicing an acceptable method of birth control from at least 14 days 
prior to Day 1 and agree to continue to use the same method of 
contraception throughout the study and for at least 12 weeks after the 
EOT (or longer, if dictated by local regulations). An acceptable method 
of birth control for men is a double-barrier method (eg, male 
condom+either diaphragm or cervical cap with or without spermicide)*. 
Men with a female partner who uses hormonal contraceptives (oral, 
injectable, or implants)*, a hormonal (IUS), or nonhormonal intrauterine 
device, and men who are vasectomized or otherwise incapable of 
fathering a child are not required to use additional contraceptive methods.
*Non-oral hormone based contraception methods (eg, injectable, 
implants, transdermal system, vaginal ring), cervical cap and diaphragm 
with spermicide are not approved in Japan. 
See Notes 1 and 2 of the inclusion criteria #9. 
13. 
Men must agree not to donate sperm during the study until 12 weeks after the EOT 
(or longer, if dictated by local regulations). 
14. 
Willing and able to adhere to the prohibitions and restrictions specified in this 
protocol (Section 4.3). 
15. 
Agree not to participate in other clinical studies for the duration of their 
participation in this study, except for observational studies and only after prior 
approval of the sponsor. 
16. 
Must voluntarily sign an ICF indicating that he or she understands the purpose of, 
and procedures required for, the study and is willing to participate in the study. 
4.2. 
Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:  
1. 
Co-infection with multiple HCV genotypes. 
2. 
Co-infection with HIV (HIV-1 or HIV-2 antibody positive) or hepatitis B virus (HBV) 
(hepatitis B surface antigen [HBsAg] positive). 
3. 
Infection with HCV genotype 3, 4, 5, or 6. 
4. 
Prior treatment with any investigational or approved HCV DAA, either in combination 
with PegIFN or IFN-free. 
5. 
Any evidence of liver disease of nonHCV etiology. This includes, but is not limited to, 
acute hepatitis A infection (immunoglobulin M), drug- or alcohol-related liver disease, 
autoimmune hepatitis, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin 
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deficiency, primary biliary cirrhosis, or any other nonHCV liver disease that is 
considered clinically significant by the investigator. 
6. 
Evidence of hepatic decompensation as assessed with Child-Pugh Class B or C or any 
of the following: history or current clinical evidence of ascites, bleeding varices, or 
hepatic encephalopathy. 
7. 
Intake of any disallowed therapies as noted in Section 8. 
8. 
History of malignancy within 5 years before screening (exceptions are squamous and 
basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, 
which is considered cured with minimal risk of recurrence) and history of hepatocellular 
carcinoma regardless of period before screening. 
9. 
Known allergies, hypersensitivity, or intolerance to AL-335, ODV, or SMV, or their 
excipients (refer to IBs and addenda of AL-335,18,16 ODV, 19,20 and SMV.21,22 
10. 
Presence of significant comorbidities, conditions, or clinically significant findings 
during screening of medical history, physical examination, laboratory testing, vital 
signs, or ECG recording for which, in the opinion of the investigator, participation 
would not be in the best interest of the subject (eg, compromise the safety or well-being) 
or that could prevent, limit, or confound the protocol-specified assessments. 
11. 
Organ transplant (other than cornea, hair transplant, or skin graft). 
12. 
History or other clinical evidence of significant cardiac findings or conditions such as: 
 
cardiac disease (eg, angina, congestive heart failure, myocardial infarction, diastolic 
dysfunction, significant arrhythmia, coronary heart disease, moderate or severe 
valvular disease, or uncontrolled hypertension) at screening 
 
screening echocardiogram left ventricular ejection fraction (LVEF) <55.0% or any 
other echocardiogram finding suggestive of clinically relevant cardiomyopathy 
 
screening abnormal ECG findings such as: significantly abnormal PR [PR interval 
>200 msec], QRS intervals or QTc >450 msec for male subjects and >470 msec for 
female subjects (based on the average of the 3 ECGs) 
 
evidence of any heart block 
 
evidence of right bundle branch block or left bundle branch block 
 
history or family history of prolonged QT syndrome (eg, torsade de pointes) or 
sudden cardiac death 
13. 
Any of the following laboratory abnormalities at screening: 
 
platelet count <75×103/µL or <75×109/L 
 
hemoglobin <11 g/dL or <6.83 mmol/L for male subjects, <10 g/dL or 
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<6.21 mmol/L for female subjects 
 
absolute neutrophil count <1.00×103/µL 
 
ALT and/or AST >10× upper limit of normal (ULN) 
 
total serum bilirubin >1.5×ULN 
 
albumin <3.5 g/dL or <35 g/L 
 
estimated glomerular filtration rate (eGFR) of <50 mL/min/1.73m2 
 
hypo-/hyperkalemia (Grade 2 or higher) 
14. 
Current or past abuse of alcohol or recreational or narcotic drugs, which in the 
investigator’s opinion would compromise the subject’s safety and/or compliance with 
the study procedures 
Note: Urine will be tested at screening to check the current use of amphetamines, 
benzodiazepines, cannabinoids, opioids and cocaine. Subjects with a positive drug test 
may only be included after consultation with the sponsor. Documentation of the 
investigator’s assessment with regard to the subject’s safety and compliance must be in 
place prior to the start of treatment. 
15. 
Subject is pregnant, planning to become pregnant (during treatment and up to 12 weeks 
after the EOT), or breast-feeding female subject (including female subject who 
discontinues breast-feeding), or male subject whose female partner is pregnant or 
planning to become pregnant (during treatment and up to 12 weeks after the EOT). 
16. 
Has received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 30 days before the planned first dose of 
study drug. 
17. 
Have findings suggestive of hepatocellular carcinoma. Subjects with cirrhosis have to 
receive an ultrasound scan, computed tomography (CT) scan, or magnetic resonance 
imaging (MRI) within 3 months prior to baseline/Day 1 to document the absence of 
findings suggestive of hepatocellular carcinoma. 
 
NOTE: Retesting of laboratory values (eg, safety laboratory or HCV RNA) that lead to 
exclusion will be allowed once during the Screening Period to assess eligibility. 
Investigators should ensure that all study enrollment criteria have been met at screening. If a 
subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria. 
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4.3. 
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation: 
1. 
Refer to Section 8, PRESTUDY AND CONCOMITANT THERAPY for details 
regarding prohibited and restricted therapy during the study. 
2. 
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements) (Sections 4.1 and 4.2).
3. 
Subjects should be informed that during SMV administration, photosensitivity reactions 
(rash confined to light-exposed areas), including serious reactions which resulted in 
hospitalization, have been reported. Photosensitivity reactions occurred most frequently 
in the first 4 weeks of treatment, but can occur at any time during treatment. Subjects 
should use sun protective measures (such as a hat, sunglasses, protective clothing, 
sunscreen) and limit exposure to natural sunlight and avoid artificial sunlight (tanning 
beds or phototherapy) from baseline until the last intake of SMV. Ideally, outdoor 
activities should be scheduled outside the hours that ultraviolet radiation is most intense, 
or should be performed in the shade. Subjects should be advised to use sun protective 
measures (such as a hat, sunglasses, protective clothing, sunscreen) during treatment 
with SMV. 
5. 
TREATMENT ALLOCATION AND BLINDING 
Treatment Allocation 
Randomization will not be used in this study. Subjects will be assigned to a treatment cohort 
based on the presence or absence of cirrhosis. 
Blinding 
As this is an open-label study, blinding procedures are not applicable. 
6. 
DOSAGE AND ADMINISTRATION 
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol (see Section 14.4).  
All subjects will receive AL-335 800 mg qd, ODV 25 mg qd, and SMV 75 mg qd. The treatment 
duration is 8 weeks for subjects without cirrhosis and 12 weeks for subjects with compensated 
cirrhosis. 
All study drugs should be taken together in the morning at approximately the same time with 
food (ie, during or within 15 minutes after completion of a meal).  
Subjects will receive study drugs in sufficient amounts for 4 weeks of treatment. Provision of 
study drugs will occur on Day 1 and Week 4 for subjects without cirrhosis or on Day 1, Week 4 
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and 8 for subjects with compensated cirrhosis. Subjects will be instructed to continue intake of 
study drugs up to 8 or 12 weeks of treatment, in order to complete the intended treatment 
duration. Subjects will be provided with a medication diary to record all dates and times of 
intake of all study drugs (see Section 7). 
For guidance on timing of dosing, dose adjustments and treatment interruptions, see Sections 6.1 
and 6.2. 
6.1. 
Timing of Doses 
Subjects will attend the study visits and study drugs will be administered as described in the 
TIME AND EVENTS SCHEDULE. 
AL-335 (800 mg), ODV (25 mg), and SMV (75 mg) will be dosed qd in a fed state starting on 
Day 1, after the baseline assessments have been completed. 
All study drugs should be taken together in the morning at approximately the same time with 
food (ie, during or within 15 minutes after completion of a meal). Intake of study drugs should 
take place on site during visits when biochemistry samples are to be taken after fasting for at 
least 8 hours, and when predose PK sampling (sparse and rich sampling) is performed. (see the 
TIME AND EVENTS SCHEDULE and TIME AND EVENTS SCHEDULE: Rich serial PK 
Assessments). At visits where study drug dosing occurs on-site, study sites should have 
arrangements in place to offer the subjects a meal. Details on the timing of dosing on days with 
PK blood sampling are presented in the TIME AND EVENTS SCHEDULE. 
The following applies if a scheduled dose of AL-335, ODV, and SMV, is missed: 
 
If the missed dose is remembered within 12 hours of the scheduled dose time, the dose 
should be taken as soon as possible. 
 
If the missed dose is remembered later than 12 hours after the scheduled dose time, the dose 
should be skipped and the next dose should be taken at the appropriate time. 
Note: All missed doses should be recorded in the electronic case report form (eCRF), based on 
information recorded in medical file after review of the diary and the pill count. 
6.2. 
Dose Adjustment and Treatment Interruption 
During the Treatment Period, dose adjustments of AL-335, ODV, and SMV are not allowed. 
The investigator should thoroughly explain to subjects the importance of completing treatment 
without interruptions. All efforts should be made to keep the subject on treatment for the entire 
treatment duration and to avoid any treatment interruptions of study drugs unless deemed 
necessary due to safety reasons. 
Temporary dose interruptions of AL-335, ODV, and SMV will be allowed as long as the 
interruption is associated with and can be linked to an AE. All efforts must be made to limit the 
duration of temporary interruptions to not more than 3 consecutive days. The sponsor must be 
notified when a temporary dose interruption occurs. In the event that AL-335, ODV, or SMV is 
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interrupted (temporarily or permanently), the possibility of continuing treatment with the 
remaining drug(s) or restarting treatment should be discussed with the sponsor on a case-by-case 
basis. Subjects should continue with the regular visit schedule during treatment interruption. 
Subjects who prematurely discontinue all study drugs will be followed up for 24 weeks after 
EOT, unless the reason for treatment discontinuation is withdrawal of consent. Additional 
unscheduled visits may be performed for safety or tolerability reasons, if needed. Subjects who 
withdraw consent during the Treatment or Posttreatment Follow-up Period will be offered an 
optional safety Follow-up Visit which needs to be scheduled 4 weeks after EOT. 
All treatment modifications, interruptions, and discontinuations will be recorded in the eCRF. 
6.3. 
Treatment Stopping Rules (for Viral Breakthrough) 
Subjects will discontinue study drugs if the stopping rule is met to limit the risk of developing 
drug resistance and to reduce unnecessary exposure to study drugs for subjects with no chance or 
only a small chance of treatment success. 
All study drugs will be discontinued for subjects with viral breakthrough, defined as a confirmed 
>1.0 log10 increase in HCV RNA from nadir or confirmed HCV RNA >2.0 log10 IU/mL in 
subjects who had previously achieved HCV RNA <LLOQ (detected or not detected) while on 
treatment. HCV RNA will be processed in real-time and continuously monitored by the sponsor 
and communicated to the investigator throughout the study. It is the responsibility of the 
investigator to monitor the HCV RNA results obtained and ensure that all study drugs are 
discontinued in subjects with viral breakthrough. Subjects should discontinue treatment as soon 
as possible once the viral breakthrough criterion is met. 
If discontinuation of the study drug is necessary, a Treatment Withdrawal Visit should be 
scheduled as soon as possible (but no later than 2 weeks) after the HCV RNA results are known 
by the investigator. 
For details on the assessments during the Treatment Withdrawal Visit, see the 
TIME AND EVENTS SCHEDULE. 
6.4. 
Study Treatment Stopping Rules  
The occurrence of any one of the following treatment-emergent events in any ongoing study 
using ODV at therapeutic doses: 
 
2nd degree Mobitz Type 2 or 3rd degree heart block; 
 
drop in EF by ≥10 points with absolute EF <50%; 
 
a cardiac event that is serious, severe or life-threatening; 
will lead to stop of recruitment and dosing in all subjects in this study if the event(s) is 
adjudicated by the DRC to be at least possibly related to the study regimen. Such event(s) will be 
reported to the sponsor medical monitor within 24 hours. Upon this notification, a safety 
assessment of the event by the DRC will take place within 72 hours and the outcome of the 
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assessment and its associated action towards the study will be reported to Health Authorities and 
Ethics Committees in compliance with safety reporting regulations, as applicable. 
7. 
TREATMENT COMPLIANCE 
The investigator or designated study-site personnel will maintain a log of all provided and 
returned study drugs. Drug supplies for each subject will be inventoried and accounted for 
throughout the study (see also Section 14.5). 
Subjects will be instructed to bring unused study drugs and empty packaging to the study site at 
each visit. 
Subjects will be provided with a medication diary at the Baseline Visit to record all dates and 
times of intake of all study drugs. In addition, on the day of PK assessments and the previous day 
for PK blood sampling for all subjects in the sparse PK substudy, it should be recorded if the 
study drugs were taken with food (ie, during or no later than 15 minutes after a meal) in the diary. 
On the days of PK assessments which are part of the rich PK substudy, the start and end times of 
the accompanying meal should be documented; on the previous day and on the day after PK 
samples (after 24h PK sample collected) which are part of the rich PK substudy, it should be 
recorded if the study drugs were taken with food (ie, during or no later than 15 minutes after a 
meal) in the diary. At the Baseline Visit, study-site personnel will instruct subjects on adherence 
with study drug administration and on how to correctly complete the medication diary. Subjects 
will be instructed to return the medication diary at each study visit until the EOT. A study-site 
personnel is to review the medication diary for adherence and perform adherence counseling at 
each on-treatment study visit. The investigator should discuss the importance of treatment 
adherence with the subject at every visit and, in case study drug intake is not according to the 
protocol, try to identify and address factors that may negatively impact adherence and, if 
applicable, notify the sponsor (see Section 6.2). 
8. 
PRESTUDY AND CONCOMITANT THERAPY 
Prestudy therapies (prescriptions or over-the-counter medications, including vitamins and herbal 
supplements, nonpharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, or exercise regimens) administered within 30 days before the start of screening must be 
recorded at screening. Consumption of large quantities of grapefruit juice (>1 liter/day) and 
phlebotomy is disallowed from baseline until EOT and from screening until the Week 12 
Follow-up Visit, respectively. 
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; nonpharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, or exercise regimens) used during the study and different from the study drugs (AL-335, 
ODV, and SMV) must be recorded in the eCRF. Recorded information will include a description 
of the type of drug, Treatment Period, dosing regimen, route of administration, and its indication. 
Patients on disallowed medication (see Table 1) are excluded from the study. Modification of an 
effective preexisting therapy should not be made for the explicit purpose of entering a subject 
into the study. 
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For study-specific rules on the use of contraceptive methods, refer to Section 4.1. 
AL-335 is metabolized by esterases and is not a substrate of any CYP enzymes. AL-335 (and 
metabolites) has demonstrated a very low inhibition potential to CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6, and CYP3A. AL-335 is a substrate for P-gp but does not inhibit 
P-gp. Coadministration of AL-335 with inhibitors of P-gp may increase AL-335 plasma 
concentrations. ALS-022399 and ALS-022227 are neither substrates nor inhibitors of P-gp, 
OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport. 
ODV has demonstrated a low inhibition potential for CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A. ODV is primarily cleared by biliary secretion, is not 
significantly metabolized, and is not expected to be involved with clinically significant DDIs 
associated with the CYP enzyme system. ODV is neither a substrate nor an inhibitor of 
transporters such as OATP1B1, OATP1B3, breast cancer resistance protein, MRP2, MRP3, and 
bile salt export pump. ODV is a low-affinity substrate of OATP1B1 and does not inhibit 
OATP1B1. ODV is not a substrate but is an inhibitor of P-gp. Coadministration of ODV with 
drugs that are substrates for P-gp transport may result in increased plasma concentrations of such 
drugs. 
SMV is a mild inhibitor of intestinal CYP3A. Coadministration of SMV with drugs that are 
primarily metabolized by CYP3A may result in mild increases in plasma concentrations of such 
drugs, which could increase or prolong therapeutic effect and adverse reactions of CYP3A 
substrates with narrow therapeutic index. Drugs that induce CYP3A may decrease SMV plasma 
concentrations and reduce the therapeutic effect of SMV. Coadministration of SMV with 
inhibitors of CYP3A may increase SMV plasma concentrations. Clinically, SMV inhibits uptake 
transporters OATP1B1, OATP1B3, and the efflux transporters P-gp/MRP1 and MRP2. 
Coadministration of SMV with drugs that are substrates for OATP1B1, OATP1B3, and P-gp 
transport may result in increased plasma concentrations of such drugs. 
An overview of disallowed concomitant medications is presented in Table 1. 
Table 1: 
Disallowed Medications  
Disallowed within 30 days of screening until the end of follow up 
 All nonHCV investigational drugs or invasive investigational medical devices 
 Experimental nonHCV vaccines 
Note: Approved nonHCV vaccines are allowed. 
Disallowed within 3 months prior to screening until the end of the study 
 Antiarrhythmic: amiodarone 
Disallowed from screening until the end of the study 
 All concomitant medications with a potential to prolong QT interval (eg, digoxin) 
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 Drugs associated with QT prolongation and/or Torsades de Pointes (QT Drug Lists by Risk Groups) provided by 
the Arizona Center for Education and Research on Therapeutics:  
 Amantadine, Amitriptyline, Amphotericin B, Anagrelide, Apomorphine, Aripiprazole, Arsenic trioxide, 
Asenapine, Atazanavir, Atomoxetine, Azithromycin, Bepridil, Bortezomib, Bosutinib, Buprenorphine, 
Capecitabine, Ceritinib, Chloral hydrate, Chloroquine, Chlorpromazine, Cilostazol, Ciprofloxacin, 
Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib, Dabrafenib, Dasatinib, 
Degarelix, Delamanid, Dexmedetomidine, Diphenhydramine, Disopyramide, Domperidone, Donepezil, 
Droperidol, Efavirenz, Eribulin mesylate, Erythromycin, Escitalopram, Esomeprazole, Famotidine, 
Fingolimod, Flecainide, Fluconazole, Fluvoxamine, Foscarnet, Furosemide, Galantamine, Garenoxacin, 
Gatifloxacin, Granisetron, Haloperidol, Hydrochlorothiazide, Hydroxychloroquine, Hydroxyzine, 
Imipramine, Indapamide, Itraconazole, Ketoconazole, Lansoprazole, Lapatinib, Lenvatinib, Leuprolide, 
Levofloxacin, Levomepromazine, Lithium, Loperamide, Methadone, Metoclopramide, Metronidazole, 
Mirabegron, Mirtazapine, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib, Norfloxacin, Nortriptyline, 
Ofloxacin, Olanzapine, Omeprazole, Ondansetron, Osimertinib, Oxaliplatin, Oxytocin, Paliperidone, 
Panobinostat, Papaverine HCl, Paroxetine, Pasireotide, Pazopanib, Pentamidine, Perphenazine, Pimozide, 
Pipamperone, Probucol, Procainamide, Promethazine, Propofol, Quetiapine, Quinidine, Quinine, Rilpivirine, 
Risperidone, Ritonavir, Roxithromycin, Saquinavir, Sertraline, Sevoflurane, Solifenacin, Sorafenib, Sotalol, 
Sulpiride, Sultopride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Tetrabenazine, Tiapride, Tizanidine, 
Tolterodine, Toremifene, Torsemide, Trazodone, Trimipramine, Vandetanib, Vardenafil, Vemurafenib, 
Venlafaxine, Voriconazole, Vorinostat, Zotepin 
Note: Please refer the comprehensive list of drugs, which include approved drugs overseas, associated with QT 
prolongation and/or Torsades de Pointes (QT Drug Lists by Risk Groups) provided by the Arizona Center for 
Education and Research on Therapeutics. 5 
Disallowed from screening until the Week 12 Follow-up Visit 
 Prescription drugs for improvement of hepatic function which could potentially affect to hepatic function 
including AST and ALT (eg. glycyrrhizinate, ursodeocycholic Acid) 
Disallowed from screening onwards until the end-of-treatment 
 Immunomodulators (eg, cyclosporine, interleukins, or systemic corticosteroids in immunosuppressive dose) 
 Any herbal or nutritional products for HCV treatment including silibinin, silybin, and silymarin (milk thistle)
 Antiarrhythmics: mexiletine, systemic lidocaine, and propafenone 
 Beta-blockers 
 Proton-pump inhibitors (eg, rabeprazole) 
 Ca-channel blockers (eg, amlodipine, bepridil, diltiazem, felodipine, nifedipine, nisoldipine,verapamil) 
 Na-channel blockers (eg, lidocaine, mexiletine, moricizine, propafenone, tocainide) 
 K-channel blockers (eg, bretylium, dronedarone, ibutilide, dofetilide) 
Disallowed from 2 weeks before baseline and during the Treatment Period 
 Potent and moderate CYP3A4 inducers, such as: 
 Antiepileptics: carbamazepine, oxcarbazepine, (fos)phenytoin, phenobarbital 
 Antituberculosis drugs: rifabutin, rifampicin, and rifapentine 
 Systemic dexamethasone (if more than a single dose) 
 Miscellaneous: products containing Hypericum perforatum (St. John’s Wort) 
 P-gp inhibitors  
Disallowed from baseline onwards until the end-of-treatment 
 Potent and moderate CYP3A4 inhibitors, such as: 
 Antibiotics (systemic): troleandomycin, and telithromycin 
 Antiretrovirals: (fos)amprenavir, delavirdine, darunavir, etravirine, indinavir, lopinavir, nevirapine, tipranavir
 Miscellaneous: cobicistat-containing products 
 CYP3A substrates with narrow therapeutic index, eg: 
 Antihistamines astemizole and terfenadine. 
 Gastrointestinal/gastroesophageal reflux disease drugs: cisapride. 
Disallowed from 14 days before baseline until the Week 4 Follow-up Visit 
 Oral contraceptives 
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Key: CYP=cytochrome P450; HCV=hepatitis C virus; P-gp=P-glycoprotein 
Notes:  
 The list of disallowed concomitant medication is not exhaustive; for drugs falling in one of the categories 
defined by respective CYP or P-gp interaction and not mentioned by name, the sponsor should be contacted 
to determine whether the drug can be allowed. 
 
 As sacubitril can interfere with BNP measurement, sacubitril-containing products are disallowed from 
screening until Week 4 Follow-up Visit. 
 
An overview of concomitant medication that should be used with caution is presented in Table 2. 
Table 2: 
Concomitant Medication to be Used With Caution 
The following concomitant medication is allowed, but should be used with caution and be started at the lowest 
possible dose, with monitoring of adverse events and desired efficacy. 
 Analgesics: ergoloid mesylates, ergotamine tartrate, dihydroergotamine, and methylergonovine 
 Lipid-lowering drugs: atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. 
 Phosphodiesterase-5 inhibitors: sildenafil and tadalafil 
 Sedatives/anxiolytics: midazolam and triazolam 
 Acid-reducing agents: antacids (eg, aluminium and magnesium hydroxide) (recommended to separate antacid 
 
and study drug administration by 4 hours), H2-receptor antagonists (eg, ranitidine) (may be administered 
 
simultaneously with or 12 hours apart from study drugs). 
 
The manufacturer’s prescribing information for SMV and the IBs of AL-335 and ODV may be 
consulted for additional details on drug-interaction potential. 
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. For any concomitant therapy given as a treatment 
for a new condition or a worsening of an existing condition, the condition must be documented 
in the Adverse Event Section of the eCRF. 
9. 
STUDY EVALUATIONS 
9.1. 
Study Procedures 
9.1.1. 
Overview 
The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of all 
measurements and evaluations applicable to this study. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject’s participation in the study. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
Dosing of cohort 2 with patients with compensated cirrhosis will only start after a DRC has 
reviewed all available relevant safety data when the first 6 subjects in cohort 1 completed the 
Week 4 visit (including but not limited to AE, Serious AE [SAE], clinical laboratory test) and no 
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new or unexpected events, which are considered clinically significant, are detected. Based on this 
review, start of dosing in cohort 2 will be notified to investigators and be opened via an 
interactive web response system (IWRS) by the sponsor. Enrollment in cohort 1 will be kept 
ongoing during the data review process. 
For subjects enrolled in cohort 1, approximately 330 or 370 mL of blood will be drawn during 
the study, and for subjects enrolled in cohort 2, approximately 390 or 430 mL of blood will be 
drawn during the study, depending on the participation in the rich PK substudy. 
The first screening assessment has to be performed within 6 weeks prior to the Baseline Visit 
(ie, Day 1). The timing of visits during the Treatment Period should be based on the start date of 
study drug intake (ie, at the Baseline Visit on Day 1). The subject should be encouraged to come 
within the following time windows: 
 
For visits on Days 2 and 3: no time window allowed. 
 
For visit at Week 1 of the Treatment Period: -1 to +1 day. 
 
For visits at Weeks 2, 3, 4, and 6, of the Treatment Period: -2 to +2 days. 
 
For visits at Weeks 8 and 10, of the Treatment Period: -2 to +2 days (Cohort 2 only). 
 
For the EOT Visit: -1 to +1 day. 
 
For visit at Week 4 of follow-up: -3 to +3 days. 
For all other scheduled visits during the 24-week Follow-up Period: -7 to +7 days. These time 
windows may be shortened when approaching a data analysis. If this is the case, sites will be 
informed. 
9.1.2. 
Screening Period 
Within 6 weeks prior to the Baseline Visit and after signing and dating the ICF, the first 
screening assessment should be performed. Screening assessments as indicated in the 
TIME AND EVENTS SCHEDULE may be split over more than one visit. After informed 
consent has been obtained, each subject should be registered via an IWRS (See the IWRS 
manual). 
A complete physical examination (including height, body weight, and body systems and, if 
considered necessary by the investigator based on the subject’s past and present medical history, 
breast, genitals, or rectal examination) will be conducted and the following will be recorded for 
each subject: demographics, medical and surgical history, concomitant diseases, prestudy 
therapies, and vital signs. 
Echocardiography and triplicate ECG will be performed at screening. Electrocardiogram and 
echocardiography findings will be recorded for each subject. 
Blood sampling for determination of the HCV geno-/subtype and HCV RNA level will be 
performed. In addition, a blood sample for hematology and biochemistry, and a urine sample for 
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urinalysis (including a urine drug screening test) will be collected. Hepatitis A, B, and C 
serologic testing, and HIV-1 and HIV-2 serologic testing will also be performed. 
A serum pregnancy test will be performed in women of childbearing potential. The FSH level 
will be tested in female subjects who are postmenopausal for less than 2 years. 
Presence or absence of cirrhosis will be determined by a fibroscan. Subjects without cirrhosis are 
defined as having had a fibroscan with a documented result of ≤12.5 kPA (performed within 
6 months of baseline/Day 1) or liver biopsy within 6 months of baseline/Day 1 showing absence 
of cirrhosis (METAVIR score of F0-F3 or Ishak score <5). Subjects with compensated cirrhosis 
are defined as having a fibroscan (performed prior report or during Screening Period) with a 
documented result of >12.5 kPA or liver biopsy (prior report or during Screening Period) 
showing cirrhosis (eg, METAVIR score of F4 or Ishak score ≥5). 
For subjects with cirrhosis, an ultrasound scan, CT scan, or MRI should be performed within 
3 months prior to baseline/Day 1, with no findings suggestive of hepatocellular carcinoma. 
Occurrence of clinical events related to AEs, pregnancies, and use of concomitant therapies will 
be reported from the time a signed ICF is obtained. 
The investigator will assess the overall eligibility of the subject to participate in the study once 
all screening values and results of any other required evaluations are available and document this 
in the source documents. Retesting of laboratory values (eg, safety laboratory or HCV RNA) that 
lead to exclusion will be allowed once using an unscheduled visit during the Screening Period to 
assess eligibility. In exceptional cases, the Screening Period can be extended, if discussed with 
and approved (documented) by the sponsor, eg, if not all the test results become available during 
the allocated 6 weeks; this will be evaluated on a case-by-case basis. 
9.1.3. 
Open-label Treatment Period 
If eligible, subjects to be treated in the study will come for the Baseline Visit (Day 1). 
Investigators should ensure that all study enrollment criteria have been met during screening. If, 
after screening but prior to the first dose of study drug, a subject’s clinical status (including any 
available laboratory results or receipt of additional medical records) changes, such that he or she 
no longer meets all eligibility criteria, then the subject should be excluded from participation in 
the study. After the investigator confirms that a subject met all criteria, site staff should register 
the subject via an IWRS on Day 1. At the Week 4 and EOT or early withdrawal visit, site staff 
should enter the information via an IWRS (See the IWRS manual). 
Information on drug dosage and administration is provided in Section 6, and information on the 
use of the medication diary is provided in Section 7. 
All baseline assessments need to be performed before study drug intake in the morning. The 
timing of the baseline morning dosing should be recorded in the eCRF. 
A pharmacogenomic blood sample for host IL28B genotyping will be collected at baseline. 
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Targeted physical examinations (ie, physical examinations directed at specific body systems as 
required based on the medical history and overall clinical presentation) (including body weight), 
vital sign measurements, and blood and urine samples for clinical laboratory assessments will be 
performed at the time points indicated in the TIME AND EVENTS SCHEDULE. 
For female subjects of childbearing potential, a urine pregnancy test will be performed on-site on 
Day 1 and every 4 or 6 weeks as indicated in the TIME AND EVENTS SCHEDULE. 
Blood sampling for the determination of the HCV RNA level (on Day 1, predose in the morning) 
and for viral sequencing will be performed at all scheduled visits. The HCV NS3/4A, NS5A, and 
NS5B regions will be sequenced pretreatment (at baseline) by default in all subjects and 
postbaseline in subjects not achieving SVR. Sequencing of additional samples may be triggered 
by the sponsor's virologist. 
Hepatitis B virus DNA will be measured with PCR testing at the EOT Visit, or Treatment 
Withdrawal Visit, and may be evaluated at any time when there is a significant increase in the 
ALT or AST levels This only refers to subjects with antiHBc and/or antiHBs positive status at 
screening and not to subjects who have received HBV vaccine and are only antiHBs positive. 
Occurrence of clinical events related to all AEs, whether serious or nonserious, pregnancies, and 
use of concomitant medication will be reported throughout the Treatment Period. 
Echocardiography and triplicate ECG (at study approved facility) will be performed at the time 
points 
indicated 
in 
the 
TIME AND EVENTS SCHEDULE. 
Additional 
ECG 
or 
echocardiography may be done at any time during the study if clinically indicated in the opinion 
of the investigator. 
All subjects will undergo sparse PK blood sampling (predose, between 2- to 4-hours postdose, 
and 
between 
4- 
to 
6-hours 
postdose) 
at 
the 
time 
points 
indicated 
in 
the 
TIME AND EVENTS SCHEDULE for the measurement of plasma concentrations of AL-335 
(and metabolites), ODV, and SMV. At the EOT visit, intake of study drugs should take place on 
site when predose PK sampling (sparse and rich sampling) is performed. At Week 4, no sparse 
PK sample will be taken for subjects participating in the rich serial PK substudy. 
In addition, rich serial PK sampling for AL-335 (and metabolites), ODV, and SMV will be 
performed in approximately more than 12 subjects (Cohorts 1 and 2 combined). Subjects 
participating in the rich serial PK substudy will undergo rich serial PK sampling at their Week-4 
Visit, at 10 different time points within the dosing interval (see the TIME AND EVENTS 
SCHEDULE: Rich serial PK Assessments). All PK blood samples will be stored and analyzed at 
the discretion of the sponsor. 
If study drug is discontinued prematurely, for reasons other than withdrawal of consent, a 
Treatment Withdrawal Visit should be scheduled as soon as possible after the EOT. The subjects 
will be followed up for 24 weeks after EOT, with visits as indicated in the 
TIME AND EVENTS SCHEDULE. If a subject discontinues treatment due to withdrawal of 
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consent, the subject will be offered an optional Treatment Withdrawal Visit, to be scheduled as 
soon as possible after withdrawal and/or a safety Follow-up Visit, which needs to be scheduled 
4 weeks after EOT. At the safety Follow-up Visit, safety assessments of the Week 4 Follow-up 
Visit need to be performed. 
A DRC will be established to monitor data with focus on the safety and on the general conduct of 
the study. Emerging safety data from this study will be reviewed at predetermined intervals.  
9.1.4. 
Posttreatment Period (Follow-up) 
All subjects will enter the 24-week Posttreatment Follow-up Period, except for subjects who 
withdraw consent. The latter subjects will be offered an optional safety Follow-up Visit, at which 
the assessments of the Week-4 Follow-up Visit need to be performed. During the Posttreatment 
Follow-up Period, site staff should enter the visit information via an IWRS at each scheduled 
visit (See the IWRS manual). 
Any subject who withdraws consent during the Posttreatment Follow-up Period and/or notifies 
the site that he or she will not return for study visits, will be invited to do a Follow-up Visit at the 
time of withdrawal to complete the full set of protocol procedures as scheduled for the Week 24 
Follow-up Visit. However, all possible efforts should be made to ensure that subjects complete 
the study. 
Targeted physical examinations (ie, physical examinations directed at specific body systems as 
required based on the medical history and overall clinical presentation) (including body weight) 
and vital sign measurements will be performed at the Week-4 and Week-24 Follow-up Visits. 
Echocardiogram and triplicate ECG will be performed at the Week-4 Follow-up Visit. 
At the Week 12 Follow-up Visit, sparse PK sample will be taken at any time for the 
measurement of plasma concentrations of ODV. 
Blood and urine samples for clinical laboratory assessments and urine pregnancy tests (for 
female subjects of childbearing potential) will be performed at the time points indicated in the 
TIME AND EVENTS SCHEDULE. 
Blood sampling for determination of the HCV RNA level and for viral sequencing will be 
performed at all scheduled visits during follow-up. During follow-up, suspected relapse, ie, 
HCV RNA ≥LLOQ after previous <LLOQ, needs to be confirmed preferably within 2 weeks 
after the result has become available, and this retest may require an unscheduled visit, which 
should be scheduled by the investigator. At the time of the retest sample for HCV RNA, a 
sample for viral sequencing will also be collected. 
All AEs, whether serious or nonserious, will be reported until the subject’s last study visit. 
Pregnancies will be reported until the end of the study. The use of concomitant medication will 
be reported throughout the Posttreatment Follow-up Period. 
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9.2. 
Safety Evaluations 
Any clinically relevant changes occurring during the study must be recorded in the Adverse 
Event Section of the eCRF. 
All AEs, whether serious or nonserious, and pregnancies will be reported from the time a signed 
ICF is obtained until the subject’s last study visit. The use of concomitant medication will be 
reported throughout the study period. 
Any clinically significant abnormalities persisting at the end of the study or early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is 
reached.The study will include the following evaluations of safety and tolerability according to 
the time points provided in the TIME AND EVENTS SCHEDULE: 
9.2.1. 
Adverse Events 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) for the duration of the study. Adverse events 
will be followed by the investigator as specified in Section 12, Adverse Event Reporting. 
9.2.2. 
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology urine samples for urinalysis will be 
collected. The investigator must review the laboratory results, document this review, and record 
any clinically relevant changes occurring from signing of the ICF onwards until the subject’s last 
study visit in the Adverse Event Section of the eCRF. The laboratory reports must be filed with 
the source documents. 
Biochemistry samples on Day 1, Week 2, Week 4, EOT, Week 4 of follow-up, and Week 12 of 
follow-up must be taken after fasting for at least 8 hours. Lipid profile, insulin, and glucose are 
only to be assessed during visits with fasting samples. 
The following tests will be performed by the central laboratory: 
 
Hematology Panel 
- hemoglobin 
- white blood cell (WBC) count 
- hematocrit 
- WBC differentialb: 
- red blood cell (RBC) counta: 
 
neutrophils 
- RBC parameters: 
 
lymphocytes 
 
mean corpuscular hemoglobin 
 
monocytes 
 
mean corpuscular hemoglobin concentration  
eosinophils 
 
mean corpuscular volume 
 
basophils 
 
- platelet count 
a 
An RBC evaluation may include abnormalities in the RBC count, RBC parameters, or RBC morphology, 
which will then be reported by the laboratory. 
b 
A WBC evaluation may include any abnormal cells, which will then be reported by the laboratory. In 
addition, any other abnormal cells in a blood smear will also be reported. 
 
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The samples will also be used for coagulation tests. Prothrombin time and activated partial 
thromboplastin time will be assessed at screening, Day 1, Week 4, Week 8 (cohort 2 only), EOT, 
follow-up Week 4, follow-up Week 12, and follow-up Week 24, and the International 
Normalized Ratio will be calculated. In addition, the hematology sample taken at screening will 
include testing for glycosylated hemoglobin. 
 
Serum Chemistry Panel 
- sodium 
- alpha-1 acid glycoprotein 
- potassium 
- lipase 
- chloride 
- CK 
- creatinine 
- lactate dehydrogenase 
- blood urea nitrogen 
- uric acid 
- glucosea 
- calcium (corrected for albumin) 
- AST 
- phosphate 
- ALT 
- serum albumin 
- gamma-glutamyltransferase 
- total protein 
- total, direct, indirect bilirubin 
- total cholesterol 
- insulina 
- high-density lipoprotein cholesterol 
- pancreatic amylase 
- low-density lipoprotein cholesterol 
- alkaline phosphatase 
- triglycerides 
- thyroid stimulating hormone (TSH)b 
- eGFR 
- B-type natriuretic peptide (BNP)c 
 
a 
The homeostasis model assessment insulin resistance (HOMA-IR) index will be derived from plasma 
insulin and plasma glucose (fasting for at least 8 hours) test results performed on the biochemistry sample 
taken after fasting at baseline, EOT, and Week 12 follow-up. 
b 
TSH is to be assessed at screening and EOT or early withdrawal. In case TSH is not within the normal 
range, testing of fT3 and fT4 will be performed. 
c 
BNP is to be assessed at baseline, Week 2, Week 4, Week 6, EOT and Week 4 follow-up for cohort 1 and 
baseline, Week 2, Week 4, Week 6, Week 8, Week 10, EOT and Week 4 follow-up for cohort 2. 
 
For each time point of the laboratory assessments, the selected central laboratory will also 
estimate the glomerular filtration rate. 
 
Urinalysis 
Dipstick 
Sediment (if dipstick result is abnormal) 
- specific gravity 
- RBCs 
- pH 
- WBCs 
- glucose 
- epithelial cells 
- protein 
- crystals 
- blood 
- casts 
- ketones 
- bacteria 
- bilirubin 
 
- urobilinogen 
 
- nitrite 
 
- leukocyte esterase 
 
If dipstick result is abnormal, microscopy will be used to examine sediment. In the microscopic examination, 
observations other than the presence of WBCs, RBCs and casts may also be reported by the laboratory. 
 
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 
Serum pregnancy testing will be performed at screening for women of childbearing potential. 
Urine pregnancy testing will be performed for women of childbearing potential only at the 
time points indicated in the TIME AND EVENTS SCHEDULE. 
 
Follicle-stimulating hormone will be tested at screening for female subjects who are 
postmenopausal for less than 2 years. 
 
Serology (HIV-1 and HIV-2 antibody, hepatitis A immunoglobulin M antibody, HBsAg, 
antiHBc, antiHBs, and hepatitis C antibody) will be performed at screening. Routine 
antibody testing will be performed to evaluate HIV infection status and additional testing 
will be done whenever clinically relevant. 
 
Hepatitis B virus DNA will be measured with PCR testing at the EOT Visit, or Treatment 
Withdrawal Visit, and may be evaluated at any time when there is a significant increase in 
the AST or ALT levels This only refers to subjects with antiHBc and/or antiHBs positive 
status at screening and not to subjects who have received HBV vaccine and are only antiHBs 
positive. 
 
An additional midstream urine sample must be provided at screening for a urine drug 
screening test. Drug screening involves analysis for amphetamines, benzodiazepines, 
cannabinoids, opioids and cocaine. 
 
In case of rash, safety blood samples (mandatory blood sample for safety in case of Grade 3 
or 4 rash and at the discretion of the investigator in case of Grade 1 or 2 rash) might be taken 
at unscheduled visits as described in Section 9.2.8.1, and are to be processed by the local 
laboratory. The following parameters will need to be tested: AST, ALT, sedimentation rate, 
complete blood cell count (including hemoglobin, hematocrit, RBC count, WBC count, 
platelet count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils), and 
creatinine. 
 
In the event a subject develops clinical signs suggestive of muscle injury (eg, proximal 
weakness, myalgias), a thorough workup (eg, assessment of CK, CK muscle-brain [CK-MB] 
fraction, aldolase, myoglobin, calcium, phosphate, creatinine, and urinalysis) for muscle 
injury should be performed by a central laboratory as described in Section 9.2.8.6. 
9.2.3. 
Electrocardiogram 
Triplicate ECGs will be performed at study approved facility at time points as indicated in the 
TIME AND EVENTS SCHEDULE. Additional monitoring of ECG may be done, if in the 
opinion of the investigator, this is clinically indicated or if needed as part of the cardiac events 
management plan (see Section 9.2.8.7). The mean of the triplicate ECGs need to be taken into 
account for decision making. The representative ECG parameters as indices are described below. 
 
Heart Rate 
 
QRS interval 
 
QTc interval 
 
QT interval 
 
U wave 
 
ST 
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 
T wave 
 
PR interval 
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw. 
The triplicate ECGs should be performed approximately 2 minutes apart over 10 seconds. 
Twelve-lead ECGs will be recorded at a paper speed of 25 mm per second until 4 regular 
consecutive complexes are available. ECG machines will record timings of ECG measurements. 
ECGs will be digitalized with local review by the investigator for immediate safety assessment. 
Digital ECG data will be transmitted to a centralized ECG over-read service provider. Over-read 
of the ECGs will be transmitted back to the site within 72 hours. 
In case of inconsistent results, a technical problem with the ECG or an incorrect application of 
the ECG leads should be ruled out. In case of any abnormal value, the ECG recording has to be 
repeated. 
Any clinically relevant changes occurring from signing of ICF onwards until the subject’s last 
study visit must be recorded in the Adverse Event Section of the eCRF. 
9.2.4. 
Echocardiography 
The cardiac monitoring requirements outlined in the protocol are critical and must be followed 
for all subjects. Repeated transthoracic echocardiography will be performed at study approved 
facilities to assess various echocardiographic parameters including LVEF at time points as 
indicated in the TIME AND EVENTS SCHEDULE. The screening assessment will serve as 
baseline value. Additional echocardiography may be done, if in the opinion of the investigator, 
this is clinically indicated or if needed as part of the cardiac events management plan (see 
Section 9.2.8.7). 
Echocardiograms will be performed according to a standard protocol as described in the study 
manual. The same technique of echocardiography must be used for each assessment. A variety of 
echocardiographic parameters, including LVEF, will be quantitated and compared over time as 
an assessment of safety by a central reader. These measures aim to reduce variability and 
enhance the precision of the study results. 
Any clinically relevant changes occurring from signing of ICF onwards until the subject’s last 
study visit must be recorded on the Adverse Event Section of the eCRF. 
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9.2.5. 
Vital Signs 
Systolic and diastolic blood pressure and pulse rate will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse rate measurements should be taken supine and preceded by at least 
5 minutes of rest in a quiet setting without distractions (eg, television, cell phones). 
Any clinically relevant changes occurring from signing of the ICF until the subject’s last study 
visit must be recorded in the Adverse Event Section of the eCRF. 
9.2.6. 
Hepatitis B Virus DNA 
Reactivation of HBV has been reported in association with successful treatment of hepatitis C in 
subjects who are infected with the HBV or patients who have a history of being infected (ie, 
HBsAg negative and antiHBc or hepatitis B surface antibody positive). If the drug is 
administered to subjects who have a history of HBV infection, attention should be paid to the 
occurrence of signs or symptoms related to reactivation of HBV by monitoring results of HBV 
markers such as HBV DNA. 
Hepatitis B virus DNA will be measured by PCR testing at the EOT Visit, or Treatment 
Withdrawal Visit, and may be evaluated any time when there is a significant increase in the AST 
or ALT levels. This only refers to subjects with antiHBc and/or antiHBs positive status at 
screening and not to subjects who have received HBV vaccine and are only antiHBs positive 
(See TIME AND EVENTS SCHEDULE). In case of need of treatment for reactivated HBV, 
subjects will permanently discontinue the study drugs and receive a standard of care for HBV 
infection at the investigator’s discretion. 
9.2.7. 
Physical Examination 
To evaluate the subject’s eligibility, a complete physical examination (including height, body 
weight, and body systems and, if considered necessary by the investigator based on the subject’s 
past and present medical history, breast, genitals, or rectal examination) will be performed at 
screening. A targeted physical examination based on the medical history and overall clinical 
presentation (including body weight) will be performed at the other time points indicated in the 
TIME AND EVENTS SCHEDULE. 
A complete physical examination includes the following: general appearance, eyes, ears, nose, 
throat, cardiovascular system, respiratory system, abdomen, and skin and mucous membranes. It 
does not include breast, genitals, or rectal examination unless considered necessary by the 
investigator based on the subject’s past and present medical history. A neurologic and 
musculoskeletal examination as well as an examination of the lymph nodes will also be 
performed. 
The height should be measured barefooted at the Screening Visit. To obtain the actual body 
weight, subjects must be weighed lightly clothed. 
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Any clinically relevant abnormalities occurring from signing of the ICF until the subject’s last 
study visit must be recorded in the Adverse Event Section of the eCRF. 
9.2.8. 
Management of Specific Toxicities 
The safety monitoring and toxicity management plan described below takes into account the 
clinical safety data of AL-335, ODV, and SMV, target organs identified in nonclinical studies of 
AL-335, ODV, and SMV. Cardiac events and increased bilirubin are considered events of special 
interest for the 3- and 2-DAA combination programs. Photosensitivity is considered an event of 
clinical interest. 
9.2.8.1. 
Rash (Including Photosensitivity Conditions) 
Subjects should be informed that they should contact their doctor immediately when they 
notice any skin reaction. The skin reaction should be evaluated in the clinic the same day (if 
possible) or the next day. 
Photosensitivity conditions fall under the general umbrella of rash events. However, 
photosensitivity reactions can be differentiated from other rash events by careful history taking 
and general physical examination. Photosensitivity skin reactions are typically triggered by 
prolonged or extreme exposure to sunlight or artificial light. These reactions may present as an 
exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, ‘V’ 
area of the neck, extensor surfaces of the forearms, and the dorsa of the hands). Photosensitivity 
reactions can be prevented by avoiding excessive sun exposure and by the use of sun protection 
measures. 
All rash events should be captured in the Adverse Event Section of the eCRF. A separate Rash 
Page will be completed in case of a rash event. For rash events considered as potential 
photosensitivity reaction, a separate Photosensitivity Page will be completed. 
Monitoring of the evolution of rash (including photosensitivity reactions) will be performed 
based on the grade (severity) of the rash (see Attachment 3). At the discretion of the investigator, 
additional visits and assessments can be performed. Management of rash will take into account 
the protocol-defined procedures outlined in Table 3. 
Discontinuation of all study drugs should be considered if a photosensitivity reaction occurs and 
subjects should be monitored until the reaction has resolved. 
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Table 3: 
Guidelines for Subjects Developing Rash Grade 1 to Grade 4 
WHO Grade 
Rash Definition 
Investigator Action 
Grade 1 Rash 
(with or without pruritus)a,d 
erythema 
May continue intake of study drugs at 
the investigator’s discretion. 
 
Blood tests for safety (recommended) 
can be done at the investigator’s 
discretion. 
Grade 2 Rash  
(with or without pruritus)b,d 
diffuse, maculopapular rash, OR dry 
desquamation 
May continue intake of study drugs at 
the investigator’s discretion. 
 
Blood tests for safety (recommended) 
can be done at the investigator’s 
discretion. 
Grade 3 Rashd 
vesiculation, moist desquamation, or 
ulceration OR 
any cutaneous event with one of the 
following: 
 
-elevations in AST/ALT >2×baseline 
value 
 
-fever >38°C or 100°F 
 
-eosinophils >1.00×103/µL 
 
-serum sicknesslike reaction 
Permanently discontinue the intake of 
SMV. AL-335 and ODV may be 
continued at the investigator’s 
discretion.c Close monitoring is 
required to prevent progression of the 
rash. 
 
No rechallenge is allowed. 
 
Blood safety tests are mandatory. 
 
Referral to a dermatologist is required.
At the discretion of the dermatologist a 
biopsy might be performed. 
Grade 4 Rashd 
exfoliative dermatitis, OR 
mucous membrane involvement, OR 
erythema multiforme major, OR 
Stevens-Johnson Syndrome, OR 
necrosis requiring surgery. 
Permanently discontinue the intake of 
all study drugs. 
 
No rechallenge is allowed. 
 
Blood safety tests are mandatory. 
 
Referral to a dermatologist is required. 
A biopsy is required. 
Key: AST=aspartate aminotransferase; ALT=alanine aminotransferase; ODV=odalasvir; SMV=simeprevir; 
WHO=World Health Organization 
a 
In case the rash evolves from a Grade 1 to a higher grade, management of the rash should follow the guidelines 
indicated for Grade 2 or Grade 3 or 4 rash, respectively (see Attachment 3). 
b 
In case the rash evolves from a Grade 2 to a Grade 3 or 4 rash, management of the rash should follow the 
guidelines specified for Grade 3 or 4 rash (see Attachment 3). 
c 
Monotherapy with any of the study drugs is not allowed. 
d 
Determine if subject was adhering to the recommended sun-protective measures. 
When safety blood samples are drawn as per the rash management guidelines, these should be 
processed by the local laboratory. The following parameters will need to be tested: AST, ALT, 
sedimentation rate, complete blood cell count (including hemoglobin, hematocrit, RBC count, 
WBC count, platelet count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils), 
and creatinine. The values of the local laboratory assessments need to be transcribed in the eCRF 
by the study-site personnel. 
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The subject may be treated symptomatically until the rash resolves. Oral antihistamines 
(eg, cetirizine and levocetirizine) and/or topical corticosteroids may provide symptomatic relief 
but effectiveness of these measures has not been established. If systemic corticosteroids for 
longer than 24 hours are required for the treatment of rash, the study drugs need to be 
permanently discontinued. If the rash is considered to be most likely due to concomitant illness 
or nonstudy drugs, standard management, including discontinuation of the likely causative agent 
should be undertaken. 
Dermatologist fees for evaluating subjects who experience a rash during the study will be 
reimbursed by the sponsor. 
The following grades are based on the World Health Organization (WHO) Toxicity Grading 
Scale (see Attachment 1) with adaptations made by the sponsor. 
Grade 1 Rash (With or Without Pruritus) 
A Grade 1 rash is defined as erythema. 
 
Subjects may continue the intake of study drugs (at the investigator’s discretion). 
 
An unscheduled visit may be performed at the investigator’s discretion as soon as possible 
after the subject contacts the investigator to report the AE. 
 
Assessment of safety blood samples by the local laboratory is recommended. The values of 
the local laboratory assessments need to be transcribed in the eCRF by the study-site 
personnel. 
Unscheduled visits may also be performed after the initial rash assessment at the investigator’s 
discretion for appropriate follow-up until resolution of the rash. At these visits, safety blood 
samples can be taken at the investigator’s discretion. For these and all subsequent local 
laboratory blood sample assessments, the values of the assessments need to be transcribed in the 
eCRF by the study-site personnel. 
The subject should be advised to contact the investigator immediately if there is any 
worsening of the rash, if any systemic signs or symptoms appear, or if mucosal involvement 
develops. If appropriate, sun protection counseling should be provided. 
In case the rash evolves from a Grade 1 to a higher grade, management of the rash should follow 
the guidelines indicated for Grade 2 or Grade 3 to 4 rash, respectively. 
Grade 2 Rash (With or Without Pruritus) 
A Grade 2 rash is defined as diffuse, maculopapular rash OR dry desquamation. 
 
Subjects may continue the intake of study drugs (at the investigator’s discretion). 
 
An unscheduled visit for initial rash evaluation is required as soon as possible after the 
subject contacts the investigator to report the AE. If a visit is not possible, telephone contact 
with the subject should take place to collect information and to give advice on the necessary 
measures to be taken. 
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 
Assessment of safety blood samples by the local laboratory is recommended. The values of 
the local laboratory assessments need to be transcribed in the eCRF by the study-site 
personnel. 
 
Referral to a dermatologist is optional but, when done, should occur preferably within 
24 hours after the onset of the rash. The investigator should obtain a copy of the 
dermatologist's report for assessment of rash. 
Unscheduled visits will also be performed after the initial rash assessment at the investigator’s 
discretion for appropriate follow-up until resolution of the rash. At these visits, safety blood 
samples can be taken at the investigator’s discretion. For these and all subsequent local 
laboratory blood sample assessments, the values of the assessments need to be transcribed in the 
eCRF by the study-site personnel. 
The subject should be advised to contact the investigator immediately if there is any 
worsening of the rash, if any systemic signs or symptoms appear, or if mucosal involvement 
develops. If appropriate, sun protection counseling should be provided. 
In case the rash evolves from a Grade 2 to a Grade 3 to 4 rash, management of the rash should 
follow the guidelines specified for Grade 3 to 4 rash. 
Grade 3 or Grade 4 Rash 
A Grade 3 rash is defined as a rash associated with: 
 
vesiculation, moist desquamation, or ulceration, OR 
 
any cutaneous event with one of the following: 
 
elevations in AST/ALT >2×baseline value 
 
fever >38°C or 100°F 
 
eosinophils >1.00×103/µL 
 
serum sicknesslike reaction 
Subjects will permanently discontinue SMV. AL-335 and ODV may be continued at the 
investigator’s discretion. Close monitoring is required to prevent progression of the rash. 
A Grade 4 rash is defined as: 
 
exfoliative dermatitis, OR 
 
mucous membrane involvement, OR 
 
erythema multiforme major, OR 
 
Stevens-Johnson Syndrome, OR 
 
necrosis requiring surgery 
 
Subjects will permanently discontinue all study drugs. No rechallenge is allowed. 
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An unscheduled (on-site) visit including a safety laboratory evaluation is required for a Grade 3 
or 4 rash as soon as possible after the subject contacts the investigator to report the AE. 
Assessment of safety blood samples by the local laboratory is required on the day of initial rash 
evaluation and the day thereafter (Days 0 and 1). The values of the local laboratory assessments 
need to be transcribed in the eCRF by the study-site personnel. Referral to a dermatologist is 
required, preferably within 24 hours after the onset of the rash. A copy of the dermatologist 
report should be collected by the investigator. 
A biopsy may be performed at the discretion of the dermatologist for Grade 3 rash and is 
required in case of a Grade 4 rash as soon as possible after the onset of rash. The investigator 
should obtain a copy of the dermatologist's report. 
Appropriate management should be undertaken and subjects should be followed until resolution 
of the rash or until clinical stability is reached. 
A complete summary of the guidelines for rash management is given in see Attachment 3. 
9.2.8.2. 
Acute Allergic Reaction 
Oral antihistamines (eg, cetirizine and levocetirizine) and/or topical corticosteroids may provide 
symptomatic relief but effectiveness of these measures has not been established. If treatment 
with systemic corticosteroids for longer than 24 hours would be required for an acute systemic 
allergic reaction, the study drugs need to be permanently discontinued. 
Management of acute allergic reactions will take into account the protocol-defined procedures 
outlined in Table 4. 
Table 4: 
Guidelines for Subjects Developing Allergic Reactions 
WHO Toxicity Grade 
Definitions 
Investigator Action 
Grade 1 
Pruritus suggestive of an allergic 
reaction without rash 
May continue study drugs or have their 
study drugs discontinued at the investigator’s 
discretion. 
Grade 2 
Localized urticaria 
May continue study drugs or have their 
study drugs discontinued at the investigator’s 
discretion. Rechallenge is not allowed. 
Grade 3 
Generalized urticaria, or 
angioedema 
Permanently discontinue study drugs. 
Grade 4 
Anaphylaxis 
Permanently discontinue study drugs. 
 
Grade 1 (Pruritus Suggestive of an Allergic Reaction Without Rash) 
Subjects may continue the intake of study drugs or have their study drugs discontinued at the 
investigator’s discretion. Close clinical follow-up is recommended to monitor for any 
progression of the AE. Subjects should be advised to contact the investigator immediately if 
there is any worsening of symptoms. 
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Grade 2 (Localized Urticaria) 
Subjects may continue the intake of study drugs or have their study drugs discontinued at the 
investigator’s discretion. Close clinical follow-up is recommended to monitor for any 
progression of the AE. Subjects should be advised to contact the investigator immediately if 
there is any worsening of symptoms, in which case the subject will permanently discontinue the 
study drugs. Rechallenge is not allowed. 
Grade 3 (Generalized Urticaria, Angioedema) and Grade 4 (Anaphylaxis) 
Subjects will immediately and permanently discontinue the intake of study drugs. Rechallenge is 
not allowed. Subjects will be treated as clinically appropriate and should be followed until 
resolution of the AE. 
9.2.8.3. 
Alanine Aminotransferase, Aspartate Aminotransferase, and Bilirubin 
Elevations 
Although an AST and ALT elevation of up to Grade 3 is common in chronic HCV infection due 
to disease activity, treatment-emergent changes from baseline in ALT and AST levels should be 
carefully evaluated and results closely monitored with unscheduled study visits, if needed. 
Isolated and asymptomatic cases (< 1%) of marked elevation of ALT and AST from baseline 
values have been reported during treatment with AL-335, ODV, and SMV. These reported cases 
were not accompanied by significant changes in bilirubin or other liver function markers. 
Increases in bilirubin (both direct and indirect) have been observed during the first weeks of 
SMV therapy. These bilirubin elevations are caused by a competitive inhibition of biliary 
transporter systems (OATP1B1) in hepatocytes. Bilirubin elevations following initiation of SMV 
therapy are typically not associated with increases in ALT or AST levels and rapidly resolve 
after completion of SMV treatment. Bilirubin elevations have been observed to a much lesser 
extent with DAA regimens where SMV is administered without RBV compared to when it is 
administered with RBV.24 
Management of treatment-emergent AST, ALT, and/or bilirubin elevations will take into account 
the protocol-defined procedures outlined in Table 5, Table 6, and Table 7. 
Table 5: 
Treatment-emergent Grade 1 to Grade 4 ALT or AST Elevation and Grade 1 to Grade 4 
Total Bilirubin Elevation 
WHO Toxicity Grade 
AST or ALT, Ranges 
Total Bilirubin, Ranges 
Grade 1 
≥1.25 to ≤2.5 × ULN 
1.1 to 1.5 × ULN 
Grade 2 
>2.5 to ≤5.0 × ULN 
>1.5 to ≤2.5 × ULN 
Grade 3 
>5.0 to ≤10.0 × ULN 
>2.5 to ≤5.0 × ULN 
Grade 4 
>10.0 × ULN 
>5.0 × ULN 
Key: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal 
Subjects may continue the intake of study drugs at the investigator’s discretion in case of 
Grade 1 and 2 increases in ALT and/or AST and/or Grade 1, 2 and 3 increases in bilirubin levels. 
In case of a Grade 3 ALT and/or AST increase or if a Grade 4 ALT and/or AST ≤2 times the 
baseline value, this laboratory abnormality must be judged by the investigator to be either “not 
related” or “doubtfully related” to the study drugs in order to continue the intake of study drugs, 
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in which case the intake of study drugs may be continued upon agreement with the sponsor. In 
subjects who continue the study drugs, close clinical follow up is recommended to monitor for 
any progressive increases. 
If a Grade 4 ALT and/or AST value is >2 times the baseline value, a confirmatory measurement 
should be performed preferably within 72 hours after receipt of the results at the study site. If the 
Grade 4 value is confirmed to be >2 times the baseline value, the study drugs should be 
discontinued (Table 6). 
In case of a Grade 4 bilirubin elevation, subjects should have a confirmatory measurement within 
72 hours after receipt of the results. If the Grade 4 value is confirmed, all study drugs should be 
discontinued (Table 7). 
Subjects should be followed until return to predose baseline value or stabilization of ALT, AST, 
and/or bilirubin elevation. 
Table 6: 
Guidelines for Subjects Developing ALT and/or AST Elevations 
WHO Toxicity Grade  
Ranges 
Investigator Action  
Grade 1 
Grade 2 
Grade 3 
≥1.25 to 2.5 × ULN
>2.5 to 5.0 × ULN 
>5.0 to 10.0 × ULN
May continue intake of study drugs at the investigator’s 
discretion. Monitor for progressive increase in ALT and/or 
AST levels. 
In order to continue the study drugs, in case of a Grade 3 
ALT and/or AST increase, this laboratory abnormality should 
be considered “not related” or “doubtfully related” to the 
study drugs. Study drugs may be continued upon agreement 
with the sponsor. 
Grade 4 
>10.0 × ULN 
May continue study drugs at the investigator’s discretion 
(upon agreement with the sponsor) if value is ≤2 times the 
baseline value and the event is considered “not related” or 
“doubtfully related” to study drugs. Subjects who continue 
should be carefully evaluated and close follow-up is 
recommended to monitor for progressive increase in ALT 
and/or AST levels. 
If the Grade 4 ALT and/or AST value is >2 times the baseline 
value, a confirmatory measurement should be performed 
within 72 hours after receipt of the results. If the value is 
confirmed, all study drugs should be discontinued. 
Key: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal 
 
Table 7: 
Guidelines for Subjects Developing Bilirubin Elevations 
WHO Toxicity Grade  
Ranges 
Investigator Action  
Grade 1 
Grade 2 
Grade 3 
≥1.1 to 1.5 × ULN 
>1.5 to 2.5 × ULN 
>2.5 to 5.0 × ULN 
May continue intake of study drugs at the investigator’s 
discretion. Monitor for progressive increase in bilirubin levels. 
Grade 4 
>5.0 × ULN 
A confirmatory measurement should be performed within 
72 hours after receipt of the results. If the value is confirmed, 
all study drugs should be discontinued. 
Key: ULN=upper limit of normal 
 
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9.2.8.4. 
Clinical Hepatitis 
Subjects should be monitored for any worsening of their hepatic disease and development of 
overt signs and symptoms (including increased fatigue, malaise, anorexia, nausea, dark urine, 
clay colored stools, bilirubinemia, jaundice, liver tenderness, hepatomegaly, and severely 
increased serum transaminase levels). 
Subjects with these signs and symptoms must seek medical attention immediately and have their 
hepatic parameters assessed. If severe worsening of hepatic disease is evident, all study drugs 
must be discontinued and the sponsor should be contacted. 
9.2.8.5. 
Pancreatic Amylase or Lipase Elevations 
For asymptomatic Grade 1, Grade 2, and Grade 3 pancreatic amylase or lipase elevations with no 
history of treatment-emergent pancreatitis or concomitant lipase increase or signs of pancreatitis, 
subjects should be carefully evaluated and closely followed. Study drugs may be continued at the 
discretion of the investigator. In the case of confirmed (within 72 hours) Grade 4 pancreatic 
amylase or lipase elevations, or the presence of signs consistent with pancreatitis, all study drugs 
should be interrupted until the diagnosis of pancreatitis is excluded. If pancreatitis is confirmed, 
all study drugs should be permanently discontinued. An overview of the laboratory ranges to 
assign grading to a laboratory value for pancreatic amylase and lipase is provided in 
Attachment 1. 
Pancreatitis must be considered whenever a subject develops abdominal pain and nausea, 
vomiting, or elevated amylase or lipase, and study drugs should be interrupted until the diagnosis 
of pancreatitis is excluded. 
9.2.8.6. 
Creatine Kinase 
Because nucleosides, as a class, have a known risk of mitochondrial toxicity, which is often 
manifested as muscle injury, this study will systematically assess study subjects for laboratory 
abnormalities which might be present after muscle injury. 
Specifically, CK is checked throughout the study Treatment Period. 
Drug-induced myopathy is a diagnosis of exclusion as the differential diagnosis for muscle 
symptoms can be broad. If a subject develops clinical signs suggestive of muscle injury 
(eg, proximal weakness and myalgias), a thorough workup (eg, assessment of CK, CK-MB 
fraction, aldolase, myoglobin, calcium, phosphate, creatinine, and urinalysis) to understand the 
etiology for the myopathy should be undertaken by a central laboratory. 
In all cases where a CK elevation triggers an evaluation of treatment stopping criteria (CK 
≥3×ULN), or where discontinuation of study drugs is planned due to the suspected muscle 
injury, the sponsor MUST be notified within 24 hours so that the clinical case and workup 
and treatment strategy can be discussed. 
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If a study subject experiences treatment-emergent CK elevations (without a concomitant 
proportionate CK-MB elevation), the following treatment stopping criteria for CK elevations 
should be applied31: 
 
In subjects (whether symptomatic or asymptomatic) without a clinical history or a 
differential diagnosis to suggest etiology of CK elevation (eg, recent exercise, other clinical 
comorbidities [eg, endocrinal, metabolic disorders] or exposure to medication with known 
risk of myopathy): 
 
If CK is ≥20×ULN, immediately redraw and repeat the test. If the repeat remains 
≥20×ULN, discontinue AL-335. Continuation of ODV and SMV should be discussed 
with the sponsor on a case-by-case basis. 
 
If CK is ≥3 – <20×ULN, continue study medication. Assess CK, CK-MB every 
~72 hours (follow-up assessments) until the CK has normalized (follow-up 
assessments). 
o 
If any follow-up CK assessment is ≥20×ULN, discontinue AL-335. Continuation of 
ODV and SMV should be discussed with the sponsor on a case-by-case basis. 
o 
If the third follow-up CK assessment (ie, ~9 days after CK elevation was first 
recognized) is more than or equal to the prior follow-up CK assessment, 
discontinue AL-335. Continuation of ODV and SMV should be discussed with the 
sponsor on a case-by-case basis. 
 
If the CK is >1.5×ULN –<3×ULN, consider repeat CK, CK-MB in ~72 hours and 
continue testing until CK decreases. This might require an unscheduled visit. 
 
In subjects with a clinical history suggestive of a nonstudy drug related etiology for a CK 
elevation (eg, recent exercise, other clinical comorbidities [eg, endocrinal or metabolic 
disorders], or exposure to medication with known risk of myopathy), study medication may 
be continued. In such instances, the putative cause of the CK elevation should be addressed 
(eg, stop further exercise or the use of suspect medication) and the CK and CK-MB should 
be assessed every ~72 hours (=follow-up assessment): 
 
If initial CK is <5×ULN, continue study medication unless follow-up CK assessments 
are increased to ≥20×ULN. 
 
If initial CK is ≥5×ULN, continue study drug dosing and assessing follow-up CK and 
CK-MB every ~72 hours. If the third follow-up CK assessment (ie, ~9 days after CK 
elevation was first recognized) is more than or equal to the prior follow-up CK 
assessment, discontinue AL-335. Continuation of ODV and SMV should be discussed 
with the sponsor on a case-by-case basis. 
If CK-MB rises commensurately with elevation of CK, an assessment for cardiac ischemic injury 
(eg, ECG, troponin) should be initiated. 
If a subject who experiences CK elevations also demonstrates clinical or laboratory evidence of 
renal insufficiency/damage or other clinically significant muscle signs or symptoms 
(eg, proximal weakness), all study medication should be stopped regardless of the magnitude of 
the CK elevation. 
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9.2.8.7. 
Cardiac Safety Monitoring 
Regular cardiac safety monitoring will be done in this study via assessments of AEs, ECGs, and 
regular echocardiograms. 
For all subjects enrolled in this study, LVEF at screening must be ≥55.0% (see Section 4.2). 
Screening echocardiography will not only be used for assessing eligibility but will also be 
considered as the baseline measurement. Appearance or changes in symptoms or findings in 
echocardiogram may trigger the following treatment stopping criteria26: 
 
Asymptomatic patients with no clinical evidence of congestive heart failure: 
 
If the absolute decrease from baseline in LVEF is ≥10.0% (eg, 59.0% to 49.0%) and 
resulting in an LVEF of <50.0%, discontinue AL-335, ODV, and SMV. 
 
If the absolute decrease from baseline in LVEF is >5.0% and ≤10.0%, or >10.0% and 
resulting in an LVEF ≥50.0%, an assessment of the subject’s clinical status, including 
symptoms, physical examination, and other clinical parameters should be made before 
deciding whether to stop or continue study drugs. 
 
For subjects with symptoms (eg, dyspnea, orthopnea) or signs of congestive heart failure (eg, 
S3 gallop, pedal edema, pulmonary edema): 
 
If the absolute decrease from baseline in LVEF is ≥5.0%, discontinue AL-335, ODV, 
and SMV. 
For all cases described above, a mandatory assessment and urgent cardiology referral should be 
initiated. The LVEF decrease must be reported to the medical monitor within 24 hours, so that 
the clinical case and workup and treatment strategy can be discussed. 
The cardiology assessment should include, but is not limited to, the following:  
 
Review of the cardiopulmonary body systems 
 
Troponin I assessment 
 
12-lead ECG 
 
Repeat echocardiography (at study approved facility) 
Echocardiography must be performed at study approved facility on any subject who develops 
symptoms or signs of possible congestive heart failure (eg, dyspnea, orthopnea, S3 gallop, pedal 
edema) during the study, regardless of the timing of such symptoms, including during the 
Follow-up Period. 
For all subjects enrolled in this study, triplicate ECGs will be taken at screening and at regular 
intervals during the study period. Appearance or changes in symptoms or clinically significant 
findings in ECG may trigger the following treatment stopping criteria: 
1. If a 1st degree AV block is diagnosed and 
a. 
The PR interval is >200 msec but ≤240 msec, study drugs can be continued. Close 
monitoring with weekly ECG is recommended. 
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b. The PR interval is >240 msec but ≤300 msec (confirmed by a repeat triplicate analysis 
at least 30 minutes after the initial assessment), an assessment of the subject’s clinical 
status, including symptoms, physical examination and other clinical parameters should 
be made and the study drugs can be continued. Close monitoring with weekly ECG is 
recommended. 
c. 
The PR interval is >300 msec (confirmed by a repeat triplicate analysis at least 
30 minutes after the initial assessment, irrespective of presence or absence of clinical 
symptoms), ODV must be discontinued. AL-335 and SMV may be continued at the 
investigator’s discretion. 
2. If a 2nd degree or higher AV block is diagnosed (confirmed by a repeat triplicate analysis at 
least 30 minutes after the initial assessment and irrespective of presence or absence of 
clinical symptoms), ODV must be discontinued. AL-335 and SMV may be continued at the 
investigator’s discretion. 
3. In case the QTc value is >500 msec (confirmed by a repeat triplicate analysis at least 
30 minutes after the initial assessment and irrespective of presence or absence of clinical 
symptoms), ODV must be discontinued. AL-335 and SMV may be continued at the 
investigator’s discretion. 
In case the QTc value increases by >60 msec from baseline, thorough evaluation of the 
clinical case and discussion with the sponsor is required to assess further treatment strategy. 
All events described above, should trigger a thorough cardiac assessment (ECG, 
echocardiography, and cardiology referral) and follow-up (eg, weekly ECG until PR interval is 
<240 msec). These events as well as any cardiac event that is serious, severe, or life-threatening 
must be reported to the medical monitor within 24 hours so that the clinical case workup and 
treatment strategy can be discussed. 
9.2.8.8. 
Renal Safety Monitoring 
Renal safety will be monitored by evaluating urine dipstick, in particular urinary proteins, serum 
creatinine levels, eGFR, and serum chemistry results. The investigator should closely monitor for 
disturbances in serum creatinine and eGFR. In case renal complications develop, subjects must 
be treated as clinically appropriate. 
The study drugs may be continued if the renal complication is considered not to be related to the 
study drugs in the opinion of the investigator. 
If the eGFR value is <30 mL/min/1.73m², the value must be confirmed by repeat testing during 
an unscheduled visit preferably within 1 week after the results become available to the study site. 
If the eGFR value is confirmed to be <30 mL/min/1.73m², all study drugs must be interrupted 
and renal function will be followed as clinically appropriate. The possibility of restarting 
treatment should be discussed with the sponsor on a case-by-case basis. 
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9.2.8.9. 
Other Toxicities 
Note: For Grade 3 or Grade 4 treatment-emergent laboratory abnormalities, subjects should 
have a confirmatory measurement performed by the local laboratory. The management scheme 
below is for confirmed treatment-emergent laboratory abnormalities and AEs not included in the 
sections above and not for isolated and/or nonconfirmed events. 
Grade 1 
Subjects who develop a Grade 1 AE or Grade 1 laboratory abnormality may continue the intake 
of study drugs. 
Grade 2 
Subjects who develop a Grade 2 AE or Grade 2 laboratory abnormality may continue or may 
discontinue the intake of study drugs based on the investigator’s clinical judgment. 
Grade 3 
Subjects who develop a Grade 3 AE or Grade 3 laboratory abnormality may continue or may 
discontinue the intake of study drugs at the investigator’s discretion if the Grade 3 AE or 
laboratory abnormality is judged by the investigator to be either “not related” or of “doubtful 
relation” to any of the study drugs. 
For subjects who develop a Grade 3 AE or Grade 3 laboratory abnormality at least possibly 
related to any of the study drugs, the sponsor needs to be informed and treatment can only be 
continued if agreed upon by the sponsor and investigator. 
Grade 4 
Subjects who develop a Grade 4 AE or Grade 4 laboratory abnormality may continue or may 
discontinue the intake of study drugs at the investigator’s discretion if the Grade 4 AE or 
laboratory abnormality is judged by the investigator to be either “not related” or of “doubtful 
relation” to any of the study drugs. 
Subjects, who develop a Grade 4 AE or Grade 4 laboratory abnormality at least possibly related 
to any of the study drugs, should discontinue all study drugs. 
9.3. 
Pharmacokinetics 
9.3.1. 
Evaluations 
Venous blood samples of approximately 5 mL will be collected for the measurement of plasma 
concentrations of AL-335 (and metabolites), ODV, and SMV at the time points specified in the 
TIME AND EVENTS SCHEDULE and TIME AND EVENTS SCHEDULE: Rich serial PK 
Assessments. At the Week 12 Follow-up Visit, venous blood samples of approximately 3 mL 
will be collected for the measurement of plasma concentrations of ODV. 
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Sparse PK Sampling 
All subjects will undergo sparse PK blood sampling at Weeks 2, 4, 6, and at the EOT (Weeks 8) 
Visit (Cohort 1), or Weeks 2, 4, 6, 8 and at the EOT (Weeks 12) Visit (Cohort 2), predose, 
between 2- to 4-hours postdose, and between 4- to 6-hours postdose for the measurement of 
plasma concentrations 
of 
AL-335 
(and 
metabolites), 
ODV, 
and 
SMV 
(see 
the 
TIME AND EVENTS SCHEDULE). At the EOT visit, intake of study drugs should take place 
on site when predose PK sampling is performed. At Week 4, no sparse PK sample will be taken 
for subjects participating in the rich serial PK substudy. At the Week 12 Follow-up Visit, sparse 
PK sample (3 mL) will be taken at any time for the measurement of plasma concentrations of 
ODV. 
On the days of sparse PK blood sampling, the exact dates and times of PK blood sampling must 
be recorded according to the Laboratory Manual. The exact date and time of study drug intake on 
the day of the PK blood sampling and the previous day need to be recorded in the eCRF. It will 
be recorded whether the subjects took their study drugs in fed state (during or within 15 minutes 
after completion of a meal) on the day of PK blood sampling and on the previous day. 
Rich Serial PK Sampling for Noncompartmental PK Analysis in the PK Subgroups 
In the rich serial PK substudy, rich serial PK blood sampling will be performed in approximately 
more than 6 subjects in each cohort. 
Subjects participating in the rich serial PK substudy will undergo rich serial PK sampling at their 
Week 4 Visit, at 10 different time points within the dosing interval (see TIME AND EVENTS 
SCHEDULE: Rich serial PK Assessments). Intake of study drugs should take place on site when 
predose PK sampling is performed. For the intensive PK samples of the rich PK substudy, 
noncompartmental PK analysis of AL-335 (and metabolites), ODV, and SMV will be performed 
using actual sampling time points and plasma concentrations obtained from rich serial PK blood 
sampling at Week 4. 
The first sample should be collected before study drug intake (within 0.5 hour before). Thereafter, 
study drugs (AL-335, ODV, and SMV) will be administered with a breakfast. Samples 2 to 10 
should be collected at 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after study drug intake. No additional 
sample is needed to cover the PK sample to be taken at any time during the visit at Week 4. This 
sampling schedule may require an overnight stay and the 24-hour PK sample must be taken 
before study drug intake on the morning following the overnight stay. 
A breakfast should be eaten completely within 30 minutes. The study drugs should be taken 
during or no later than 15 minutes after completing the breakfast. 
On the days of rich PK blood sampling, the exact dates and times of PK blood sampling must be 
recorded according to the Laboratory Manual.  The exact date and time of study drug intake on 
the day of the PK blood sampling and the previous day need to be recorded in the eCRF. In 
addition, start and end times of accompanying meal on the day of the PK sampling need to be 
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recorded. It will be recorded whether the subjects took their study drugs in fed state (during or 
within 15 minutes after completion of a meal) on the day prior to the visit. 
9.3.2. 
Analytical Procedures 
Plasma samples will be analyzed to determine concentrations of AL-335 (and metabolites), ODV, 
SMV using validated, specific, and sensitive methods (eg, liquid chromatography-mass 
spectrometry/mass spectrometry) by or under the supervision of the sponsor. 
If required, some plasma samples may be analyzed to document the presence of circulating 
metabolites or to determine protein binding using a qualified research method. 
The bioanalytical reports, including a description of the assay and a summary of the assay 
performance data, will be included in the final clinical study report as an addendum. 
9.3.3. 
Pharmacokinetic Parameters 
The plasma concentration-time data of AL-335 (and metabolites), ODV, and SMV from all 
subjects will be used for population PK (popPK) model development and/or popPK model 
update.  
PopPK modeling will be used to describe the concentration-time profiles and estimate the 
exposure parameters for AL-335 (and metabolites), ODV, and SMV. 
The following exposure parameters for AL-335 (and metabolites), ODV, and SMV will be 
derived using Bayesian feedback analysis: AUC24h and predose plasma concentration (C0h). 
For subjects participating in the rich serial PK substudy, noncompartmental PK analysis for 
AL-335 (and metabolites), ODV, and SMV will be performed using actual sampling time points 
and plasma concentrations obtained from rich serial PK blood sampling at Week 4 for 
approximately more than 6 subjects in each cohort. The following PK parameters for AL-335 
(and metabolites), ODV, and SMV will be derived: C0h, Cmax, tmax, Cmin, AUC24h, and the 
apparent total clearance of the drug from plasma after oral administration (CL/F). 
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations 
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure 
parameters (C0h
 and AUC24h) with SVR4, SVR12, and SVR24 and with safety endpoints may be 
explored graphically. 
9.5. 
Efficacy Evaluations 
9.5.1. 
HCV RNA Levels 
Blood samples for the determination of HCV RNA levels will be taken at all scheduled visits and 
processed in real time. Determination of HCV RNA levels will be performed by a central 
laboratory contracted by the sponsor. Plasma HCV RNA levels will be determined using an 
in vitro nucleic acid amplification test for quantification of HCV RNA in human plasma. The 
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procedures for sample collection, processing, and storage will be provided in the laboratory 
manual. 
On Day 1, a blood sample should be taken at predose in the morning. The timing of the morning 
dose at baseline should be recorded in the eCRF. 
Results of the HCV RNA measurements will be communicated to the investigator and the 
sponsor throughout the study. It is the responsibility of the investigator to monitor the HCV RNA 
results obtained and ensure that all study drugs are discontinued in subjects with viral 
breakthrough (see Section 6.3). 
During follow-up, suspected relapse, ie, HCV RNA ≥LLOQ after previous <LLOQ, needs to be 
confirmed preferably within 2 weeks after the result has become available, and this retest may 
require an unscheduled visit which should be scheduled by the investigator. At the time of the 
retest sample for HCV RNA, a sample for viral sequencing will also be collected. 
Changes in HCV RNA levels will not be reported as AEs or SAEs. 
9.5.2. 
Resistance Determinations 
Sequencing of the HCV NS3/4A, NS5A, and NS5B regions will be performed to identify 
preexisting sequence polymorphisms and characterize emerging HCV variants. 
Samples 
for 
viral 
sequencing 
will 
be 
taken 
at 
visits 
as 
specified 
in 
the 
TIME AND EVENTS SCHEDULE. 
The HCV NS3/4A, NS5A, and NS5B regions will be sequenced pretreatment (at baseline) by 
default in all subjects and postbaseline in subjects not achieving SVR. Sequencing of additional 
samples may be triggered by the sponsor's virologist. 
Changes in viral genotype will be evaluated by the sponsor's virologist. They will not be reported 
as AEs or SAEs. 
Additional exploratory characterization of the viral genotype and phenotype may be performed. 
No human DNA analysis will be performed on these samples. 
9.6. 
Pharmacogenomic Evaluations 
One mandatory blood sample for host IL28B genotyping will be collected at the Baseline Visit, 
providing the opportunity to explore the influence of a genetic polymorphism upstream of the 
IL28B gene (rs12979860) on treatment outcome to the drug regimen assessed in this study. No 
other analysis will be performed with this sample. 
Determination of the subject’s IL28 genotype will be performed on human genomic DNA by 
techniques allowing amplification of the DNA and identification of the polymorphism. 
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9.7. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. 
Refer to the TIME AND EVENTS SCHEDULE for the timing and frequency of all sample 
collections. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided to the study sites. Collection, handling, storage, and 
shipment of samples must be under the specified, and where applicable, controlled temperature 
conditions as indicated in the laboratory manual. 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY 
10.1. 
Completion 
A subject will be considered to have completed the study if he or she has completed assessments 
at the Week 24 Follow-up Visit. 
10.2. 
Discontinuation of Study Treatment/Withdrawal from the Study 
Discontinuation of Study Treatment 
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
treatment before the end of the treatment regimen. 
A subject's study treatment must be discontinued if (see Section 9.2.8 for more details): 
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the subject to discontinue study treatment 
 
The subject becomes pregnant 
 
The subject has a Grade 4 rash; see Section 9.2.8.1 
 
The subject has a Grade 3 or 4 allergic reaction; see Section 9.2.8.2 
 
The subject has a confirmed Grade 4 ALT and/or AST value that is >2 times the baseline 
value; see Section 9.2.8.3 
 
The subject has a confirmed Grade 4 bilirubin elevation; see Section 9.2.8.3 
 
The subject has severe worsening of hepatic disease; see Section 9.2.8.4 
 
The subject has a confirmed diagnosis of pancreatitis; see Section 9.2.8.5 
 
The subject has clinical signs suggestive of muscle injury; see Section 9.2.8.6 
 
The subject has evidence of cardiac toxicity, see Section 9.2.8.7 
 
The subject has evidence of renal toxicity, see Section 9.2.8.8. 
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 
The subject has a Grade 4 AE or a Grade 4 laboratory abnormality at least possibly related 
to 1 of the study drugs; see Section 9.2.8.9 
Note: For laboratory abnormalities triggering treatment discontinuation, see the toxicity 
management plans described in Section 9.2.8. 
 
The subject requires treatment with any of the medications reported on the list of disallowed 
medications; see Section 8. 
 
The subject meets a treatment stopping rule for viral breakthrough (see Section 6.3) 
 
One of the study treatment stopping rules is met (see Section 6.4). 
If a subject prematurely discontinues study treatment for above-mentioned reasons, he or she will 
proceed with a Treatment Withdrawal Visit and will subsequently enter the Posttreatment 
Follow-up Period. Additional unscheduled visits may be performed for safety/tolerability reasons, 
if needed. 
Withdrawal From the Study 
A subject will be withdrawn from the study for any of the following reasons: 
 
Lost to follow-up 
 
Withdrawal of consent 
 
Death 
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. 
Subjects who withdraw consent during the Treatment or Posttreatment Follow-up Period, the 
subject will be offered an optional Treatment Withdrawal Visit, to be scheduled as soon as 
possible after withdrawal and/or a safety Follow-up Visit which needs to be scheduled 4 weeks 
after EOT. At the safety Follow-up Visit, safety assessments of the Week 4 Follow-up Visit need 
to be performed. Any subject who withdraws consent during the Posttreatment Follow-up Period 
and/or notifies the site that he or she will not return for study visits, will be invited to do a 
Follow-up Visit at the time of withdrawal to complete the full set of protocol procedures as 
scheduled for the Week 24 Follow-up Visit. However, all possible efforts should be made to 
ensure that subjects complete the study. 
The subject will have to withdraw from the present study, if the subject enrolls in a clinical study 
with an investigational drug (including investigational vaccines). 
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Withdrawal From the Use of Samples in Future Research 
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF. 
11. 
STATISTICAL METHODS 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP). 
The primary analyses will be performed when all subjects have completed the Week 12 
Follow-up visit (12 weeks after the end of Treatment Period) or discontinued earlier from the 
study. The final analysis (as secondary analysis) will be performed when all subjects have 
completed the last study-related visit or discontinued earlier from the study. 
11.1. 
Subject Information 
For all subjects who receive at least 1 dose of study drug, descriptive statistics will be provided. 
11.2. 
Sample Size Determination 
Since this is an exploratory study, no formal sample size calculation has been performed. 
With a total sample size of 40 subjects, the probability to observe an AE with an incidence of 
10.0% is 99.0%. The probability to observe an AE with an incidence of 1.0%, 2.5%, and 5.0% is 
33.0%, 64.0%, and 87.0%, respectively. With 20 subjects per cohort, the probability to observe 
an AE with an incidence of 10.0% is 88.0%. The probability to observe an AE with an incidence 
of 1.0%, 2.5%, and 5.0% is 18.0%, 40.0%, and 64.0%, respectively in a cohort. 
With an expected SVR rate of 90.0%, and 40 subjects in 2 cohorts combined, the corresponding 
95%, 2-sided CI is 76.3% to 97.2%. With 95% SVR, the corresponding 95% CI ranges from 
83.1% to 99.4%. With an expected SVR rate of 90.0%, and 20 subjects per cohort, the 
corresponding 95%, 2-sided CI is 68.3% to 98.8%. With 95.0% SVR, the corresponding 95% CI 
ranges from 75.1% to 99.9% in a cohort. 
Therefore, a total sample size of approximately 40 subjects is considered sufficient to explore the 
safety and efficacy of the combination regimen consisting of AL-335, ODV, and SMV in this 
study from a clinical point of view. 
11.3. 
Interim Analysis 
No formal interim analysis will be performed; however, a DRC will be commissioned to 
regularly monitor the safety in interim data review. 
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11.4. 
Safety Analyses 
The incidence of AEs will be summarized by body system and preferred term for each cohort 
and total. Changes from baseline in clinical laboratory values, vital signs, and ECG parameters 
will be presented descriptively. The percentage of subjects with abnormal clinical laboratory, 
vital signs, and ECG parameter values will be presented. 
The safety analyses will be done separately for each study period (screening, treatment, and 
follow-up). 
Adverse Events 
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are AEs 
with onset during the Treatment Period or that are a consequence of a preexisting condition that 
has worsened since baseline. All reported AEs will be included in the analysis. For each AE, the 
percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment cohort. In addition, comparisons between treatment cohorts will be 
provided if appropriate. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or an 
SAE. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary table of laboratory data. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed 
values and changes from baseline at each scheduled time point. A graphical presentation of 
changes in laboratory tests will be made as applicable. 
Laboratory abnormalities will be assessed according to the WHO Toxicity Grading Scale (see 
Attachment 1) and the normal ranges of the clinical laboratory. Laboratory abnormalities will be 
tabulated by treatment cohort. 
Electrocardiogram 
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from pretreatment 
values. 
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made. 
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The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, RR interval, 
QT interval, and QTc interval using the following correction methods: QTcF (primary correction 
method)10 and QT corrected according to Bazett's formula (QTcB).3 
QTc data will be analyzed according to the International Conference on Harmonisation 
(ICH) E14 Step 4 Guidance (May 2005)14 (see also Attachment 2). 
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of subjects with QTc interval >450 msec, >480 msec, or 
>500 msec will be summarized, as will the percentage of subjects with QTc interval increases 
from baseline >30 msec or >60 msec. 
All clinically relevant abnormalities in ECG waveform that are changes from the baseline 
readings will be reported (eg, changes in T-wave morphology or the occurrence of U-waves. 
Echocardiography 
Echocardiographic data will be summarized by key parameters, including LVEF. Descriptive 
statistics for the echocardiography parameters will be calculated at baseline and for observed 
values and changes from baseline at each scheduled time point. Frequency tabulations of the 
abnormalities will be made. 
Descriptive statistics of LVEF and mean change from baseline will be summarized at each 
scheduled time point. Time of onset for LVEF decrease and duration, the percentage of subjects 
with a decrease in LVEF >10.0% from baseline, with reversible decrease in LVEF and with no 
resolution of the decreased LVEF will be summarized. 
All clinically significant abnormal findings on echocardiography that are changes from baseline 
readings will be reported. 
Vital Signs 
Descriptive statistics of pulse rate, and blood pressure (systolic and diastolic) (supine) values and 
changes from baseline will be summarized at each scheduled time point. The percentage of 
subjects with values beyond clinically important limits will be summarized (see Attachment 2). 
11.5. 
Pharmacokinetic Analyses 
Population PK Analysis for all Subjects 
The PK samples (sparse and rich) taken from all subjects in the study (see 
TIME AND EVENTS SCHEDULE and TIME AND EVENTS SCHEDULE: Rich serial PK 
Assessments), will be used for popPK model development and/or popPK model update. PopPK 
analysis of plasma concentration-time data of AL-335 (and metabolites), ODV, and SMV from 
all subjects will be performed using nonlinear mixed-effects modeling. If deemed necessary, data 
will be combined with data from other studies. PopPK modeling will be used to describe the 
concentration-time profiles and estimate the exposure parameters (AUC24h and C0h) of AL-335 
(and metabolites), ODV, and SMV. Available baseline subject characteristics (demographics, 
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body weight, laboratory variables, genotype, etc) may be explored as potential covariates 
affecting PK parameters. Details will be given in a popPK analysis plan and the results of the 
popPK analysis will be presented in a separate popPK report. 
Data will be listed for all subjects with available plasma concentrations. Subjects will be 
excluded from the PK analysis if their data do not allow for accurate assessment of PK (eg, 
incomplete administration of the study drug; missing information of dosing and sampling times; 
concentration data not sufficient for PK parameter calculation). 
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All subjects and samples excluded from the analysis will be 
clearly documented in the popPK report. 
For each cohort, descriptive statistics, including arithmetic mean, standard deviation (SD), 
coefficient of variation, median, minimum, maximum, and geometric mean will be performed for 
all individually estimated exposure parameters (AUC24h and C0h) of AL-335 (and metabolites), 
ODV, and SMV. 
Rich Serial PK Sampling for Noncompartmental PK Analysis in the PK Subgroups 
For each cohort, descriptive statistics will be provided for the plasma concentrations at each 
sampling time point and the PK parameters derived. 
All individual concentrations at each sampling time point and all individual PK parameters will 
be listed. For each subject, plasma concentration-time data will be graphically presented. 
Similarly, graphs of the mean plasma concentration-time profiles and overlay graphs with 
combined individual plasma concentration-time profiles will be produced. PK parameters will be 
subjected to an exploratory graphical analysis. Additional analyses may be performed if deemed 
warranted. 
11.6. 
Pharmacokinetic/Pharmacodynamic Analyses 
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure 
parameters (AUC24h and C0h) with SVR4, SVR12, and SVR24 and with safety endpoints may be 
explored. These relationships will be presented in a graphical display. 
Details will be given in a PK/pharmacodynamic (PD) analysis plan and the results of the PK/PD 
analysis will be presented in a separate PK/PD report. 
11.7. 
Efficacy Analyses 
The primary analyses will be performed when all subjects have reached the SVR12 time point 
(Week 12 Follow-up Visit) or discontinued earlier. The final analysis (as secondary analysis) 
will be performed when all subjects have completed the last study-related visit (SVR24 time 
point; Week 24 Follow-up Visit) or discontinued earlier. 
The efficacy analyses will be performed on the full analysis set (FAS), defined as all subjects 
who received at least 1 dose of the study drug (AL-335, ODV, or SMV) and have at least 
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1 postbaseline efficacy measurement in the current study. Additional sensitivity analyses on 
efficacy may be performed after excluding subjects with early treatment discontinuation due to 
nonvirologic reasons or missing data at SVR4, SVR12, or SVR24 time points, as well as on the 
per-protocol set (PPS), defined as the FAS subjects without a prespecified major protocol 
deviation. 
For each treatment cohort, the proportion of subjects who achieve SVR4, SVR12, and SVR24 
will be calculated. A 2-sided 95% CI will be constructed around the SVR. 
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment 
cohort. 
The potential association between treatment outcome and baseline subject and disease 
characteristics such as prior treatment history, IL28B genotype (rs12979860), presence of 
cirrhosis, HCV RNA level, and HCV geno/subtype will be explored. 
Criteria for Endpoints 
HCV RNA levels will be used to determine the response to HCV treatment: virologic response 
and failure (on-treatment failure and viral relapse). Refer to the DEFINITIONS OF TERMS for 
more details. 
Resistance Determination Analyses 
The results of viral sequencing will be evaluated by the sponsor’s virologist. Pretreatment 
polymorphisms in the HCV NS3/4A, NS5A, and NS5B regions in all subjects and relevant 
changes in the HCV NS3/4A, NS5A, and NS5B regions in subjects not achieving SVR will be 
tabulated and described. The effect of pretreatment HCV NS3/4A, NS5A, and NS5B 
polymorphisms on treatment outcome will be explored. 
Changes in viral sequence will not be reported as AEs or SAEs. 
11.8. 
Pharmacogenomic Analyses 
Baseline IL28B genotyping data will be tabulated. Subgroup analyses will be done to explore the 
effect of the IL28B genotype (rs12979860) on efficacy by means of descriptive statistics and 
frequency tabulations. 
11.9. 
Data Review Committee 
A DRC will be established to monitor data with focus on the safety and on the general conduct of 
the study. Emerging safety data from this study will be reviewed at predetermined intervals.  
To conduct this study carefully in light of securing subjects' safety, dosing of cohort 2 with 
patients with compensated cirrhosis will only start after a DRC has reviewed all available 
relevant safety data when the first 6 subjects in cohort 1 completed the Week 4 visit (including 
but not limited to AE, SAE, clinical laboratory test) and no new or unexpected events, which are 
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considered clinically significant, are detected. DRC may require to review data of further 
patients before deciding about the start of dosing in cohort 2. 
In addition the DRC is responsible for the ad-hoc safety assessment of cardiac events that 
potentially qualify for a study treatment stopping rule (see Section 6.4). 
The DRC will consist of at least 1 medical expert in the relevant therapeutic area, 1 cardiologist 
(for the review and interpretation of any cardiac safety data) and at least 1 statistician. The DRC 
responsibilities, authorities, and operating procedures will be documented in the DRC charter. 
The DRC is a committee within the sponsor’s organization that is independent of the sponsor’s 
study team. 
12. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. 
The sponsor shall notify the concerned Health Authorities of any urgent safety measures and 
potential serious breaches in accordance with the sponsor’s internal procedures and in line with 
the timelines defined in local regulations. 
12.1. 
Definitions 
12.1.1. 
Adverse Event Definitions and Classifications 
Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or noninvestigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or noninvestigational) product, whether or not related to that 
medicinal (investigational or noninvestigational) product. (Definition per ICH) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
Adverse Events, for time of last AE recording). 
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Serious Adverse Event 
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening 
(the subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 
 
Is medically important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious. 
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality). 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For AL-335, ODV, and SMV, the expectedness of an AE 
will be determined by whether or not it is listed in the IB and addenda. 
Adverse Event Associated With the Use of the Drug 
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2. 
12.1.2. 
Attribution Definitions 
Not Related 
An AE that is not related to the use of the drug. 
Doubtful 
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
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Possible 
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded. 
Probable 
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s). 
Very Likely 
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.3. 
Severity Criteria 
An assessment of severity grade will be made using the following general categorical descriptors 
outlined in the WHO Toxicity Grading Scale in Attachment 1. 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
12.2. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to: 
 
Overdose of a sponsor study drug 
 
Suspected abuse/misuse of a sponsor study drug 
 
Inadvertent or accidental exposure to a sponsor study drug 
 
Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion) 
 
Exposure to a sponsor study drug from breastfeeding 
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the Serious Adverse Event page of the eCRF. 
12.3. 
Procedures 
12.3.1. 
All Adverse Events 
All AEs and special reporting situations, whether serious or nonserious, will be reported from the 
time a signed and dated ICF is obtained until completion of the subject's last visit. Serious 
adverse events, including those spontaneously reported to the investigator must be reported using 
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the Serious Adverse Event Form. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the protocol. 
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether 
they are protocol-specific assessments. 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the eCRF their opinion concerning the relationship of 
the AE to study therapy. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions. 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). The investigator 
(or sponsor where required) must report SUSARs to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. 
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:  
 
Study number 
 
Statement, in the local language(s), that the subject is participating in a clinical study 
 
Investigator's name and 24-hour contact telephone number 
 
Local sponsor's name and 24-hour contact telephone number (for medical staff only) 
 
Site number 
 
Subject number 
 
Any other information that is required to do an emergency breaking of the blind 
12.3.2. 
Serious Adverse Events 
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event. 
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by 
facsimile (fax). 
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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
 
The event resolves 
 
The event stabilizes 
 
The event returns to baseline, if a baseline value/status is available 
 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following: 
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility). 
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE. 
 
Hospitalization in view of the logistic challenges related to the visit schedule of the rich PK 
substudy (see Section 9.3 and TIME AND EVENTS SCHEDULE: Rich serial PK 
Assessments). 
The cause of death of a subject in a study, whether or not the event is expected or associated with 
the study drug, is considered an SAE. 
12.3.3. 
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form from the time a signed and dated ICF is obtained 
until the end of the study. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and must be reported 
using the Serious Adverse Event Form. Any subject who becomes pregnant during the study 
must discontinue further study treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above. 
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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
12.4. 
Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document. 
13. 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures. 
13.1. 
Procedures 
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event. 
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor. 
13.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document. 
14. 
STUDY DRUG INFORMATION 
14.1. 
Physical Description of Study Drug(s) 
The AL-335 supplied for this study will be formulated as 400-mg tablets. It will be manufactured 
by Patheon Can and provided under the responsibility of the sponsor. Refer to the current IB for 
a list of excipients.16,18 
The ODV supplied for this study is formulated as 25-mg film-coated tablets. It will be 
manufactured by Catalent US and provided under the responsibility of the sponsor. Refer to the 
current IB for a list of excipients. 19,20 
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The SMV supplied for this study will be formulated as 75-mg capsules (G034). It will be 
manufactured and provided under the responsibility of the sponsor. Refer to the current IB and its 
addendum for the list of excipients.21,22 
14.2. 
Packaging 
The study drug will be packaged in individual subject kits. Each kit will consist of the following 
study drugs, which will be packaged in bottles. 
Study drug 
Package 
Pharmaceutical form 
AL-335: 400 mg 
30 count bottle 
Tablet 
ODV: 25 mg 
30 count bottle 
Tablet 
SMV: 75 mg 
30 count bottle 
Capsule 
 
All study drugs will be dispensed in child-resistant packaging. 
14.3. 
Labeling 
Study drug labels will contain information to meet the applicable regulatory requirements. 
14.4. 
Preparation, Handling, and Storage 
The study drugs must be stored in a secure area and administered only to the subjects enrolled 
into this clinical study, in accordance with the conditions specified in this protocol. 
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage. 
14.5. 
Drug Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects must be instructed to return all original containers, whether empty 
or containing study drug. All study drug will be stored and disposed of according to the sponsor's 
instructions. Study-site personnel must not combine contents of the study drug containers. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
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the same subject. Whenever a subject brings his or her study drug to the study site for pill count, 
this is not seen as a return of supplies. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor. 
15. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
 
Investigator's Brochure’s for AL-335, ODV, and SMV, and their addenda 
 
Site investigational product procedure manual 
 
Echocardiography manual 
 
ECG manual 
 
Laboratory manual 
 
Medication diaries 
 
Electronic Data Capture (eDC) Manual 
 
Sample ICF 
 
Contact information page 
 
IWRS manual 
16. 
ETHICAL ASPECTS 
16.1. 
Study-Specific Design Considerations 
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled. 
16.2. 
Regulatory Ethics Compliance 
16.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
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16.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations): 
 
Final protocol and, if applicable, amendments 
 
Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
 
Investigator's Brochure (or equivalent information) and amendments/addenda 
 
Sponsor-approved subject recruiting materials 
 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
 
Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB) 
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects 
 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials, 
and subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 
 
Revision(s) to ICF and any other written materials to be provided to subjects 
 
If applicable, new or revised subject recruiting materials approved by the sponsor 
 
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
 
New edition(s) of the IB and amendments/addenda 
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually) 
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug 
 
New information that may adversely affect the safety of the subjects or the conduct of the 
study 
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
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 
Report of deaths of subjects under the investigator's care 
 
Notification if a new investigator is responsible for the study at the site 
 
Development Safety Update Report and Line Listings, where applicable 
 
Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct). 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion. 
16.2.3. 
Informed Consent 
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any 
study-related activity. The ICF(s) that is/are used must be approved by both the sponsor and by 
the reviewing IEC/IRB and be in a language that the subject can read and understand. The 
informed consent should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor 
policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of his or her disease. Subjects will be told 
that alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the subject agrees to allow his or 
her study physician to recontact the subject for the purpose of obtaining consent for additional 
safety evaluations, and subsequent disease-related treatments, if needed. The physician may also 
recontact the subject for the purpose of obtaining consent to collect information about his or her 
survival status. 
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The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject. 
Where local regulations require, a separate ICF may be used for the required DNA 
(IL28B genotype) component of the study. 
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained. 
If any new information that may be relevant to the subject’s willingness to participate in the 
study becomes available, the investigator should inform the subject and ensure the subject signs 
a revised consent form, if applicable. 
16.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries. 
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
Exploratory, pharmacodynamic, and PK research is not conducted under standards appropriate 
for the return of data to subjects. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to subjects or investigators, unless required by law or local regulations. 
Privacy and confidentiality of data generated in the future on stored samples will be protected by 
the same standards applicable to all other clinical data. 
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16.2.5. 
Long-term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand AL-335, ODV, and 
SMV, to understand differential drug responders, and to develop tests/assays related to AL-335, 
ODV, and SMV and HCV infection.  The research may begin at any time during the study or the 
poststudy storage period.  
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.2) 
16.2.6. 
Country Selection 
This study will only be conducted in Japan, where the intent is to launch the developed product. 
17. 
ADMINISTRATIVE REQUIREMENTS 
17.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, 
or when the relevant competent authority has raised any grounds for nonacceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When 
the change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it. 
17.2. 
Regulatory Documentation 
17.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met. 
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17.2.2. 
Required Prestudy Documentation 
The following documents must be provided to the sponsor before shipment of study drug to the 
study site: 
 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee. 
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study. 
 
Regulatory authority approval or notification, if applicable 
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable 
 
Documentation of investigator qualifications (eg, curriculum vitae) 
 
Completed investigator financial disclosure form from the principal investigator, where 
required 
 
Signed and dated clinical trial agreement, which includes the financial agreement 
 
Any other documentation required by local regulations 
The following documents must be provided to the sponsor before enrollment of the first subject: 
 
Completed investigator financial disclosure forms from all subinvestigators 
 
Documentation of subinvestigator qualifications (eg, curriculum vitae) 
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable 
 
Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable 
17.3. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
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and date of birth. In cases where the subject is not enrolled into the study, the date seen and date 
of birth will be used. 
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study. 
17.4. 
Source Documentation 
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following 
to confirm data collected in the eCRF: subject identification, eligibility, and study identification; 
study discussion and date of signed informed consent; dates of visits; results of safety and 
efficacy parameters as required by the protocol; record of all AEs and follow-up of AEs; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
The author of an entry in the source documents should be identifiable. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). 
The following data will be recorded directly into the eCRF and will be considered source data: 
 
Race 
 
Blood pressure and pulse rate 
 
Height and weight 
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows: 
 
Referral letter from treating physician or 
 
Complete history of medical notes at the site 
 
Discharge summaries 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents. 
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
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the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation. 
17.5. 
Case Report Form Completion 
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate 
and correct. 
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF. Study-specific data will be transmitted in a secure manner to the sponsor within the 
timeframe agreed upon between the sponsor and the study site. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
eCRF in English. Study-site personnel must enter the data into the eCRF as soon as possible after 
a subject visit, and the forms should be available for review at the next scheduled monitoring 
visit. 
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the eCRF, this can be done in either of the following ways: 
 
Study-site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool). 
 
Study-site manager can generate a query for resolution by the study-site personnel. 
 
Clinical data manager can generate a query for resolution by the study-site personnel. 
17.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRF for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources. 
17.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
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Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports. 
17.8. 
Monitoring 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by 
the sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documents will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. 
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17.9. 
Study Completion/Termination 
17.9.1. 
Study Completion/End of Study 
The study will be considered to be completed with the last visit for the last subject participating 
in the study. The final data from the study site will be sent to the sponsor (or designee) after 
completion of the final subject visit at that study site, in the time frame specified in the Clinical 
Trial Agreement. 
17.9.2. 
Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of subjects by the investigator 
 
Discontinuation of further study drug development 
17.10. On-site Audits 
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
17.11. Use of Information and Publication 
All information, including but not limited to information regarding AL-335 ODV, and SMV or 
the sponsor's operations (eg, patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, and any data, including pharmacogenomic or PK 
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research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and 
use this information only to accomplish this study, and will not use it for other purposes without 
the sponsor's prior written consent. 
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of AL-335 ODV, and SMV and thus may 
be disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study and laboratory data from 
the selected laboratory that were transmitted into the sponsor’s database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or PK 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
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contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law. 
 
 
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REFERENCES 
1. 
Achillion Pharmaceuticals, Inc. Achillion reports 100% SVR12 from second cohort of patients in the 
previously-completed six week Phase 2 trial evaluating odalasvir (ACH-3102) and sofosbuvir for genotype 1 
HCV (“proxy study”). New Haven, Conn., Sept 17, 2015 (Globe Newswire). Available at: 
http://ir.achillion.com/releasedetail.cfm?ReleaseID=932025. Accessed 21 Sep 2015. 
2. 
Asahina Y, Izumi N, Hiromitsu K, et al. JSH Guidelines for the Management of Hepatitis C Virus Infection: A 
2016 update for genotype 1 and 2. Hepatol Res. 2016 Feb;46(2):129-65. 
3. 
Bazett HC. An analysis of the time-relationship of electrocardiograms. Heart. 1920;7:353-380. 
4. 
Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006; 
3(2):47-52. 
5. 
CredibleMeds® Combined list of drugs that prolong QT and/or cause Torsades de Pointes (TDP), Arizona 
Center for Education and Research on Therapeutics. 13 June 2016. Available at: 
https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf. Accessed 11 Jul 2016. 
6. 
Daklinza (daclatasvir) [EU Summary of Product Characteristics]. Bristol-Myers Squibb; Jul 2015. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003768/WC500172848.pdf. Accessed 05 Jul 2016. 
7. 
Davis G, Alter M, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a 
multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010; 138: 513-521. 
8. 
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis 
C virus infection. J Hepatol. 2014; 60: 392-420. 
9. 
Exviera (dasabuvir) [EU Summary of Product Characteristics]. Abbvie Ltd; 2015. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003837/WC500182233.pdf. Accessed 17 Mar 2016. 
10. Fridericia, LS. Die systolendauer im Elektokardiogramm bei normalen Menschen und bei Herzkranken. 
Acta Med Scand. 1920;53:469-486. 
11. Ge D, Fellay J, Thompson A, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral 
clearance. Nature. 2009;461:399-401. 
12. Gower E, Estes C, Blach et al. Global epidemiology and genotype distribution of the hepatitis C virus infection. 
J Hepatol. 2014; 61(1S): S45-S57. 
13. Harvoni (sofosbuvir/ledipasvir) [EU Summary of Product Characteristics]. Gilead Sciences International Ltd; 
2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003850/WC500177995.pdf. Accessed 17 Mar 2016 
14. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005. 
15. Investigator’s Brochure: ACH-0143102 Version 6. Achillion Pharmaceuticals, Inc (Jul 2015). 
16. Investigator's Brochure: AL-335. Addendum 1 to Edition 2. Alios BioPharma, Inc (5 Apr 2016). 
17. Investigator's Brochure: AL-335. Addendum 2 to Edition 2. Alios BioPharma, Inc (Jul 2016). 
18. Investigator's Brochure: AL-335. Edition 2. Alios BioPharma Inc. (4 Sep 2015). 
19. Investigator's Brochure: Odalasvir (JNJ-64289901, ACH-0143102). Addendum 4 to Edition 6. JRD (Jul 2016). 
20. Investigator's Brochure: Odalasvir (JNJ-64289901, ACH-0143102). Edition 6. Achillion Pharmaceuticals, Inc 
(27 Jul 2015). 
21. Investigator's Brochure: Simeprevir (TMC435). Addendum 1 to Edition 9. JRD (1 Mar 2016). 
22. Investigator's Brochure: Simeprevir (TMC435). Edition 9. JRD (28 Sep 2015). 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
128 
Approved, Date: 27 July 2017  
23. Kohli A, Sims Z, Nelson A, et al. Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: final 
results of the SYNERGY trial. Data presented at the 21st Conference on Retroviruses and Opportunistic 
Infections (CROI), Boston, MA, USA. 3-6 Mar 2014. Available at: 
http://www.natap.org/2014/CROI/croi_04.htm. Accessed 21 Jul 2016. 
24. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir with/without ribavirin for treating 
chronic HCV genotype 1 infection in prior null-responder to peginterferon/ribavirin and treatment-naïve 
patients (COSMOS: a randomized study). Lancet 2014; 384(9556): 1756-1765. 
25. Lee MK, Yang HI, Yuan Y, L’Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus 
infection. World J Gastroenterol. 2014; 20(28): 9270-9280. 
26. Martin M et al. Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review of 
expert recommendations. The Oncologist 2009;14:1-11. 
27. Messina JP, Humphreys I, Flaxman A et al. Global distribution and prevalence of Hepatitis C virus genotypes. 
Hepatology. 2015; 61(1): 77-87. 
28. Olysio [EU Summary of Product Characteristics]. Beerse: Janssen Cilag International, NV; Aug 2015. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002777/WC500167867.pdf. Accessed 17 March 2016. 
29. Olysio [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP; 2014. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205123s003lbl.pdf. Accessed 21 Jun 2016. 
30. Omata M, Kanda T, Yokosuka O. et al. Features of hepatitis C virus infection, current therapies and ongoing 
clinical trials in ten Asian Pacific countries. Hepatol Int. 2015;9:486–507. 
31. Pasternak R, et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins.  
JACC. 2002;40:567-72. 
32. Sovaldi [EU Summary of Product Characteristics]. Cambridge: Gilead Sciences International Ltd; Jul 2015. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002798/WC500160597.pdf. Accessed 21 Jun 2016. 
33. Sovriad [Japan Package Insert]. Janssen Pharmaceutical K.K.; 2016. 
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/800155_6250037M1028_1_12. Accessed 
08 Aug 2016. 
34. Technivie (ombitasvir/paritaprevir/ritonavir) US Product Information, Abbvie Ltd; June 2016. 
http://www.rxabbvie.com/pdf/technivie_pi.pdf. Accessed 21 Jul 2016. 
35. Viekirax (ombitasvir/paritaprevir/ritonavir) [EU Summary of Product Characteristics], Abbvie Ltd; 2015. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003839/WC500183997.pdf. Accessed 17 Mar 2016. 
36. World Health Organization. Hepatitis C fact sheet N°164, updated Jul 2015. Available at: 
http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed: 17 Mar 2016. 
37. World Health Organization. Hepatitis C. Available at: http://www.who.int/mediacentre/factsheets/fs164/en/. 
Accessed 26 Jul 2016. 
38. Zeuzem S, Hezode C, Bronowicki J-P, et al. Daclatasvir in combination with simeprevir with or without 
ribavirin for hepatitis C virus genotype 1 infection. Data presented at the 21st Conference on Retroviruses and 
Opportunistic Infections (CROI), Boston, MA, USA. 3-6 Mar 2014. Available at: 
http://www.natap.org/2014/CROI/croi_09.htm. Accessed 17 March 2016. 
 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
129 
Approved, Date: 27 July 2017  
Attachment 1: WHO Scale for Determining the Severity of Adverse Events 
February 2003 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate grade of 
severity: 
 
GRADE 1 
Mild 
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required. 
GRADE 2 
Moderate 
Mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention/ therapy required. 
GRADE 3 
Severe 
Marked limitation in activity; some assistance usually required; 
medical intervention/therapy required; hospitalizations possible. 
GRADE 4 
Potentially 
life-threateninga 
Extreme limitation in activity; significant assistance required; 
significant medical intervention/therapy required; hospitalization 
or hospice care probable. 
a Revised by the sponsor 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
For parameters not included in the following Toxicity Tables, sites should refer to the “Guide For 
Estimating Severity Grade” located above. 
 
Criteria are generally grouped by body system. Some protocols may have additional protocol-specific 
grading criteria, which will supersede the use of these tables for specified criteria. 
NCT02993250


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Clinical Protocol 64294178HPC2003 Amendment 5 
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Approved, Date: 27 July 2017  
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematology 
Hemoglobin 
9.5-10.5 gm/dL 
8.0-9.4 gm/dL 
6.5-7.9 gm/dL 
<6.5 gm/dL 
Absolute Neutrophil 
Count 
1000-1500/mm³ 
750-999/mm³ 
500-749/mm³ 
<500/mm³ 
Platelets 
75,000-99,000/mm³ 50,000-74,999/mm³
20,000-49,999/mm³ <20,000/mm³ 
Prothrombin Time 
(PT) 
≥1.01 to ≤1.25 x 
ULN 
>1.25 to ≤1.50 x 
ULN 
>1.50 to ≤3.00 x 
ULN 
>3.00 x ULN 
Activated Partial 
Thromboplastin 
Time (aPTT) 
≥1.01 to ≤1.66 x 
ULN 
>1.66 to ≤2.33 x 
ULN 
>2.33 to ≤3.00 x 
ULN 
>3.00 x ULN 
Fibrinogen 
≥0.75 to ≤0.99 x 
LLN 
≥0.50 to <0.75 x 
LLN 
≥0.25 to <0.50 x 
LLN 
<0.25 x LLN 
Fibrin Split Product 20-40 mcg/mL 
41-50 mcg/mL 
51-60 mcg/mL 
>60 mcg/mL 
Methemoglobin 
5.0%-9.9% 
10.0%-14.9% 
15.0%-19.9% 
>20.0% 
Liver Enzymes 
AST (SGOT) 
≥1.25 to ≤2.50 x 
ULN 
>2.50 to ≤5.00 x 
ULN 
>5.00 to ≤10.00 x 
ULN 
>10.00 x ULN 
ALT (SGPT) 
≥1.25 to ≤2.50 x 
ULN 
>2.50 to ≤5.00 x 
ULN 
>5.00 to ≤10.00 x 
ULN 
>10.00 x ULN 
Gamma-
glutamyltransferase 
≥1.25 to ≤2.50 x 
ULN 
>2.50 to ≤5.00 x 
ULN 
>5.00 to ≤10.00 x 
ULN 
>10.00 x ULN 
Alkaline 
Phosphatase 
≥1.25 to ≤2.50 x 
ULN 
>2.50 to ≤5.00 x 
ULN 
>5.00 to ≤10.00 x 
ULN 
>10.00 x ULN 
Amylase 
≥1.1 to ≤1.5 x ULN >1.5 to ≤2.0 x ULN
>2.0 to ≤5.0 x ULN >5.0 x ULN 
Chemistries 
Hyponatremia 
130-135 mEq/L 
123-129 mEq/L 
116-122 mEq/L 
<116 mEq/L or 
mental status 
changes or 
seizures 
Hypernatremia 
146-150 mEq/L 
151-157 mEq/L 
158-165 mEq/L 
>165 mEq/L or 
mental status 
changes or 
seizures 
Hypokalemia 
3.0-3.4 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L or 
intensive 
replacement Rx 
required or 
hospitalization 
required 
<2.0 mEq/L or 
paresis or ileus or 
life-threatening 
arrhythmia 
Hyperkalemia 
5.6-6.0 mEq/L 
6.1-6.5 mEq/L 
6.6-7.0 mEq/L 
>7.0 mEq/L or 
life-threatening 
arrhythmia 
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
mental status 
changes or coma 
Hyperglycemia 
(nonfasting and no 
prior diabetes) 
116-160 mg/dL 
161-250 mg/dL 
251-500 mg/dL 
>500 mg/dL or 
ketoacidosis or 
seizures 
Hypocalcemia 
(corrected for 
8.4-7.8 mg/dL 
7.7-7.0 mg/dL 
6.9-6.1 mg/dL 
<6.1 mg/dL or 
life-threatening 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
131 
Approved, Date: 27 July 2017  
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
albumin) 
arrhythmia or 
tetany 
Hypercalcemia 
(corrected for 
albumin) 
10.6-11.5 mg/dL 
11.6-12.5 mg/dL 
12.6-13.5 mg/dL 
>13.5 mg/dL or 
life-threatening 
arrhythmia 
Hypomagnesemia 
1.4-1.2 mEq/L 
1.1-0.9 mEq/L 
0.8-0.6 mEq/L 
<0.6 mEq/L or 
life-threatening 
arrhythmia 
Hypophosphatemia 2.0-2.4 mg/dL 
1.5-1.9 mg/dL or 
replacement Rx 
required 
1.0-1.4 mg/dL 
intensive Rx or 
hospitalization 
required 
<1.0 mg/dL or 
life-threatening 
arrhythmia 
Hyperbilirubinemia ≥1.1 to ≤1.5 x ULN >1.5 to ≤2.5 x ULN
>2.5 to ≤5.0 x ULN >5.0 x ULN 
Lipasea 
≥1.1 to ≤1.5 x ULN >1.5 to ≤3.0 x ULN
>3.0 to ≤5.0 x ULN >5.0 x ULN 
Blood urea nitrogen ≥1.25 to ≤2.50 x 
ULN 
>2.50 to ≤5.00 x 
ULN 
>5.00 to ≤10.00 x 
ULN 
>10.00 x ULN 
Creatinine 
≥1.1 to ≤1.5 x ULN >1.5 to ≤3.0 x ULN
>3.0 to ≤6.0 x ULN >6.0 x ULN or 
required dialysis 
Urinalysis 
Proteinuria 
1+ or <0.3% or 
<3g/L or 
200 mg-1 gm 
loss/day 
2-3+ or 0.3%-1.0% 
or 3-10 g/L or 
1-2 gm loss/day 
4+ or >1.0% or 
>10 g/L or 2-3.5 gm 
loss/day 
nephrotic 
syndrome or 
>3.5 gm loss/day 
Hematuria 
microscopic only 
gross, no clots 
gross + clots 
obstructive or 
required 
transfusion 
Cardiac Dysfunction 
Cardiac Rhythm 
- 
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent; 
no Rx required 
requires Rx 
Hypertension 
transient inc. 
>20 mm; no Rx 
recurrent, chronic, 
>20 mm, Rx 
required 
requires acute Rx; 
no hospitalization 
requires 
hospitalization 
Hypotension 
transient orthostatic 
hypotension, no Rx 
symptoms 
correctable with oral 
fluids Rx 
requires IV fluids; 
no hospitalization 
required 
requires 
hospitalization 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no Rx 
symptomatic 
effusion; pain; ECG 
changes 
tamponade; 
pericardiocentesis 
or surgery required
Hemorrhage, Blood 
Loss 
microscopic/occult 
mild, no transfusion gross blood loss; 
1-2 units transfused 
massive blood 
loss; >3 units 
transfused 
a Revised by the sponsor 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
132 
Approved, Date: 27 July 2017  
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Respiratory 
Cough 
transient; no Rx 
treatment associated 
cough local Rx 
uncontrolled 
- 
Bronchospasm, 
Acute 
transient; no Rx 
<80.0%-70.0% FEV1 
(or peak flow) 
requires Rx 
normalizes with 
bronchodilator; 
FEV1 50%-70% (or 
peak flow) 
no normalization 
with bronchodilator; 
FEV1 25%-50% (or 
peak flow 
retractions) 
cyanosis: FEV1 
<25.0% (or peak 
flow) or intubated
Gastrointestinal 
Stomatitis 
mild discomfort; no 
limits on activity 
some limits on 
eating/drinking 
eating/talking very 
limited 
requires IV fluids
Nausea 
mild discomfort; 
maintains reasonable 
intake 
moderate discomfort; 
intake decreased 
significantly; some 
activity limited 
severe discomfort; 
no significant 
intake; activities 
limited 
minimal fluid 
intake 
Vomiting 
transient emesis 
occasional/moderate 
vomiting 
orthostatic 
hypotension or IV 
fluids required 
hypotensive shock 
or hospitalization 
required for IV 
fluid therapy 
Constipation 
mild 
moderate 
severe 
distensions 
w/vomiting 
Diarrhea 
transient 3-4 loose 
stools/day 
5-7 loose stools/day
orthostatic 
hypotension or 
>7 loose stools/day 
or required IV fluids 
hypotensive shock 
or hospitalization 
for IV fluid 
therapy required 
Neuro & Neuromuscular 
Neuro-Cerebellar 
slight incoordination 
dysdiadochokinesis
intention tremor, 
dysmetria, slurred 
speech; nystagmus 
locomotor ataxia 
incapacitated 
Mood 
mild anxiety or 
depression 
moderate anxiety or 
depression and 
therapy required 
severe anxiety or 
depression or mania; 
needs assistance 
acute psychosis; 
incapacitated, 
requires 
hospitalization 
Neuro Control 
(ADL = activities of 
daily living) 
mild difficulty 
concentrating; no 
Rx; mild 
confusion/agitation; 
ADL unaffected 
moderate 
confusion/agitation 
some limitation of 
ADL; minimal Rx 
severe 
confusion/agitation 
needs assistance for 
ADL; therapy 
required 
toxic psychosis; 
hospitalization 
Muscle Strength 
subjective weakness 
no objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function
objective weakness 
function limited 
paralysis 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
133 
Approved, Date: 27 July 2017  
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Other Parameters 
Fever: oral, 
>12 hours 
37.7-38.5 °C or 
100.0-101.5 °F 
38.6-39.5 °C or 
101.6-102.9 °F 
39.6-40.5 °C or 
103-105 °F 
>40.5 °Ca or  
>105 °F 
Headache 
mild, no Rx  
transient, moderate; 
Rx required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
required repeated 
narcotic therapy 
Fatigue 
no decrease in ADL normal activity 
decreased 
25.0%-50.0% 
normal activity 
decreased >50.0% 
can’t work 
unable to care for 
self 
Allergic Reaction 
pruritus without rash localized urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Local Reaction 
tenderness or 
erythema 
induration <10 cm or 
phlebitis or 
inflammation 
induration >10 cm 
or ulceration 
necrosis 
Mucocutaneousa 
erythema 
diffuse, 
maculopapular rash, 
or dry desquamation
vesiculation, moist 
desquamation or 
ulceration, or any 
cutaneous eventa 
exfoliative 
dermatitis, mucous 
membrane 
involvement, 
erythema 
multiforme major, 
Stevens-Johnson 
Syndrome, or 
necrosis requiring 
surgerya 
Key: FEV1=forced expiratory volume in 1 second; IV=intravenous; LLN=lower limit of normal; 
Rx=therapy; ULN=upper limit of normal 
 
a Revised by the sponsor 
 
 
 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
134 
Approved, Date: 27 July 2017  
Attachment 2: Cardiovascular Safety – Abnormalities  
 
The following abnormalities will be defined for vital sign measurements: 
Abnormality Code 
Vital Sign Parameters 
Pulse 
Diastolic Blood Pressure 
Systolic Blood Pressure 
Abnormalities on actual values 
Abnormally low 
50 bpm 
50 mm Hg 
90 mm Hg 
Grade 1 or mild 
- 
>90 mm Hg to 
<100 mm Hg 
>140 mm Hg to 
<160 mm Hg 
Grade 2 or moderate 
- 
100 mm Hg to 
<110 mm Hg 
160 mm Hg to 
<180 mm Hg 
Grade 3 or severe 
- 
110 mm Hg 
180 mm Hg 
Abnormally high 
120 bpm
- 
- 
The classification of AEs related to hypotension and hypertension will be done according to the WHO 
Toxicity Grading Scale (see also Attachment 1). 
 
Toxicity grading for PR interval will be performed according to the Division of Aids (DAIDS) grading 
table for the severity of adult and pediatric adverse events version 1.0, December 2004; clarification 
August 2009. 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially life-
threatening 
Prolonged PR interval 
Adult >16 years 
PR interval 
0.20 – 0.25 sec* 
PR interval 
>0.25 sec 
Type II 2nd degree 
AV block OR 
Ventricular pause 
>3.0 sec 
Complete AV 
block 
*Revised by the sponsor. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
135 
Approved, Date: 27 July 2017  
Attachment 3: Visit Schedule for Rash Management 
 
This visit schedule summarizes the visits and assessments to be performed in case of rash. At the 
investigator’s discretion, additional visits and assessments can be performed. Local laboratory blood 
sample assessments will be documented/collected as described in the text below. 
 
 
 
Grade 1 Rash 
Grade 2 Rash 
Grade 3 or 4 Rash 
Day 0a 
 
Study medication MAY 
be CONTINUED. 
 
Unscheduled visit (on-
site) for initial rash 
evaluation may be 
performed at the 
investigator’s discretion.
 
Assessment of safety 
blood sample by local 
laboratory 
RECOMMENDED. 
 
Study medication MAY 
be CONTINUED. 
 
Unscheduled visit (on-
site) for initial rash 
evaluation 
REQUIRED. 
 
If a visit is not possible, 
telephone contact with 
the subject should take 
place to collect 
information and to give 
advice on the necessary 
measures to be taken. 
 
Assessment of safety 
blood sample by local 
laboratory 
RECOMMENDED. 
 
Referral to 
dermatologist 
OPTIONAL 
(preferably within 24 
hours after onset of rash, 
if performed). 
 
 
Grade 3: SMV MUST 
be permanently 
DISCONTINUED. 
AL-335 and ODV 
MAY be 
CONTINUED at the 
investigator’s 
discretion. Close 
monitoring is 
REQUIRED to 
prevent progression of 
the rash. 
 
Grade 4: Study 
medication MUST 
be permanently 
DISCONTINUED. 
Rechallenge is NOT 
ALLOWED. 
 
Unscheduled visit for 
initial rash evaluation 
as soon as possible 
after the subject 
contacts the 
investigator to report 
the event REQUIRED.
 
Assessment of safety 
blood sample by local 
laboratory 
REQUIRED. 
 
Referral to 
dermatologist 
REQUIRED 
(preferably within 24 
hours after onset 
of rash). 
 
Biopsy REQUIRED 
for grade 4 rash 
(as soon as possible 
after onset of rash). 
Biopsy at the 
dermatologist’s 
discretion for grade 3 
rash. 
Day 1 
 
 
 
Follow-up visit (on-
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
136 
Approved, Date: 27 July 2017  
 
Grade 1 Rash 
Grade 2 Rash 
Grade 3 or 4 Rash 
site) REQUIRED. 
 
Assessment of safety 
blood sample by local 
laboratory 
REQUIRED. 
Further 
Visits 
 
Appropriate unscheduled 
Follow-up Visits at the 
investigator’s discretion 
until resolution of rash.b 
 
At these visits, safety 
blood samples can be 
taken at the investigator's 
discretion. 
 
Appropriate 
unscheduled Follow-up 
Visits at the 
investigator’s discretion 
until resolution of rash.b 
 
At these visits, safety 
blood samples must be 
taken. 
 
Appropriate follow-up 
REQUIRED until 
resolution of rash or 
until clinical stability is 
reached. 
a 
Note that Day 0 of the rash is the first day of Investigator assessment and not the first day of rash as reported by 
the subject. 
b 
In case rash progresses from a grade 1 or a Grade 2 to a higher grade, start follow-up schedule for Grade 2, 3, or 
4 rash as appropriate. 
NCT02993250


AL-335, odalasvir, TMC435  (simeprevir)  
 
 
Clinical Protocol 64294178HPC2003 Amendment 5 
137 
Approved, Date: 27 July 2017  
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality. 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date:
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
Ei Fujikawa 
Institution: 
Janssen Pharmaceutical K.K. 
Signature: 
electronic signature appended at the end of the protocol 
Date:
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
NCT02993250

SAP_000.pdf: 
1 
Approved, Date: 8 June 2018  
Janssen Pharmaceutical K.K. * 
 
 
Statistical Analysis Plan for Primary Analysis, and Final Analysis 
 
A Phase 2a, Multicenter, Open-label Study to Investigate the Safety, Pharmacokinetics, 
and Efficacy of Combination Treatment of AL-335, Odalasvir, and Simeprevir in Japanese 
Subjects With Chronic Hepatitis C Genotype 1 or 2 Virus Infection, With or Without 
Compensated Cirrhosis who are Direct-acting Antiviral Treatment-naïve 
 
Protocol 64294178HPC2003; Phase 2a 
 
AL-335, Odalasvir, TMC435(simeprevir) 
 
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used 
throughout the protocol to represent Janssen Pharmaceutical K.K. 
 
 
Status: 
Approved 
Date: 
8 June 2018 
Prepared by: 
Janssen Pharmaceutical K.K. 
Document No.: EDMS-ERI-164033457 
 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP).  
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 
NCT02993250


AL-335, Odalasvir, TMC435(simeprevir)   
 
 
 
Statistical Analysis Plan 64294178HPC2003  
2 
Approved, Date: 8 June 2018  
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
ABBREVIATIONS ........................................................................................................................................ 4 
1. 
INTRODUCTION .................................................................................................................................. 5 
1.1. 
Trial Objectives ................................................................................................................................ 5 
1.2. 
Trial Design ...................................................................................................................................... 6 
1.2.1. 
Endpoints ...................................................................................................................................... 6 
1.3. 
Statistical Hypotheses for Trial Objectives ....................................................................................... 7 
1.4. 
Sample Size Justification ................................................................................................................. 7 
1.5. 
Randomization and Blinding ............................................................................................................ 7 
2. 
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 7 
2.1. 
Visit Windows and Phase Definition ................................................................................................ 7 
2.2. 
Pooling Algorithm for Analysis Centers .......................................................................................... 10 
2.3. 
Analysis Sets .................................................................................................................................. 10 
2.4. 
Definition of Subgroups .................................................................................................................. 10 
3. 
SUBJECT INFORMATION ................................................................................................................ 10 
3.1. 
Demographics and Baseline Characteristics ................................................................................. 10 
3.2. 
Disposition Information ................................................................................................................... 11 
3.3. 
Treatment Adherence .................................................................................................................... 12 
3.4. 
Extent of Exposure ......................................................................................................................... 12 
3.5. 
Protocol Deviations ........................................................................................................................ 12 
3.6. 
Prior and Concomitant Medications ............................................................................................... 12 
3.7. 
Medical History ............................................................................................................................... 13 
4. 
EFFICACY ......................................................................................................................................... 13 
4.1. 
Level of Significance ...................................................................................................................... 13 
4.2. 
Data Handling Rules ...................................................................................................................... 13 
4.3. 
Efficacy Endpoints .......................................................................................................................... 13 
4.3.1. 
Definitions ................................................................................................................................... 14 
4.3.2. 
Analysis Methods ........................................................................................................................ 17 
4.3.3. 
Treatment Stopping Rules .......................................................................................................... 18 
5. 
VIROLOGY ........................................................................................................................................ 19 
5.1. 
Virology Assessments .................................................................................................................... 19 
5.1.1. 
Viral strain typing ........................................................................................................................ 19 
5.1.2. 
Viral sequencing ......................................................................................................................... 19 
5.2. 
Virology Definitions ........................................................................................................................ 19 
5.3. 
Virology Time Points and Samples ................................................................................................ 20 
5.4. 
Virology Analyses ........................................................................................................................... 20 
5.4.1. 
HCV geno/subtype analyses ...................................................................................................... 20 
5.4.2. 
Resistance analyses ................................................................................................................... 21 
5.4.2.1. 
Baseline ................................................................................................................................... 21 
5.4.2.2. 
Post-Baseline ........................................................................................................................... 21 
5.4.2.3. 
Over the Study Period ............................................................................................................. 21 
6. 
SAFETY ............................................................................................................................................. 21 
6.1. 
Adverse Events .............................................................................................................................. 21 
6.1.1. 
Definitions ................................................................................................................................... 21 
6.1.2. 
Analysis Methods ........................................................................................................................ 22 
6.2. 
Clinical Laboratory Tests................................................................................................................ 23 
6.2.1. 
Definitions ................................................................................................................................... 24 
6.2.2. 
Analysis Methods ........................................................................................................................ 24 
6.3. 
Vital Signs and Physical Examination Findings ............................................................................. 25 
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6.3.1. 
Definitions ................................................................................................................................... 25 
6.3.2. 
Analysis Methods ........................................................................................................................ 25 
6.4. 
Electrocardiogram .......................................................................................................................... 26 
6.4.1. 
Definitions ................................................................................................................................... 26 
6.4.2. 
Analysis Methods ........................................................................................................................ 27 
6.5. 
Echocardiography .......................................................................................................................... 28 
6.5.1. 
Definitions ................................................................................................................................... 28 
6.5.2. 
Analysis Methods ........................................................................................................................ 28 
6.6. 
Patient Profiles ............................................................................................................................... 29 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 29 
7.1. 
Pharmacokinetics ........................................................................................................................... 29 
7.2. 
Immune Response ......................................................................................................................... 29 
7.3. 
Pharmacodynamics ........................................................................................................................ 29 
7.4. 
Pharmacokinetic/Pharmacodynamic Relationships ....................................................................... 29 
ATTACHMENTS ......................................................................................................................................... 30 
APPENDIX 1: PHASE ALLOCATION/COMBINING AES ......................................................................... 30 
APPENDIX 2A: SEARCH TERMS FOR EVENTS OF SPECIAL/CLINICAL INTEREST ......................... 32 
APPENDIX 2B: RASH – SMQ19.1 ............................................................................................................ 33 
APPENDIX 3: CARDIAC EVENTS - SMQ19.1 .......................................................................................... 34 
 
 
 
NCT02993250


AL-335, Odalasvir, TMC435(simeprevir)   
 
 
 
Statistical Analysis Plan 64294178HPC2003  
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ABBREVIATIONS 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
BMI 
Body Mass Index 
CFB 
Change from Baseline 
CTP 
Clinical Trial Protocol 
DAA 
Direct-Acting Antivirals 
DRC 
Data Review Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram / Echocardiography 
eCRF 
Electronic Case Report Form 
EOT 
End Of Treatment 
HCV 
Hepatitis C Virus 
IA 
Interim Analysis 
ITT 
Intent-To-Treat 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
NAP 
Not Applicable 
ODV 
Odalasvir 
PT 
Preferred Term 
QD 
Quaque Die, Once Daily 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI 
Standard International 
SMV 
Simeprevir 
SOC 
System Organ Class 
WHO 
World Health Organization  
 
 
 
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AL-335, Odalasvir, TMC435(simeprevir)   
 
 
 
Statistical Analysis Plan 64294178HPC2003  
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Approved, Date: 8 June 2018  
1. 
INTRODUCTION 
This 64294178HPC2003 Statistical Analysis Plan (SAP) covers Cut-Off Analysis, Primary 
Analysis and Final Analysis. It contains definitions of analysis sets, derived variables and 
statistical methods for the analysis. Separate document for DPS is also provided. A separate SAP 
was written for the Data Review Committee (DRC) analyses. 
Please refer to the study protocol for the background for the study. 
1.1. 
Trial Objectives 
Primary Objectives 
 
To evaluate the safety and tolerability of a combination treatment of AL-335, ODV, and 
SMV for 8 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 chronic HCV 
infection without cirrhosis and for 12 weeks in DAA-naïve Japanese subjects with genotype 
1 or 2 chronic HCV infection with compensated cirrhosis. 
Secondary Objectives  
 
To evaluate the PK of AL-335 (and metabolites), ODV, and SMV in plasma in Japanese 
subjects with genotype 1 or 2 chronic HCV infection with or without compensated cirrhosis 
who are DAA-naïve. 
 
To evaluate the efficacy, ie, SVR4, SVR12, and SVR24, of a combination treatment with 
AL-335, ODV, and SMV for 8 weeks in DAA-naïve Japanese subjects with genotype 1 or 2 
chronic HCV infection without cirrhosis and for 12 weeks in DAA-naïve Japanese subjects 
with genotype 1 or 2 chronic HCV infection with compensated cirrhosis. 
 
To evaluate on-treatment viral kinetics in an 8 or 12-week treatment regimen containing AL-
335, ODV, and SMV in subjects who are DAA- naïve. 
 
To evaluate the incidence of on-treatment failure during an 8 or 12-week treatment regimen 
containing AL-335, ODV, and SMV in subjects who are DAA-naïve. 
 
To evaluate the incidence of viral relapse after an 8 or 12-week treatment regimen 
containing AL-335, ODV, and SMV in subjects who are DAA-naïve. 
Exploratory Objectives  
 
To explore relationships of exposure of AL-335 (and metabolites), ODV, and SMV with 
SVR and safety.   
 
To evaluate the impact of the patient and disease characteristics at baseline on SVR, 
including but not limited to prior treatment history, IL28B genotype, presence of cirrhosis, 
HCV RNA level, and HCV geno/subtype. 
 
To evaluate the impact of the presence of HCV NS3/4A, NS5A, and/or NS5B 
polymorphisms at baseline on treatment outcome. 
 
To assess the emergence of resistant variants in subjects not achieving SVR. 
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1.2. 
Trial Design 
This is a Phase 2a, multicenter, open-label study. It consists of a 6-week Screening Period, 
followed by the 8-week or 12-week Treatment Period, and the 24-week Posttreatment Follow-up 
Period.  
Approximately 20 DAA-naïve chronic HCV genotype 1 or 2-infected subjects without cirrhosis 
will be assigned to Cohort 1, and approximately 20 DAA-naïve chronic HCV genotype 1 or 2-
infected subjects with compensated cirrhosis will be assigned to Cohort 2.  
 
Cohort 1 (N=20, chronic hepatitis C without cirrhosis): 
AL-335 800 mg once daily + ODV 25 mg once daily + SMV 75 mg once daily for 8 weeks 
 
Cohort 2 (N=20, chronic hepatitis C with compensated cirrhosis): 
AL-335 800 mg once daily + ODV 25 mg once daily + SMV 75 mg once daily for 12 weeks 
To conduct this study carefully in light of securing subjects’ safety, after 6 subjects in Cohort 1 
completed the Week 4 visit, DRC will review all available relevant safety data to make a 
decision about start of dosing in Cohort 2.  
Further trial design details are available in the protocol.  
1.2.1. 
Endpoints 
Primary Endpoint 
Safety data, including but not limited to adverse events (AEs), 12-lead electrocardiograms 
(ECGs), echocardiograms, and clinical laboratory results (including chemistry, hematology, and 
urine). 
Secondary Endpoints 
 
PK parameters for AL-335 (and metabolites), ODV, and SMV in plasma  
 
The proportion of subjects who have an SVR4, SVR12, and SVR24 
 
The proportion of subjects with viral relapse 
 
The proportion of subjects with on-treatment failure 
 
The proportion of subjects with on-treatment virologic response: 
 
HCV RNA not detected 
 
HCV RNA <LLOQ 
 
Time to achieve HCV RNA not detected or HCV RNA <LLOQ 
Exploratory Endpoints 
 
The effect of the presence or absence at baseline of HCV NS5A, NS5B, and/or NS3/4A 
polymorphisms on treatment outcome 
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Statistical Analysis Plan 64294178HPC2003  
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 
The changes in the HCV NS3/4A, NS5A and/or NS5B sequences in subjects not achieving 
SVR 
 
Impact of baseline condition on SVR (including but not limited to prior treatment history, 
IL28B genotype, presence of cirrhosis, HCV RNA level, and HCV geno/subtype) 
1.3. 
Statistical Hypotheses for Trial Objectives 
The study is hypothesis-generating. No formal hypothesis will be tested  
1.4. 
Sample Size Justification 
Since this is an exploratory study, no formal sample size calculation has been performed. 
With a total sample size of 40 subjects, the probability to observe an AE with an incidence of 
10.0% is 99.0%. The probability to observe an AE with an incidence of 1.0%, 2.5%, and 5.0% is 
33.0%, 64.0%, and 87.0%, respectively. With 20 subjects per cohort, the probability to observe 
an AE with an incidence of 10.0% is 88.0%. The probability to observe an AE with an incidence 
of 1.0%, 2.5%, and 5.0% is 18.0%, 40.0%, and 64.0%, respectively in a cohort. 
With an expected SVR rate of 90.0%, and 40 subjects in 2 cohorts combined, the corresponding 
95%, 2-sided confidence interval (CI) is 76.3% to 97.2%. With 95.0% SVR, the corresponding 
95% CI ranges from 83.1% to 99.4%. With an expected SVR rate of 90.0%, and 20 subjects per 
cohort, the corresponding 95%, 2-sided CI is 68.3% to 98.8%. With 95.0% SVR, the 
corresponding 95% CI ranges from 75.1% to 99.9% in a cohort. 
Therefore, a total sample size of approximately 40 subjects is considered sufficient to explore the 
safety and efficacy of the combination regimen consisting of AL-335, ODV, and SMV in this 
study from a clinical point of view. 
1.5. 
Randomization and Blinding 
Randomization and Blinding will not be used as this is an open-label study. Subjects will be 
assigned to a treatment cohort based on the presence or absence of cirrhosis. 
2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Visit Windows and Phase Definition 
Phases will be constructed as indicated in Table 1 and Table 2. 
Table 1: 
Phase Definition Part 1 
Cohort 
W-6 
D1 
D2 
D3 
W1 
W2
W3
W4
W6
W8
- 
- 
W4
FU
W8 
FU 
W12 
FU 
W18
FU
W24
FU
Cohort 1 
Scr. 
AL-335 + ODV + SMV 8 weeks 
- 
- 
Follow up 
Weeks 
W-6 
D1 
D2 
D3 
W1 
W2
W3
W4
W6
W8
W10
W12
W4
FU
W8 
FU 
W12 
FU 
W18
FU
W24
FU
Cohort 2 
Scr. 
AL-335 + ODV + SMV 12 weeks 
Follow up 
 
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Statistical Analysis Plan 64294178HPC2003  
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Table 2: 
Phase Definition Part 2 
Trial phase 
Start date 
End date 
Screening 
(phase 0) 
Minimum of Date of signing the informed 
consent and Date of the first screening visit 
1 day before first study drug administration 
Treatment 
(phase 1) 
Date of first study drug administration 
Date of last study drug intake + 3 days 
Follow-up 
(phase 2) 
Phase 1 end date +1 day 
Trial termination date (date of last contact) 
 
Date of First Study Drug Administration:  In the above computations, missing data for first study 
drug intake may be imputed as the date of baseline visit. 
Date of Last Study Drug Administration:  In the above computations, missing data for last study 
drug intake may be imputed for cut-off analysis and subjects discontinued as follows:  
1. Cut-off analyses:  Date of Last Study Drug Intake = Min (Data cutoff date, Date of baseline 
visit + 8 or 12 weeks depending on cohort). 
2. Date of Last Study Drug Intake =  
a. 
Date of the early treatment withdrawal visit, if nonmissing otherwise 
b. Date of 1st available Follow-up visit – 28, if nonmissing otherwise 
c. 
Date of last contact. 
Reference date is defined as: 
 
Screening and Treatment Phases:  Reference date = Date of first study drug intake (if 
nonmissing), otherwise date of baseline visit. 
 
Follow-up Phase:  Reference date = Start Date of follow-up phase. 
The number of days in the phase (Relative day) is defined as: 
 
Visits on or after the reference date:  Relative day = visit date – reference date+1    
 
Visits before the reference date:        Relative day = visit date – reference date 
 
Actual EOT visit is defined as the last visit in the Treatment phase. 
All visits (regardless of the investigated parameter) will be allocated to analysis time points 
based on the number of days in phase (relative day) as indicated in Table 3. 
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Statistical Analysis Plan 64294178HPC2003  
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Table 3: 
Visit Windows 
Trial phase 
Target day 
Analysis time point 
(numeric version) 
Analysis time point 
Time interval 
(Relative day) 
Cohort 1 
Screening 
phase 
+ ∞ 
-1 
Screening 
<0 
Treatment 
phase 
1 
0 
Baselinea 
<=1 
2 
0.2 
Day 2 
[2,2] 
3 
0.3 
Day 3 
[3,5] 
7 
1 
Week 1 
[6,11] 
14 
2 
Week 2 
[12,18] 
21 
3 
Week 3 
[19,25] 
28 
4 
Week 4 
[26,35] 
42 
6 
Week 6 
[36,49] 
56 
8 
Week 8 
[50, + ∞] 
last visit while on 
study therapy or within 
3 days after the day of 
last dose 
999 
EOT 
 
Follow-up 
phase 
25 
16 
Follow-Up Week 4 
[1,39] 
53 
20 
Follow-Up Week 8 
[40,67] 
81 
24 
Follow-Up Week 12 
[68,102] 
123 
30 
Follow-Up Week 18 
[103,144] 
165 
36 
Follow-Up Week 24 
[145, + ∞] 
Cohort 2 
Screening 
phase 
-∞ 
-1 
Screening 
<0 
Treatment 
phase 
1 
0 
Baselinea 
<=1 
2 
0.2 
Day 2 
[2,2] 
3 
0.3 
Day 3 
[3,5] 
7 
1 
Week 1 
[6,11] 
14 
2 
Week 2 
[12,18] 
21 
3 
Week 3 
[19,25] 
28 
4 
Week 4 
[26,35] 
42 
6 
Week 6 
[36,49] 
56 
8 
Week 8 
[50,63] 
70 
10 
Week 10 
[64,77] 
84 
12 
Week 12 
[78, + ∞] 
last visit while on 
study therapy or within 
3 days after the day of 
last dose 
999 
EOT 
 
Follow-up 
phase 
25 
16 
Follow-Up Week 4 
[1,39] 
53 
20 
Follow-Up Week 8 
[40,67] 
81 
24 
Follow-Up Week 12 
[68,102] 
123 
30 
Follow-Up Week 18 
[103,144] 
165 
36 
Follow-Up Week 24 
[145, + ∞] 
Note:  
Target day in follow up phase equals target day in the protocol minus 3 days due to definition of start of follow-up 
phase. 
If two visits fall within the same interval, the last measurement within the interval will be used for descriptive 
statistics/tabulations per time point and graphics in order to have only one evaluation per subject per analysis 
time point. If two measurements occur on the same day, the measurement with highest sequence number will be 
used. Listings will include all values. 
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Statistical Analysis Plan 64294178HPC2003  
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2.2. 
Pooling Algorithm for Analysis Centers 
No pooling of analysis subcenters will be performed in this study. 
2.3. 
Analysis Sets 
Safety Analysis Set: All enrolled subjects who received at least 1 dose of study drug (AL-335, 
ODV, or SMV). 
Full Analysis Set (FAS): All enrolled subjects who received at least 1 dose of study drug (AL-
335, ODV, or SMV) and have at least 1 postbaseline efficacy measurement. 
Non-VF Excluded Set: All FAS subjects excluding subjects with early treatment discontinuation 
due to nonvirologic reasons or missing data at SVR4, SVR12, or SVR24 time points. 
All analyses except for efficacy, and virology analyses will be done on safety analysis set. The 
efficacy analyses will be performed on full analysis set. Selected virology analyses will be using 
non-VF excluded set as needed. Demographic and baseline characteristics should be done on the 
safety. 
2.4. 
Definition of Subgroups 
The subgroups will be used to perform analyses on efficacy endpoints are: 
 
Age category [≤65; >65] 
 
BMI [<25; ≥25] 
 
IL28B genotype (CC, CT, TT); and also (CC, non-CC) 
 
Gender (male, female) 
 
HCV geno/subtype (1a, 1b, 1other, 1a with Q80K, 1a without Q80K, 2a, 2b, 2c, 2other) 
 
baseline HCV RNA categories (<6,000,000 IU/mL, ≥6,000,000 IU/mL) 
The subgroups will be used to perform analyses on safety endpoints are: 
 
Age category [≤65; >65] 
 
BMI [<25; ≥25] 
 
Gender (male, female) 
3. 
SUBJECT INFORMATION 
3.1. 
Demographics and Baseline Characteristics 
Descriptive statistics or tabulation will be provided, in addition to listings, for the following 
parameters: 
Demographic parameters 
 
Gender (male, female) 
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Statistical Analysis Plan 64294178HPC2003  
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 
Age at screening (years) 
 
Age at screening (years, categories: ≤45; >45 - ≤65; >65) 
 
Race (Asian) 
 
Ethnicity (Not Hispanic or Not Latino) 
 
Weight at baseline (kg) 
 
BMI at baseline = weight (at baseline, in kg)/ (height (at screening, in meters))2, rounded to 
1 decimal (although available in the raw data, BMI will be recalculated from weight and 
height) 
 
BMI at baseline (categories: <25, 25-<30, ≥30) 
Baseline disease characteristics 
 
baseline HCV RNA (original and log10 units)   
 
baseline HCV RNA categories (<6,000,000 IU/mL, ≥6,000,000 IU/mL)  
 
HCV geno/subtype 1a, 1b, 1other, 1a with Q80K, 1a without Q80K, 2a, 2b, 2c, 2other 
 
Prior IFN with or without RBV taken (Yes or No) 
 
IL28B subtype (CC, CT, TT) 
 
For subjects with Fibroscan Results:   
 
Fibroscan Metavir Fibrosis Result (kPa) 
 
Fibroscan Metavir Fibrosis stage (F0/F1, F2, F3, F4) 
 
For subjects with Biopsy Results (Each subject has either Metavir or Ishak scoring):  
 
Biopsy Metavir Fibrosis stage (F0/F1, F2, F3, F4) 
 
Metavir Inflammation grade (A0, A1, A2, A3)  
 
Biopsy Ishak Fibrosis stage (0, 1, 2, 3, 4, 5, 6) 
 
Ishak Inflammation grade (1-3, 4-8, 9-12, 13-18) 
 
Time since diagnosis (years) (= (baseline date – date of diagnosis + 1)/365.25, rounded to 1 
decimal) 
3.2. 
Disposition Information 
Tabulations will be provided for the following disposition information: 
 
Number of subjects screened, enrolled and treated 
 
Number of subjects with a visit per analysis time point 
 
Number of subjects prematurely discontinuing any single study medication and the reason 
for discontinuation (obtained from the treatment disposition page of the electronic case 
report form [eCRF]) 
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Statistical Analysis Plan 64294178HPC2003  
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 
Number of subjects prematurely discontinuing the trial and the reason for discontinuation. 
Reasons for discontinuation are obtained from the trial disposition page of the eCRF.  
3.3. 
Treatment Adherence 
For each of the three drugs (AL-335, Odalasvir, SMV), the actual amount (actual dose over 
actual treatment duration) of study drug relative to the planned cumulative total dose (planned 
dose over planned duration) will be summarized. 
For each drug, the number (%) of subjects with ≤3 and >3 consecutive days of dose interruption 
will be tabulated. The number of subjects without a dose interruption will also be tabulated. 
Summary statistics for the total number of days of dose interruption for subjects with at least one 
day of dose interruption will also be tabulated. Further, for each drug, the number (%) of subjects 
with ≤3, 4 - ≤6, and >6 cumulative days of dose interruption will be tabulated. 
3.4. 
Extent of Exposure 
Treatment duration (in weeks) is derived as follows for each of the three drugs (AL-335, 
Odalasvir, SMV): 
 
(Last date of exposure – first date of exposure + 1) / 7 
Note: treatment interruptions will not be taken into account for the above definition. 
Treatment duration and total dose received will be summarized descriptively by treatment cohort. 
Treatment duration for subjects who did not complete treatment will also be summarized 
descriptively by treatment cohort. 
3.5. 
Protocol Deviations 
All major protocol deviations will be tabulated. Additionally, all protocol deviations (major and 
minor) will be listed. Major protocol deviations that may affect the assessment of efficacy will be 
flagged in the listing. 
3.6. 
Prior and Concomitant Medications 
Prior medications will be tabulated by treatment cohort. Concomitant medications will be 
tabulated by treatment cohort and by phase. Concomitant medications are allocated to phases 
based on their start and stop date. The concomitant medications will be allocated to a phase 
during which they were applied. A concomitant medication can be allocated to more than one 
phase.  
Incomplete dates (ie, day and/or month and/or year missing): 
 
In case of a partial start date, the therapies are allocated to the phases using the available 
partial information, no imputation is done. If, for instance, for a therapy start date only 
month and year is available, these data are compared with the month and year info of the 
phases. 
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 
In case of a completely missing start date, the therapy is considered as having started before 
the trial. 
 
 In case of a completely missing end date, the therapy is considered as ongoing at the end of 
the trial. 
3.7. 
Medical History 
Frequency tabulations of medical history will be provided. A listing of medical history will also 
be provided. 
4. 
EFFICACY 
4.1. 
Level of Significance 
No significance testing will be performed in this study. However, a 95% CI will be constructed 
around the proportion of subjects with SVR and other virologic response parameters. 
4.2. 
Data Handling Rules 
Plasma HCV RNA will be determined using an in vitro nucleic acid amplification test for the 
quantification of HCV RNA in human plasma using a sensitive assay (COBAS® 
AmpliPrep/COBAS® TaqMan® HCV Test v2.0, lower limit of quantification [LLOQ] = limit of 
detection [LOD] = 15 IU/mL). HCV RNA determination will be performed at a central 
laboratory. 
Before performing continuous analyses or log transformations, HCV RNA results of ‘<LLOQ 
IU/mL HCV RNA DETECTED’ will be converted to LLOQ-1 IU/mL and ‘HCV RNA  NOT 
DETECTED’ will be converted to LOD-2 IU/mL. 
Note: We subtract 2 from the LOD to distinguish between ‘<LLOQ IU/mL HCV RNA 
DETECTED’ and ‘<HCV RNA NOT DETECTED’ in all cases, as the LLOQ could equal the 
LOD. 
For the purpose of sensitivity analysis, missing  HCV RNA  data for subjects who discontinued 
early will be imputed using Last Observation Carry Forward(LOCF).  
4.3. 
Efficacy Endpoints 
The efficacy endpoints are listed as below: 
 
The proportion of subjects who have an SVR4, SVR8, SVR12, SVR18 and SVR24; 
 
The proportion of subjects with viral relapse 
 
The proportion of subjects with on-treatment failure 
 
The proportion of subjects with on-treatment virologic response (HCV RNA Not Detected 
or HCV RNA <LLOQ) 
 
Time to achieve on-treatment virologic response (HCV RNA Not Detected or HCV RNA 
<LLOQ) 
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Statistical Analysis Plan 64294178HPC2003  
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4.3.1. 
Definitions 
SVRx is defined as follows: 
 
1=success: 
 
at the time point of SVR 
o 
HCV RNA Not Detected or 
o 
HCV RNA <LLOQ and 
 the sample is a confirmation* sample or 
 the sample is the last available HCV RNA measurement or 
 at the next available measurement, HCV RNA Not Detected or HCV RNA 
<LLOQ Detected 
o 
≥ LLOQ quantifiable and 
 the sample is not a confirmatory sample* and 
 not the last available measurement in the study and 
 a next measurement is available and HCV RNA Not Detected or HCV RNA 
<LLOQ for this next measurement 
 
0= failure: otherwise 
* Confirmed means that the criterion should be fulfilled at 2 or more consecutive time points or 
at the last observed time point. 
Add ‘The LLOQ for the HCV RNA COBAS® AmpliPrep/COBAS® TaqMan® Test v2.0, used 
in this study, is 15 IU/mL.’ as a footnote. 
Time point of SVR24 is defined as: 
 
24 weeks after the actual EOT (Select the measurement in the SVR24 analysis window. If 
>1 measurements are present in this window then select the one latest in time.) 
 
or, if not available, the first available measurement at least 24 weeks after the actual EOT (ie, 
the first available measurement after the SVR24 analysis window) 
 
or, if not available, the last measurement available in the SVR18 analysis window, on 
condition that the time point of SVR24 has been reached 
 
or, if not available, the last measurement available in the SVR12 analysis window, on 
condition that the time point of SVR24 has been reached 
 
or, if not available, the subject is considered to have not achieved SVR24.  
Time point of SVR18 is defined as: 
 
18 weeks after the actual EOT (Select the measurement in the SVR18 analysis window. If 
>1 measurements are present in this window then select the one latest in time.) 
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 
or, if not available, the first available measurement at least 18 weeks after the actual EOT (ie, 
the first available measurement after the SVR18 analysis window) 
 
or, if not available, the last measurement available in the SVR12 analysis window, on 
condition that the time point of SVR18 has been reached 
 
or, if not available, the subject is considered to have not achieved SVR18.  
Time point of SVR12 is defined as: 
 
12 weeks after the actual EOT (Select the measurement in the SVR12 analysis window. If 
>1 measurements are present in this window then select the one latest in time.) 
 
or, if not available, the first available measurement at least 12 weeks after the actual EOT (ie, 
the first available measurement after the SVR12 analysis window) 
 
or, if not available (ie, no measurement at least 12 weeks after the actual EOT), the subject 
is considered a failure.  
Time point SVR4 and time point SVR8 are defined similarly as time point SVR12 as above. 
Evaluated in the treatment phase: 
On-Treatment Virologic Response is defined as follows: 
 
0 = HCV RNA result not satisfying a specified threshold 
 
1 = HCV RNA result satisfying a specified threshold 
The following thresholds will be considered at any time point during treatment: 
 
HCV RNA Not Detected 
 
HCV RNA <lower limit of quantification (LLOQ) (detected or not detected)  
Note: virologic response will always be calculated as on-treatment response; therefore, the 
denominator will only include those subjects with valid on-treatment HCV RNA per analysis 
time point. 
Other definitions of virologic response: 
vRVR (Very Rapid Virologic Response): HCV RNA Not Detected at Week 2 of treatment (the 
denominator for the proportion of subjects with vRVR will be the number of subjects who have a 
nonmissing Week 2 measurement while on therapy (or within 3 days of the date of last dose)) 
RVR (Rapid Virologic Response): HCV RNA Not Detected at Week 4 of treatment (the 
denominator for the proportion of subjects with RVR will be the number of subjects who have a 
nonmissing Week 4 measurement while on therapy (or within 3 days of the date of last dose)) 
Time to On-treatment Virologic Response is defined as:  The number of days since the first day 
of medication intake until the first day that the threshold (HCV RNA Not Detected or HCV RNA 
<LLOQ) was achieved. 
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On-treatment Failure is defined as: Subjects who do not achieve SVR12, with confirmed HCV 
RNA ≥LLOQ at the actual EOT. Includes subjects with: 
 
viral breakthrough, defined as a confirmed* increase of >1.0 log10 IU/mL in HCV RNA 
from nadir, or confirmed HCV RNA >2.0 log10 IU/mL in subjects whose HCV RNA had 
previously been <LLOQ while on treatment. 
 
other with confirmed HCV RNA ≥LLOQ at the actual EOT (eg, completed study drug 
treatment, discontinued due to AEs, withdrawal of consent). 
*Confirmed means that the criterion should be fulfilled at 2 or more consecutive time points or at 
the last observed time point. 
The proportion of subjects with a viral breakthrough is defined as follows: 
 
0 = subject has not had a viral breakthrough (see definition above) up to the considered time 
point 
 
1 = subject has a viral breakthrough at the considered timepoint or has had a viral 
breakthrough before (regardless of the HCV RNA result at the considered time point) 
Evaluated in the treatment and follow-up phases: 
Failure: subjects not achieving SVR12 including: 
 
In the treatment phase: On-treatment failure (see above) 
 
In the follow-up phase: Posttreatment failure, includes subjects with: 
 
Viral relapse after completed treatment 
 
Viral relapse after premature discontinuation of treatment 
 
Missing HCV RNA at timepoint of SVR12. 
Type of failure: if more than 1 type of failure occurs, the order as presented below should be 
respected:  
1. Viral Relapse 
2. Viral breakthrough  
3. Confirmed HCV RNA ≥LLOQ at EOT 
4. Missing at timepoint of SVR12 
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Evaluated in the follow-up phase: 
Viral relapse is defined as follows: 
1 = viral relapse 
o 
Subject is not achieving SVR12 (see above)  
and 
o 
Subject is not an on-treatment failure (see above)  
and 
o 
 Post treatment HCV RNA measurement fulfill one of the following conditions: 
o 
at least 2 consecutive measurements are ≥ LLOQ IU/mL quantifiable  
or 
o 
the last available measurement is ≥ LLOQ IU/mL quantifiable 
0 = no viral relapse: at least one posttreatment measurement available and not a viral relapse 
2 = no posttreatment HCV RNA measurements available 
Note: viral relapse will only be assessed for those subjects with no on-treatment failure. The 
denominator will only include those subjects with values 0 and 1. 
Late Viral relapse is defined as follows: 
1 = late viral relapse 
o 
Subject is achieving SVR12 (see above)  
and 
o 
 Post treatment HCV RNA measurement beyond the SVR12 time point fulfill one 
the following conditions: 
 at least 2 consecutive measurements are ≥ LLOQ IU/mL quantifiable  
or 
o 
the last available measurement is ≥ LLOQ IU/mL quantifiable 
0 = no late viral relapse: at least one measurement after the time point of SVR12 available 
and not a late viral relapse. 
2 =no measurement after time point of SVR12 available. 
Note: late viral relapse will only be assessed for those subjects with no on-treatment failure and 
no viral relapse. The denominator will only include those subjects with values 0 and 1. 
4.3.2. 
Analysis Methods 
All efficacy analyses will be using the full analysis set by cohort.  
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Descriptive statistics (n, mean (SD), median, interquartile ranges and ranges) per time point by 
treatment cohort for the continuous parameters (actual values and change from baseline in log10 
for HCV RNA). Corresponding listings will be presented. Mean (SD) plots will be produced for 
actual values and change from baseline in log10 for HCV RNA by treatment cohort. 
Tabulations (numbers, proportions and 95% CI) per cohort and time point for SVR4, SVR8, 
SVR12, SVR18 and SVR24 will be provided. The sensitivity analysis with LOCF applied to 
missing HCV RNA data will also be performed. The number and proportion of subjects with on-
treatment failure and on-treatment virologic response will be tabulated by cohort and overall. 
Corresponding listings will be presented.  
For time to on-treatment virologic response, descriptive statistics (n, mean (SD), median, 
interquartile ranges and ranges) by treatment cohort will be tabulated.  
Subgroup analyses as defined in Section 2.4 will be performed for the selected endpoints. 
In addition, the reason for failure will be explored by type of failure (see definition of failure 
above). If more than one type of failure occurs, the order as presented below should be respected: 
1. viral relapse 
2. viral breakthrough 
3. confirmed HCV RNA ≥LLOQ at the actual EOT 
4. missing at time point of SVR12  
4.3.3. 
Treatment Stopping Rules 
All study drugs will be discontinued for any subject with viral breakthrough (see the definition in 
Section 4.3.1). Additionally, an individual subject may stop one or all study drugs if a specific 
toxicity is met (see Section 6.4 of the protocol for full details). 
The occurrence of any one of the following treatment-emergent events in any ongoing study 
using ODV at therapeutic doses: 
 
2nd degree Mobitz Type 2 or 3rd degree heart block; 
 
drop in EF by ≥10 points with absolute EF <50%; 
 
a cardiac event that is serious, severe or life-threatening; 
will lead to stop of recruitment and dosing in all subjects in the current study if adjudicated by 
the DRC to be at least possibly related to the study regimen. Such event(s) will be reported to the 
sponsor medical monitor within 24 hours. Upon this notification, a safety assessment of the event 
by the DRC will take place within 48 hours and the outcome of the assessment and its associated 
action towards the study will be reported to Health Authorities and Ethics Committees in 
compliance with safety reporting regulations, as applicable. 
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5. 
VIROLOGY 
5.1. 
Virology Assessments 
5.1.1. 
Viral strain typing 
The HCV geno/subtype is determined at screening for study eligibility/stratification using the 
HCV LiPA v2.0 test and in case no result is obtained the NS5B-based test is used as reflex. In 
addition, the HCV geno/subtype is determined at baseline for efficacy and virology analyses 
using the NS5B-based test. In case no result at baseline is obtained, the screening results are used 
for efficacy and virology analyses. 
5.1.2. 
Viral sequencing 
The HCV NS3/4A, NS5A and NS5B regions are sequenced using Next Generation Sequencing 
(1% read frequency cut-off) in all subjects at baseline and postbaseline in subjects not achieving 
SVR, focusing on the time of virologic failure and the end of study. 
5.2. 
Virology Definitions 
Baseline polymorphisms are defined as amino acid differences from a HCV reference strain 
with a read frequency ≥15%. The reference strains used for the genotypes included in the study 
are shown in Table 4. 
Table 4: 
Reference Strain for Genotypes 
Genotype 
Reference Strain 
(GenBank Accession ID) 
1a 
H77 (NC_004102) 
1b 
Con1 (AJ238799) 
Other genotype 1 subtypes or subtype unknown 
H77 (NC_004102) 
2 
JFH-1 (AB047639) 
 
Treatment-emergent substitutions are defined as amino acids detected postbaseline ≥15% and 
not detected (ie, <1%) at baseline. 
Treatment-enriched substitutions are amino acids detected at baseline with a read frequency 
≥1% and <15%, and with an increase in read frequency of at least 15% postbaseline. 
Return to Baseline is defined as a treatment-emergent substitution which is no longer detected 
(ie <1%) at end of study, but instead the baseline amino acid is observed. 
Resistance-associated substitutions (RASs) are amino acids present at baseline or postbaseline 
at the positions of interest (see below) in the sequenced regions which are known to confer 
resistance to one of the drugs. Of note, not all amino acids at the positions of interest are RASs. 
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HCV NS3 positions of interest: 
 
List of 18 positions associated with resistance to NS3/4A protease inhibitors: 36, 41, 43, 54, 
55, 80, 107, 122, 132, 138, 155, 156, 158, 168, 169, 170, 174 and 175 
 
List of 8 positions associated with resistance to SMV: 43, 80, 122, 132, 155, 156, 168 and 
170 
HCV NS5A positions of interest: 
 
List of 18 positions associated with resistance to NS5A inhibitors: 6, 21, 23, 24, 28, 29, 30, 
31, 32, 37, 38, 52, 54, 58, 62, 64, 92, and 93 
 
List of 8 position associated with resistance to ODV: 28, 29, 30, 31, 32, 58, 92, and 93 
HCV NS5B positions of interest: 
 
List of 9 positions associated with resistance to nucleotide analog NS5B polymerase 
inhibitors: 96, 142, 159, 223, 226, 282, 316, 320, and 321 
Virologic Failure (VF): subjects not achieving SVR12 for virologic reasons, including on-
treatment failure, ie, viral breakthrough (VBT) or confirmed HCV RNA ≥LLOQ at end of 
treatment (EOT) for subjects who completed treatment, and viral relapse. 
Non-VF excluded population: FAS population excluding the subjects who did not achieve 
SVR12 due to reasons other than VF, including subjects with missing data at the SVR12 time 
point and subjects who discontinued all treatment prematurely (eg AE or withdrawal of consent). 
5.3. 
Virology Time Points and Samples 
Baseline: the sample taken at baseline or, if not available, the sample taken at screening is used. 
Time of (virologic) failure: the sample taken at virologic failure (ie at VBT, at actual EOT for 
subjects with confirmed HCV RNA ≥LLOQ at EOT or at relapse) with sequencing data available 
or, if not available, the first available sample after virologic failure with sequencing data 
available is used. 
End of Study (EOS): the last available sample with sequencing data available in the study is 
used. 
5.4. 
Virology Analyses 
5.4.1. 
HCV geno/subtype analyses 
The number of subjects by HCV geno/subtype for study analyses will be tabulated in frequency 
outputs (n, %). In addition, a cross-tabulation will compare the HCV geno/subtypes determined 
at screening (LiPA with NS5B-based reflex) versus baseline (NS5B-based test). 
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5.4.2. 
Resistance analyses 
5.4.2.1. 
Baseline 
The prevalence of baseline polymorphisms, ie the number of subjects with baseline 
polymorphism, will be tabulated in frequency outputs (n, %) and the amino acid changes from 
reference at baseline will be listed for all subjects using a 1% cut-off. In addition, subgroup 
analyses by the presence of baseline polymorphisms may be tabulated to evaluate the impact on 
response as needed. 
5.4.2.2. 
Post-Baseline 
Time of Failure 
For subjects with failure, the incidence of treatment-emergent and treatment-enriched 
substitutions will be tabulated (if N ≥10) in frequency outputs (n, %) and the amino acid changes 
from reference will be listed for all subjects with postbaseline sequencing data using a 1% cut-
off. 
End of Study 
The return to baseline at end of study for the subjects with failure and treatment-emergent 
substitutions at time of failure will be tabulated (if N≥10) in frequency outputs (n, %) as well as 
the treatment-emergent substitutions at end of study in the subjects who did not return to baseline.  
5.4.2.3. 
Over the Study Period 
For the subjects with failure HCV RNA profiles and listings include the reason of failure, 
relevant baseline disease and demographic characteristics, all amino acid changes from reference 
at baseline, time of failure and end of study using a 1% cut-off as well as the sequencing follow-
up time will be generated. Similar HCV RNA profiles and listings will be generated for subjects 
with a late viral relapse.  
Kaplan-Meier graphs and descriptive statistics will be calculated (if N≥5) to evaluate the time to 
return to baseline sequence in subjects with failure and treatment-emergent substitutions at time 
of failure. 
6. 
SAFETY 
Unless specified, all safety analysis will use safety analysis set.  
6.1. 
Adverse Events 
All reported adverse events (AEs) that are onset during the treatment or follow up phases will be 
included in the analysis. The verbatim terms used in the eCRF by investigators to identify AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
6.1.1. 
Definitions 
AEs are allocated to the study phases. The phase allocation of AEs consists of a combination of 
two steps:  
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 
AEs are allocated to phases 
 
Overlapping/consecutive AEs are combined.  
This is detailed in Appendix 1. 
Treatment-emergent Adverse Events (TEAEs) are AEs that start on or after the first dose or 
that are a consequence of a preexisting condition that has worsened since baseline. 
AE Duration is calculated as: AE End date – AE Start date + 1. 
Prevalence: is defined as the total number of events that occurred (not necessarily new 
occurrence) in a given time period. The denominator for calculating prevalence and comparable 
incidence (new occurrences during the same time period) rates will be based on the number of 
subjects still on treatment at the start of the time period. Note that prevalence counts any AEs 
regardless whether they are new or sustained from onset prior to the start of the current time 
interval while comparable incidence refers to new AEs only reported in the current time interval. 
Events of Special Interest:  
 
Cardiac Events 
 
Increased Bilirubin 
Events of Clinical Interest:  
 
Rash (all type) 
 
Photosensitivity conditions 
 
Pruritus 
Note: the search terms for events of special/clinical interest related to MedDRA and MedDRA 
SMQ are listed in Appendix 2. 
6.1.2. 
Analysis Methods 
For Adverse Events: 
An overall summary will be provided for all adverse events by treatment cohort for each 
treatment phase separately (Screening phase, treatment phase, follow-up phase and treatment and 
follow-up phases). Any AEs, serious AEs, AEs with fatal outcome, AEs by WHO toxicity, 
treatment related AEs, AEs leading to permanent stop of study medication and relation to HCV 
infection. 
The incidence and the incidence rate of treatment-emergent AEs by system organ class (SOC) 
and preferred term (PT) will be tabulated for each treatment phase separately (Screening phase, 
treatment phase, follow-up phase and treatment and follow-up phases). TEAEs in at least 10% of 
subjects will be tabulated separately,  
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The incidence and incidence rate of AEs with WHO toxicity grade 3 or 4, SAEs, at least possibly 
treatment related (AL-335, ODV, and SMV) AEs, AE with fatal outcome and AEs leading to 
permanent stop of study medication will be tabulated by system organ class (SOC) and preferred 
term (PT).  
The incidence and comparable prevalence rate per 2-week time interval for any AEs will be 
tabulated to evaluate the safety profile over time (treatment and follow-up phase). 
Treatment-emergent AEs will be tabulated by SOC and PT for subgroups: Age and BMI (refer to 
Section 2.4) 
A table will be provided for subjects who met study stopping rules, such as 2nd degree Mobitz 
Type 2 or 3rd degree heart block, cardiac event that is serious, severe or life-threatening. Drop in 
LVEF for Echocardiographic(ECHO) by ≥10 points with absolute LVEF <50% will be presented 
too. 
Listings will be provided for: all AEs, serious AEs, fatal AEs, AEs leading to permanent stop of 
AL-335, AEs leading to permanent stop of ODV, AEs leading to permanent stop of SMV 
andgrade 3-4 AEs. Also AE listing will be provided for the events which meet study stopping 
rules. AEs which occur in screening will also be included in the listings. 
For events of interest:  
A summary table will be provided for subject incidence with events of interest in treatment and 
follow-up phases.  
The incidence rates of the events of interest by WHO toxicity grades, treatment relationship, with 
fatal outcome, as an SAE, leading to permanent stop of study medications will be generated in a 
summary table using frequency and percentage. 
 The incidence rates will be summarized by PT for each event of interest, and it will be 
summarized for AEs with worst toxicity grade of 3 or 4 separately as well. 
The incidence and prevalence per 2-week time interval will be summarized. 
Subgroup analysis by Age, BMI and Gender (refer to Section 2.4) will be conducted for each 
event of interest by PT.  
6.2. 
Clinical Laboratory Tests 
Clinical lab data are collected at the screening, baseline, week 1, week 2, week 4, week 6 (BNP 
only), week 8 (cohort 1), week 10 (cohort 2), EOT, follow up week 4, follow up week 8, follow 
up week 12, follow up week 18, and follow up week 24 time points.  
Baseline: Defined as Day 1 measurement, if available. If not available, then the last assessment 
before the first administration of study drug will be used. 
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6.2.1. 
Definitions 
World Health Organization (WHO) Toxicity grades:  
Grades assigned by the central lab will be used. In case no toxicity grades are defined for a test, 
the abnormalities (above/below normal range) will be used.  The abnormalities ‘abnormally low’ 
and ‘abnormally high’ are considered equally important, ie, if a subject has as well an 
abnormally low as an abnormally high value post baseline, both abnormalities are shown in the 
tables. (This means that the sum of the percentages can be more than 100%). If, for a specific test, 
the grading list provides distinct limits for abnormally low (=hypo) values as well as for 
abnormally high (=hyper) values, this test should be repeated for hyper and hypo limits 
separately in cross-tabulations and in the ADaM database.   
For toxicity grades, no distinction will be made between test results of samples obtained under 
fasting and under nonfasting conditions: in case limits under fasting and nonfasting conditions 
differ, the limits of the conditions (fasting/nonfasting) of scheduled visits as planned in the 
clinical trial protocol (CTP) will always be used, also for samples obtained under a different 
condition (eg, samples of withdrawal visits).   
Treatment-emergent:  
An abnormality (toxicity grade or abnormality based on normal ranges) will be considered 
treatment-emergent if it is worse than the baseline. If the baseline is missing, the abnormality is 
always considered as treatment-emergent.  A shift from ‘abnormally low’ at baseline to 
‘abnormally high’ post baseline (or vice versa) is also treatment-emergent. 
6.2.2. 
Analysis Methods 
All analyses will be performed on the treatment and follow-up phases. 
Descriptive statistics for the actual values and changes from baseline per timepoint will be 
performed for all lab parameters with continues values over time by treatment cohort. 
Lab toxicity grade and abnormality will be described by frequency and percentage of subjects 
using below methods:  
 
Tabulation of the worst treatment-emergent toxicity grade of laboratory parameters 
 
Tabulation by worst grade of laboratory parameters where at least one subject had worst 
treatment emergent WHO toxicity grade >=3 during the Treatment Phase 
 
Cross-tabulation of the worst toxicity grades versus baseline  
 
Cross-tabulation of toxicity grades versus baseline over time  
 
Cross-tabulation of the worst laboratory parameter abnormalities versus baseline 
Listing is provided for subjects with toxicity grade 3 or greater. The lab results for subjects who 
had cardiac events will be listed as well. 
All analyses will be done on standardized international (SI)-converted values. 
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6.3. 
Vital Signs and Physical Examination Findings 
Vital signs are assessed at following time points: Screening, Baseline, Day 2, Weeks1, 2, 3, 4, 6, 
8, 10 and 12 (10 & 12 for cohort 2), EOT, FU Week 4, and Week 24. 
Baseline: Defined as Day 1 measurement, if available. If not available, then the last assessment 
before the first administration of study drug will be used. 
Assessed vital sign parameters are pulse rate, systolic blood pressure (SBP) and diastolic blood 
pressure (DBP). All measurements should be taken supine and preceded by at least 5 minutes of 
rest. 
6.3.1. 
Definitions 
Pulse rate, SBP and DBP are classified in the following abnormality codes: 
Table 5: 
Abnormality Codes for Vital Signs 
 
Pulse (bpm) 
DBP (mm Hg) 
SBP (mm Hg) 
Abnormally low 
 50 
 50 
 90 
Grade 1 or mild 
- 
> 90 - < 100 
> 140 - < 160 
Grade 2 or moderate 
- 
 100 - < 110 
 160 - < 180 
Grade 3 or severe 
- 
 110 
 180 
Abnormally high 
 120 
- 
- 
  
In determining the abnormalities, the following rules are applied: 
 
The worst grades/abnormalities are determined over the whole observational period (over 
both the treatment and follow-up phases), including postbaseline scheduled and unscheduled 
measurements 
 
The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered equally 
important, ie, if a subject has as well an abnormally low as an abnormally high or graded 
value postbaseline, both abnormalities are shown in the tables. (This means that the sum of 
the percentages can be more than 100%) 
Treatment-emergent:  
An abnormality will be considered treatment-emergent if it is worse than the baseline. If the 
baseline is missing, the abnormality is always considered as treatment-emergent. A shift from 
‘abnormally low’ at baseline to ‘abnormally high’ or ‘grade …’ post baseline (or vice versa) is 
also treatment-emergent. 
6.3.2. 
Analysis Methods 
All analyses will be performed on the treatment and follow-up phases. Vital signs data will be 
analyzed using descriptive statistics on actual values and change from baseline over time by 
treatment cohort. 
Abnormality of vital signs will be described by frequency and percentage using below methods:  
 
Tabulation of the worst treatment-emergent abnormality of vital signs 
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 
Tabulation of normality/abnormality of vital signs over time 
 
Cross-tabulations for the worst abnormality versus baseline  
Physical examination data will only be listed. 
6.4. 
Electrocardiogram  
The electrocardiogram (ECG) variables that will be analyzed are heart rate, PR interval, QRS 
interval, RR interval, QT interval, and QT interval corrected for heart rate according to Bazett’s 
QT correction (QTcB) and Fridericia’s QT correction (QTcF). 
ECG data will be collected for the following time points: screening, baseline, day 2, day 3, 
weeks 1-4, 6, 8, 10 (cohort 2), EOT and follow up week 4. Baseline is the day 1 measurement, if 
available. If not available, the last assessment before the first administration of study drug will be 
used. 
6.4.1. 
Definitions 
For absolute HR, PR and QRS, the following abnormality categories are defined (Table 6). 
Table 6: 
Abnormality Categories for ECG 
 
HR 
PR 
QRS 
abnormally low 
≤ 50 bpm 
< 120 ms 
NAP 
abnormally high 
≥ 120 bpm 
> 200 ms 
≥ 120 ms 
 
Toxicity grading for PR interval will be performed according to the Division of Aids (DAIDS) 
grading table for the severity of adult and pediatric adverse events version 1.0, December 2004; 
clarification August 2009. Please see the Table 7. 
Table 7: 
Toxicity Grading for PR Interval 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially life-
threatening 
Prolonged PR interval 
Adult >16 years 
PR interval 
0.20 – 0.25 sec* 
PR interval 
>0.25 sec 
Type II 2nd degree 
AV block OR 
Ventricular pause 
>3.0 sec 
Complete AV 
block 
*Revised by the sponsor. 
 
The toxicity of PR interval will also be coded using the DAIDS grading table (version 2.0, dated 
2014) as follows (http://rsc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8): 
 
Grade 1: 210 to <250 msec  
 
Grade 2: ≥250 msec OR Type I 2nd degree AV block  
 
Grade 3: Type II 2nd degree AV block OR Ventricular pause ≥3000 msec 
 
Grade 4: Complete AV block 
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Analysis for PR will be conducted for all of definitions above (Abnormally high vs low, and 
toxicity grade per protocol and DAIDS 2.0). 
Please note the information for ventricular pause will be provided from medical team. 
For absolute QTc parameters the following abnormality categories are defined (based on the ICH 
E14 Guidance): 
 
QTc ≤450 msec (normal) 
 
450 msec <QTc ≤480 msec (borderline) 
 
480 msec <QTc ≤500 msec (prolonged)  
 
QTc >500 msec (pathologically prolonged). 
For increases from baseline in QTc (msec) the following categories are defined (based on ICH 
E14 Guidance):  
 
< 30 msec (normal) 
 
≥ 30 – 60 msec (borderline) 
 
> 60 msec (abnormally high) 
Only increases in QTc ≥30 msec will be considered as abnormalities. 
In determining the abnormalities, the following rules are applied: 
 
The worst abnormalities are determined over the whole observational period (over both the 
treatment and Follow up phases), including postbaseline scheduled and unscheduled 
measurements. 
 
The abnormalities ‘abnormally low’ and ‘abnormally high’ are considered equally important, 
ie, if a subject has as well an abnormally low as an abnormally high value postbaseline, both 
abnormalities are shown in the tables. (This means that the sum of the percentages can by 
more than 100%) 
Treatment-emergent:  
An abnormality will be considered treatment-emergent if it is worse than the baseline. If the 
baseline is missing, the abnormality is always considered as treatment-emergent. 
6.4.2. 
Analysis Methods 
All analyses will be performed on the treatment and follow-up phases by treatment cohort.  
The average of triplicate measurements at each time point will be used for analysis.  
Descriptive statistics for the ECG parameters will be calculated for observed values and changes 
from baseline (CFB) at each scheduled time point.  
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For individual ECG parameters, the abnormality will be tabulated using frequency and 
percentage through below methods: 
 
Tabulation of the worst treatment-emergent ECG abnormalities 
 
Tabulation of ECG normality/abnormalities over time 
 
Cross-Tabulation of the Worst ECG Abnormalities in Actual Value versus baseline value 
 
Cross-Tabulation of the Worst QTc Increase versus the abnormality on the actual value 
A listing of ECG abnormalities (all parameters) will be provided.  It will contain both actual and 
CFB values. 
6.5. 
Echocardiography 
Echocardiographic (ECHO) data will include Left Ventricular (LV) Ejection Fraction (LVEF) in 
percent (%).  Additional parameters include:  
 
Systolic Volume (mL) 
 
Diastolic Volume (mL) 
 
LV Fractional Shortening (%) 
 
LV Posterior Wall (PW) Diastolic Thickness (cm) 
 
Ventricular Septum Diastolic Thickness (cm)  
ECHO data will be collected in the following time points: screening, week 4, week 8, EOT, 
follow up week 4. The last assessment before the first administration of study drug will be used 
as the baseline. 
6.5.1. 
Definitions 
The following definitions are applicable to the ECHO analyses: 
 
Reversible decrease in LVEF is defined as a decrease of >10% from baseline, which is 
followed by an increase or a decrease of <=5% from baseline. 
 
No resolution in LVEF is defined as a decrease of >10% from baseline, which is not 
followed by an increase or a decrease of <=5% from baseline. 
6.5.2. 
Analysis Methods 
All analyses will be performed over the treatment and follow-up phases by treatment cohort. 
Descriptive statistics for the ECHO parameters will be calculated for observed values and 
changes from baseline at each scheduled time point. Number and percent of subjects abnormally 
low, normal, and abnormally high ECHO parameters by week of study will be summarized for 
each ECHO parameter.  
Number and percentage of subjects with a maximum LVEF change from baseline over all 
postbaseline visits will be reported for the following categories: decline of >10%, decline of >5 - 
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≤10%, decline of ≤=5%, increase of >5 - <=10%, increase of >10%, and increase of <5%. Each 
of the following will also be summarized: The number and percentage of subjects with a 
maximum decline of baseline over all postbaseline visits of >10% AND: 
 
Resulting in a LVEF% of <50%. 
 
A maximum decline of baseline of >10% with reversible decrease.  
 
A maximum decline of baseline of >10% with no resolution. 
And the time to onset for LVEF decrease and duration will also be summarized. 
Number and percentage of subjects will be summarized by postbaseline visit for subjects who 
have a decrease in LVEF of: 
 
>5% but <=10%  
 
>10% 
A listing of ECHO with actual value, change from baseline, or all parameters will be provided. 
6.6. 
Patient Profiles 
A set of patient profiles will be produced for each subject.  Data presented will include baseline 
characteristics, medical history, disposition, study drug exposure, adverse events, HCV RNA 
levels, lab parameters, ECG parameters, and concomitant medications.  Lab parameters will 
include Bilirubin (all version), AST, ALT, ALP, GGT, Creatine Kinase, Amylase, Lipase, BNP, 
e-GFR. 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetic (PK) analysis and Pharmacokinetic/Pharmacodynamic analysis will be 
performed by PK analysis vender and results will be reported by PK analysis vender. 
Pharmacodynamic (PD) analysis is not planned. 
7.1. 
Pharmacokinetics 
Details of the analysis plan and summary of results from Pharmacokinetic analyses will be 
provided in a separate report by PK analysis vender. 
7.2. 
Immune Response 
Not applicable. 
7.3. 
Pharmacodynamics 
PD analysis is not planned. 
7.4. 
Pharmacokinetic/Pharmacodynamic Relationships 
The Pharmacokinetic/Pharmacodynamic relationship of plasma concentrations and ECG 
parameters will be evaluated. Details of the analysis plan and summary of results from 
Pharmacokinetic/Pharmacodynamic analyses will be provided in a separate report. 
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ATTACHMENTS 
APPENDIX 1: PHASE ALLOCATION/COMBINING AES 
STEP 1: allocation of events to the phases 
Adverse events present in the SDS database are allocated to phases based on their start date. If 
the start date of an event falls between (or on) the start and stop date of a phase, the AE is 
attributed to that phase. 
Incomplete dates (ie, day and/or month and/or year missing) 
 
Partial start or stop dates: 
1. The partial start date (ie, missing day) will be imputed with the first day of the month 
unless the month/year is the same as the month/year of an analysis phase.  In this 
situation the incomplete start date will be imputed with the start date of that phase.  If 
the start date of the year is given without specification of the month and date, the partial 
missing start date will be imputed with the maximum of the first day of the given year 
and the first date of the first phase. 
2. The partial missing end date (ie, missing day) will be imputed with the last day of the 
month.  If the end date of the year is given without specification of the month and date, 
the partial missing end date will be imputed with the minimum of the last day of the 
given year and the end date of the last phase. 
 
Completely missing start date: the event is allocated to the first active treatment phase (the 
start date is imputed with the treatment phase start date), except if the end date of the AE 
falls before the start of the first active treatment phase, in which case it is assigned to the 
screening phase (the start date is imputed with the screening phase start date). 
 
Completely missing end date: the following decision rules apply 
1. For completed and discontinued subjects: 
 
In case the end date is not flagged as ongoing the date will remain missing. 
 
In case the end date is flagged as ongoing the date is imputed by the end date of 
the last phase. 
2. For ongoing subjects: 
 
Missing end dates are imputed by the end date of the last phase (ie, the cut-off 
date). 
STEP 2: combining adverse events 
Overlapping/consecutive events are defined as events of the same subject with the same 
preferred term who have at least 1 day in overlap or for which the start date of an event is 1 day 
after the end date of the preceding event. Overlapping/consecutive events may be combined into 
one AE or not, according to the following rules: 
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1. In case a nonactive phase (eg, Screening) is followed by an active phase, and the 
overlapping/consecutive events start in both phases, they are allocated to their respective 
phase and are considered as separate events. 
2. In case overlapping/consecutive events start within a single phase, they are considered as 
one and the same AE. The individual events who contribute to this AE are retained as 
individual records in the ADAM database but are assigned the same onset, phase, and total 
duration. 
3. In case an active phase is followed by a nonactive phase (eg, Follow-Up), and the 
overlapping/consecutive events start in both phases, they are allocated to the active phase 
and are considered as one and the same AE. The individual events who contribute to this AE 
are retained as individual records in the ADAM database but are assigned the same duration, 
onset and active phase. 
4. In case a nonactive phase is followed by a nonactive phase, and the overlapping/consecutive 
events start in both phases, they are allocated to their respective phase and are considered as 
separate AEs. 
Events can only be combined into one and the same AE if their start and stop dates are complete. 
In case the completely missing end date is imputed, this date is also considered as a complete 
date. 
 
 
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Statistical Analysis Plan 64294178HPC2003  
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APPENDIX 2A: SEARCH TERMS FOR EVENTS OF SPECIAL/CLINICAL INTEREST 
 
MedrDRA Term 
Level 
Searching Terms 
Events of special interest 
 
 
Cardiac Events 
SMQ 
Please see Appendix 3 
Increased Bilirubin 
MedDRA PTs 
Bilirubin conjugated abnormal  
Bilirubin conjugated increased  
Bilirubin excretion disorder  
Bilirubinuria  
Blood bilirubin abnormal  
Blood bilirubin increased  
Blood bilirubin unconjugated increased  
Hyperbilirubinaemia  
Icterus index increased 
Jaundice  
Jaundice cholestatic  
Jaundice extrahepatic obstructive  
Jaundice hepatocellular  
Ocular icterus  
Urine bilirubin increased  
Yellow skin 
Events of clinical interest 
 
 
Rash (all type) 
MedDRA HLTs, 
PTs 
Erythemas - HLT 
Papulosquamous conditions - HLT 
Rashes, eruptions and exanthems NEC - HLT 
PT:  
Photodermatosis 
Photosensitivity reaction 
Polymorphic light eruption 
Solar dermatitis 
Sunburn 
SMQ 
SMQ-Severe cutaneous adverse reaction: narrow 
scope and selected terms of the broad scope(refer 
Appendix 3) 
Pruritus 
MedDRA HLT 
Pruritus NEC 
Photosensitivity conditions 
MedDRA PTs 
Photodermatosis 
Photosensitivity reaction 
Polymorphic light eruption 
Solar dermatitis 
Sunburn  
 
 
 
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Statistical Analysis Plan 64294178HPC2003  
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APPENDIX 2B: RASH – SMQ19.1 
SMQ 19.1: “Severe cutaneous adverse reaction” 
SCOPE 
Preferred Term 
NARROW 
CUTANEOUS VASCULITIS 
NARROW 
DERMATITIS BULLOUS 
NARROW 
DERMATITIS EXFOLIATIVE 
NARROW 
DERMATITIS EXFOLIATIVE GENERALISED 
NARROW 
ERYTHEMA MULTIFORME 
NARROW 
OCULOMUCOCUTANEOUS SYNDROME 
NARROW 
SKIN NECROSIS 
NARROW 
STEVENS-JOHNSON SYNDROME 
NARROW 
TOXIC EPIDERMAL NECROLYSIS 
NARROW 
ACUTE GENERALISED EXANTHEMATOUS PUSTULOSIS 
NARROW 
TOXIC SKIN ERUPTION 
NARROW 
EPIDERMAL NECROSIS 
NARROW 
EXFOLIATIVE RASH 
NARROW 
DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC 
SYMPTOMS 
BROAD 
BLISTER 
BROAD 
BULLOUS IMPETIGO 
BROAD 
DRUG ERUPTION 
BROAD 
EPIDERMOLYSIS BULLOSA 
BROAD 
MUCOCUTANEOUS ULCERATION 
BROAD 
NIKOLSKY'S SIGN 
BROAD 
PEMPHIGOID 
BROAD 
PEMPHIGUS 
BROAD 
SKIN EROSION 
BROAD 
SKIN EXFOLIATION 
BROAD 
EPIDERMOLYSIS 
BROAD 
ACQUIRED EPIDERMOLYSIS BULLOSA 
 
 
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Statistical Analysis Plan 64294178HPC2003  
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APPENDIX 3: CARDIAC EVENTS - SMQ19.1 
 
Narrow/Broad 
PT Term 
Cardiac arrhythmias (SMQ) 
 
Arrhythmia related investigations, signs and symptoms (SMQ)
 
 
 
 
Narrow 
Chronotropic incompetence 
 
 
 
 
Narrow 
Electrocardiogram repolarisation abnormality 
 
 
 
 
Narrow 
Electrocardiogram RR interval prolonged 
 
 
 
 
Narrow 
Electrocardiogram U-wave abnormality 
 
 
 
 
Narrow 
Sudden cardiac death 
 
 
 
 
Broad 
Bezold-Jarisch reflex 
 
 
 
 
Broad 
Bradycardia 
 
 
 
 
Broad 
Cardiac arrest 
 
 
 
 
Broad 
Cardiac death 
 
 
 
 
Broad 
Cardiac telemetry abnormal 
 
 
 
 
Broad 
Cardio-respiratory arrest 
 
 
 
 
Broad 
Central bradycardia 
 
 
 
 
Broad 
Electrocardiogram abnormal 
 
 
 
 
Broad 
Electrocardiogram ambulatory abnormal 
 
 
 
 
Broad 
Electrocardiogram change 
 
 
 
 
Broad 
Heart rate abnormal 
 
 
 
 
Broad 
Heart rate decreased 
 
 
 
 
Broad 
Heart rate increased 
 
 
 
 
Broad 
Loss of consciousness 
 
 
 
 
Broad 
Palpitations 
 
 
 
 
Broad 
Rebound tachycardia 
 
 
 
 
Broad 
Sudden death 
 
 
 
 
Broad 
Syncope 
 
 
 
 
Broad 
Tachycardia 
 
 
 
 
Broad 
Tachycardia paroxysmal 
 
Cardiac arrhythmia terms (incl bradyarrhythmias and tachyarrhythmias) (SMQ) 
 
 
Bradyarrhythmias (incl conduction defects and disorders of sinus node function) 
(SMQ) 
 
 
 
Bradyarrhythmia terms, nonspecific (SMQ)
 
 
 
 
Narrow 
Bradyarrhythmia 
 
 
 
 
Narrow 
Ventricular asystole 
 
 
 
Conduction defects (SMQ)
 
 
 
 
Narrow 
Accessory cardiac pathway 
 
 
 
 
Narrow 
Adams-Stokes syndrome 
 
 
 
 
Narrow 
Agonal rhythm 
 
 
 
 
Narrow 
Atrial conduction time prolongation 
 
 
 
 
Narrow 
Atrioventricular block 
 
 
 
 
Narrow 
Atrioventricular block complete 
 
 
 
 
Narrow 
Atrioventricular block first degree 
 
 
 
 
Narrow 
Atrioventricular block second degree 
 
 
 
 
Narrow 
Atrioventricular conduction time shortened 
 
 
 
 
Narrow 
Atrioventricular dissociation 
 
 
 
 
Narrow 
Bifascicular block 
 
 
 
 
Narrow 
Brugada syndrome 
 
 
 
 
Narrow 
Bundle branch block 
 
 
 
 
Narrow 
Bundle branch block bilateral 
 
 
 
 
Narrow 
Bundle branch block left 
 
 
 
 
Narrow 
Bundle branch block right 
 
 
 
 
Narrow 
Conduction disorder 
 
 
 
 
Narrow 
Defect conduction intraventricular 
 
 
 
 
Narrow 
Electrocardiogram delta waves abnormal 
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Statistical Analysis Plan 64294178HPC2003  
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Narrow/Broad 
PT Term 
 
 
 
 
Narrow 
Electrocardiogram PQ interval prolonged 
 
 
 
 
Narrow 
Electrocardiogram PQ interval shortened 
 
 
 
 
Narrow 
Electrocardiogram PR prolongation 
 
 
 
 
Narrow 
Electrocardiogram PR shortened 
 
 
 
 
Narrow 
Electrocardiogram QRS complex prolonged 
 
 
 
 
Narrow 
Electrocardiogram QT prolonged 
 
 
 
 
Narrow 
Electrocardiogram repolarisation abnormality 
 
 
 
 
Narrow 
Lenegre's disease 
 
 
 
 
Narrow 
Long QT syndrome 
 
 
 
 
Narrow 
Paroxysmal atrioventricular block 
 
 
 
 
Narrow 
Sinoatrial block 
 
 
 
 
Narrow 
Trifascicular block 
 
 
 
 
Narrow 
Ventricular dyssynchrony 
 
 
 
 
Narrow 
Wolff-Parkinson-White syndrome 
 
 
 
Disorders of sinus node function (SMQ)
 
 
 
 
Narrow 
Nodal arrhythmia 
 
 
 
 
Narrow 
Nodal rhythm 
 
 
 
 
Narrow 
Sinus arrest 
 
 
 
 
Narrow 
Sinus arrhythmia 
 
 
 
 
Narrow 
Sinus bradycardia 
 
 
 
 
Narrow 
Sinus node dysfunction 
 
 
 
 
Narrow 
Wandering pacemaker 
 
 
Cardiac arrhythmia terms, nonspecific (SMQ)
 
 
 
 
Narrow 
Arrhythmia 
 
 
 
 
Narrow 
Heart alternation 
 
 
 
 
Narrow 
Heart rate irregular 
 
 
 
 
Narrow 
Pacemaker generated arrhythmia 
 
 
 
 
Narrow 
Pacemaker syndrome 
 
 
 
 
Narrow 
Paroxysmal arrhythmia 
 
 
 
 
Narrow 
Pulseless electrical activity 
 
 
 
 
Narrow 
Reperfusion arrhythmia 
 
 
 
 
Narrow 
Withdrawal arrhythmia 
 
 
Tachyarrhythmias (incl supraventricular and ventricular tachyarrhythmias) 
(SMQ) 
 
 
 
Supraventricular tachyarrhythmias (SMQ)
 
 
 
 
Narrow 
Arrhythmia supraventricular 
 
 
 
 
Narrow 
Atrial fibrillation 
 
 
 
 
Narrow 
Atrial flutter 
 
 
 
 
Narrow 
Atrial parasystole 
 
 
 
 
Narrow 
Atrial tachycardia 
 
 
 
 
Narrow 
Junctional ectopic tachycardia 
 
 
 
 
Narrow 
Sinus tachycardia 
 
 
 
 
Narrow 
Supraventricular extrasystoles 
 
 
 
 
Narrow 
Supraventricular tachyarrhythmia 
 
 
 
 
Narrow 
Supraventricular tachycardia 
 
 
 
 
Broad 
ECG P wave inverted 
 
 
 
 
Broad 
Electrocardiogram P wave abnormal 
 
 
 
 
Broad 
Retrograde p-waves 
 
 
 
Tachyarrhythmia terms, nonspecific (SMQ)
 
 
 
 
Narrow 
Anomalous atrioventricular excitation 
 
 
 
 
Narrow 
Cardiac fibrillation 
 
 
 
 
Narrow 
Cardiac flutter 
 
 
 
 
Narrow 
Extrasystoles 
 
 
 
 
Narrow 
Tachyarrhythmia 
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Statistical Analysis Plan 64294178HPC2003  
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Approved, Date: 8 June 2018  
 
Narrow/Broad 
PT Term 
 
 
 
Ventricular tachyarrhythmias (SMQ)
 
 
 
 
Narrow 
Accelerated idioventricular rhythm 
 
 
 
 
Narrow 
Cardiac fibrillation 
 
 
 
 
Narrow 
Parasystole 
 
 
 
 
Narrow 
Rhythm idioventricular 
 
 
 
 
Narrow 
Torsade de pointes 
 
 
 
 
Narrow 
Ventricular arrhythmia 
 
 
 
 
Narrow 
Ventricular extrasystoles 
 
 
 
 
Narrow 
Ventricular fibrillation 
 
 
 
 
Narrow 
Ventricular flutter 
 
 
 
 
Narrow 
Ventricular parasystole 
 
 
 
 
Narrow 
Ventricular pre-excitation 
 
 
 
 
Narrow 
Ventricular tachyarrhythmia 
 
 
 
 
Narrow 
Ventricular tachycardia 
Cardiac failure (SMQ) 
 
 
 
 
Narrow 
Acute left ventricular failure 
 
 
 
 
Narrow 
Acute pulmonary oedema 
 
 
 
 
Narrow 
Acute right ventricular failure 
 
 
 
 
Narrow 
Cardiac asthma 
 
 
 
 
Narrow 
Cardiac failure 
 
 
 
 
Narrow 
Cardiac failure acute 
 
 
 
 
Narrow 
Cardiac failure chronic 
 
 
 
 
Narrow 
Cardiac failure congestive 
 
 
 
 
Narrow 
Cardiac failure high output 
 
 
 
 
Narrow 
Cardiogenic shock 
 
 
 
 
Narrow 
Cardiopulmonary failure 
 
 
 
 
Narrow 
Cardiorenal syndrome 
 
 
 
 
Narrow 
Chronic left ventricular failure 
 
 
 
 
Narrow 
Chronic right ventricular failure 
 
 
 
 
Narrow 
Cor pulmonale 
 
 
 
 
Narrow 
Cor pulmonale acute 
 
 
 
 
Narrow 
Cor pulmonale chronic 
 
 
 
 
Narrow 
Ejection fraction decreased 
 
 
 
 
Narrow 
Hepatic congestion 
 
 
 
 
Narrow 
Hepatojugular reflux 
 
 
 
 
Narrow 
Left ventricular failure 
 
 
 
 
Narrow 
Low cardiac output syndrome 
 
 
 
 
Narrow 
Neonatal cardiac failure 
 
 
 
 
Narrow 
Obstructive shock 
 
 
 
 
Narrow 
Pulmonary oedema 
 
 
 
 
Narrow 
Pulmonary oedema neonatal 
 
 
 
 
Narrow 
Radiation associated cardiac failure 
 
 
 
 
Narrow 
Right ventricular ejection fraction decreased 
 
 
 
 
Narrow 
Right ventricular failure 
 
 
 
 
Narrow 
Ventricular failure 
 
 
 
 
Broad 
Artificial heart implant 
 
 
 
 
Broad 
Atrial natriuretic peptide abnormal 
 
 
 
 
Broad 
Atrial natriuretic peptide increased 
 
 
 
 
Broad 
Bendopnoea 
 
 
 
 
Broad 
Brain natriuretic peptide abnormal 
 
 
 
 
Broad 
Brain natriuretic peptide increased 
 
 
 
 
Broad 
Cardiac cirrhosis 
 
 
 
 
Broad 
Cardiac contractility modulation therapy 
 
 
 
 
Broad 
Cardiac index decreased 
NCT02993250


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Statistical Analysis Plan 64294178HPC2003  
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Approved, Date: 8 June 2018  
 
Narrow/Broad 
PT Term 
 
 
 
 
Broad 
Cardiac output decreased 
 
 
 
 
Broad 
Cardiac resynchronisation therapy 
 
 
 
 
Broad 
Cardiac ventriculogram abnormal 
 
 
 
 
Broad 
Cardiac ventriculogram left abnormal 
 
 
 
 
Broad 
Cardiac ventriculogram right abnormal 
 
 
 
 
Broad 
Cardiomegaly 
 
 
 
 
Broad 
Cardio-respiratory distress 
 
 
 
 
Broad 
Cardiothoracic ratio increased 
 
 
 
 
Broad 
Central venous pressure increased 
 
 
 
 
Broad 
Diastolic dysfunction 
 
 
 
 
Broad 
Dilatation ventricular 
 
 
 
 
Broad 
Dyspnoea paroxysmal nocturnal 
 
 
 
 
Broad 
Heart transplant 
 
 
 
 
Broad 
Hepatic vein dilatation 
 
 
 
 
Broad 
Jugular vein distension 
 
 
 
 
Broad 
Left ventricular dilatation 
 
 
 
 
Broad 
Left ventricular dysfunction 
 
 
 
 
Broad 
Left ventricular enlargement 
 
 
 
 
Broad 
Lower respiratory tract congestion 
 
 
 
 
Broad 
Myocardial depression 
 
 
 
 
Broad 
Nocturnal dyspnoea 
 
 
 
 
Broad 
N-terminal prohormone brain natriuretic peptide 
abnormal 
 
 
 
 
Broad 
N-terminal prohormone brain natriuretic peptide 
increased 
 
 
 
 
Broad 
Oedema 
 
 
 
 
Broad 
Oedema due to cardiac disease 
 
 
 
 
Broad 
Oedema neonatal 
 
 
 
 
Broad 
Oedema peripheral 
 
 
 
 
Broad 
Orthopnoea 
 
 
 
 
Broad 
Peripheral oedema neonatal 
 
 
 
 
Broad 
Peripheral swelling 
 
 
 
 
Broad 
Post cardiac arrest syndrome 
 
 
 
 
Broad 
Prohormone brain natriuretic peptide abnormal 
 
 
 
 
Broad 
Prohormone brain natriuretic peptide increased 
 
 
 
 
Broad 
Pulmonary congestion 
 
 
 
 
Broad 
Right ventricular dilatation 
 
 
 
 
Broad 
Right ventricular dysfunction 
 
 
 
 
Broad 
Right ventricular enlargement 
 
 
 
 
Broad 
Scan myocardial perfusion abnormal 
 
 
 
 
Broad 
Stroke volume decreased 
 
 
 
 
Broad 
Surgical ventricular restoration 
 
 
 
 
Broad 
Systolic dysfunction 
 
 
 
 
Broad 
Venous pressure increased 
 
 
 
 
Broad 
Venous pressure jugular abnormal 
 
 
 
 
Broad 
Venous pressure jugular increased 
 
 
 
 
Broad 
Ventricular assist device insertion 
 
 
 
 
Broad 
Ventricular dysfunction 
 
 
 
 
Broad 
Ventricular dyssynchrony 
Cardiomyopathy (SMQ) 
 
 
 
 
Narrow 
Atrial septal defect acquired 
 
 
 
 
Narrow 
Biopsy heart abnormal 
 
 
 
 
Narrow 
Cardiac amyloidosis 
 
 
 
 
Narrow 
Cardiac hypertrophy 
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Statistical Analysis Plan 64294178HPC2003  
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Narrow/Broad 
PT Term 
 
 
 
 
Narrow 
Cardiac sarcoidosis 
 
 
 
 
Narrow 
Cardiac septal hypertrophy 
 
 
 
 
Narrow 
Cardiac siderosis 
 
 
 
 
Narrow 
Cardiomyopathy 
 
 
 
 
Narrow 
Cardiomyopathy acute 
 
 
 
 
Narrow 
Cardiomyopathy alcoholic 
 
 
 
 
Narrow 
Cardiomyopathy neonatal 
 
 
 
 
Narrow 
Cardiotoxicity 
 
 
 
 
Narrow 
Congestive cardiomyopathy 
 
 
 
 
Narrow 
Cytotoxic cardiomyopathy 
 
 
 
 
Narrow 
Diabetic cardiomyopathy 
 
 
 
 
Narrow 
Ejection fraction abnormal 
 
 
 
 
Narrow 
Ejection fraction decreased 
 
 
 
 
Narrow 
Eosinophilic myocarditis 
 
 
 
 
Narrow 
HIV cardiomyopathy 
 
 
 
 
Narrow 
Hypertensive cardiomyopathy 
 
 
 
 
Narrow 
Hypertrophic cardiomyopathy 
 
 
 
 
Narrow 
Ischaemic cardiomyopathy 
 
 
 
 
Narrow 
Metabolic cardiomyopathy 
 
 
 
 
Narrow 
Myocardial calcification 
 
 
 
 
Narrow 
Myocardial fibrosis 
 
 
 
 
Narrow 
Myocardial haemorrhage 
 
 
 
 
Narrow 
Non-obstructive cardiomyopathy 
 
 
 
 
Narrow 
Peripartum cardiomyopathy 
 
 
 
 
Narrow 
Pulmonary arterial wedge pressure increased 
 
 
 
 
Narrow 
Restrictive cardiomyopathy 
 
 
 
 
Narrow 
Right ventricular ejection fraction decreased 
 
 
 
 
Narrow 
Stress cardiomyopathy 
 
 
 
 
Narrow 
Tachycardia induced cardiomyopathy 
 
 
 
 
Narrow 
Thyrotoxic cardiomyopathy 
 
 
 
 
Narrow 
Ventricular septal defect acquired 
 
 
 
 
Narrow 
Viral cardiomyopathy 
 
 
 
 
Broad 
Abnormal precordial movement 
 
 
 
 
Broad 
Acquired cardiac septal defect 
 
 
 
 
Broad 
Acute left ventricular failure 
 
 
 
 
Broad 
Alcohol septal ablation 
 
 
 
 
Broad 
Allergic myocarditis 
 
 
 
 
Broad 
Arrhythmia 
 
 
 
 
Broad 
Arrhythmia supraventricular 
 
 
 
 
Broad 
Artificial heart implant 
 
 
 
 
Broad 
Ascites 
 
 
 
 
Broad 
Atrial hypertrophy 
 
 
 
 
Broad 
Atrial pressure increased 
 
 
 
 
Broad 
Autoimmune myocarditis 
 
 
 
 
Broad 
Bendopnoea 
 
 
 
 
Broad 
Blood pressure diastolic abnormal 
 
 
 
 
Broad 
Blood pressure diastolic decreased 
 
 
 
 
Broad 
Blood pressure diastolic increased 
 
 
 
 
Broad 
Blood pressure fluctuation 
 
 
 
 
Broad 
Blood pressure inadequately controlled 
 
 
 
 
Broad 
Blood pressure systolic abnormal 
 
 
 
 
Broad 
Blood pressure systolic decreased 
 
 
 
 
Broad 
Blood pressure systolic increased 
 
 
 
 
Broad 
Cardiac aneurysm 
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Statistical Analysis Plan 64294178HPC2003  
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Approved, Date: 8 June 2018  
 
Narrow/Broad 
PT Term 
 
 
 
 
Broad 
Cardiac arrest 
 
 
 
 
Broad 
Cardiac contractility modulation therapy 
 
 
 
 
Broad 
Cardiac electrophysiologic study abnormal 
 
 
 
 
Broad 
Cardiac failure 
 
 
 
 
Broad 
Cardiac failure acute 
 
 
 
 
Broad 
Cardiac failure chronic 
 
 
 
 
Broad 
Cardiac failure congestive 
 
 
 
 
Broad 
Cardiac function test abnormal 
 
 
 
 
Broad 
Cardiac imaging procedure abnormal 
 
 
 
 
Broad 
Cardiac index abnormal 
 
 
 
 
Broad 
Cardiac index decreased 
 
 
 
 
Broad 
Cardiac index increased 
 
 
 
 
Broad 
Cardiac monitoring abnormal 
 
 
 
 
Broad 
Cardiac operation 
 
 
 
 
Broad 
Cardiac output decreased 
 
 
 
 
Broad 
Cardiac pseudoaneurysm 
 
 
 
 
Broad 
Cardiac resynchronisation therapy 
 
 
 
 
Broad 
Cardiac ventricular scarring 
 
 
 
 
Broad 
Cardiac ventriculogram abnormal 
 
 
 
 
Broad 
Cardiac ventriculogram left abnormal 
 
 
 
 
Broad 
Cardiac ventriculogram right abnormal 
 
 
 
 
Broad 
Cardiomegaly 
 
 
 
 
Broad 
Cardiothoracic ratio increased 
 
 
 
 
Broad 
Cardiovascular disorder 
 
 
 
 
Broad 
Cardiovascular function test abnormal 
 
 
 
 
Broad 
Chest pain 
 
 
 
 
Broad 
Chest X-ray abnormal 
 
 
 
 
Broad 
Computerised tomogram thorax abnormal 
 
 
 
 
Broad 
Coxsackie carditis 
 
 
 
 
Broad 
Coxsackie myocarditis 
 
 
 
 
Broad 
Cytomegalovirus myocarditis 
 
 
 
 
Broad 
Decreased ventricular preload 
 
 
 
 
Broad 
Diastolic dysfunction 
 
 
 
 
Broad 
Dilatation atrial 
 
 
 
 
Broad 
Dilatation ventricular 
 
 
 
 
Broad 
Directional Doppler flow tests abnormal 
 
 
 
 
Broad 
Dyspnoea 
 
 
 
 
Broad 
ECG signs of ventricular hypertrophy 
 
 
 
 
Broad 
Echocardiogram abnormal 
 
 
 
 
Broad 
Electrocardiogram abnormal 
 
 
 
 
Broad 
Electrocardiogram change 
 
 
 
 
Broad 
Endocardial fibroelastosis 
 
 
 
 
Broad 
External counterpulsation 
 
 
 
 
Broad 
Gonococcal heart disease 
 
 
 
 
Broad 
Heart and lung transplant 
 
 
 
 
Broad 
Heart transplant 
 
 
 
 
Broad 
Hepatomegaly 
 
 
 
 
Broad 
Hyperdynamic left ventricle 
 
 
 
 
Broad 
Increased ventricular preload 
 
 
 
 
Broad 
Irregular breathing 
 
 
 
 
Broad 
Labile blood pressure 
 
 
 
 
Broad 
Left atrial dilatation 
 
 
 
 
Broad 
Left atrial enlargement 
 
 
 
 
Broad 
Left ventricular dilatation 
NCT02993250


AL-335, Odalasvir, TMC435(simeprevir)   
 
 
 
Statistical Analysis Plan 64294178HPC2003  
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Approved, Date: 8 June 2018  
 
Narrow/Broad 
PT Term 
 
 
 
 
Broad 
Left ventricular end-diastolic pressure decreased 
 
 
 
 
Broad 
Left ventricular enlargement 
 
 
 
 
Broad 
Left ventricular failure 
 
 
 
 
Broad 
Left ventricular heave 
 
 
 
 
Broad 
Lupus myocarditis 
 
 
 
 
Broad 
Lyme carditis 
 
 
 
 
Broad 
Malarial myocarditis 
 
 
 
 
Broad 
Mental status changes 
 
 
 
 
Broad 
Multiple gated acquisition scan abnormal 
 
 
 
 
Broad 
Myocardiac abscess 
 
 
 
 
Broad 
Myocardial necrosis marker increased 
 
 
 
 
Broad 
Myocarditis 
 
 
 
 
Broad 
Myocarditis bacterial 
 
 
 
 
Broad 
Myocarditis helminthic 
 
 
 
 
Broad 
Myocarditis infectious 
 
 
 
 
Broad 
Myocarditis meningococcal 
 
 
 
 
Broad 
Myocarditis mycotic 
 
 
 
 
Broad 
Myocarditis post infection 
 
 
 
 
Broad 
Myocarditis septic 
 
 
 
 
Broad 
Myocarditis syphilitic 
 
 
 
 
Broad 
Myocarditis toxoplasmal 
 
 
 
 
Broad 
Myoglobinaemia 
 
 
 
 
Broad 
Myoglobinuria 
 
 
 
 
Broad 
Nocturia 
 
 
 
 
Broad 
Nuclear magnetic resonance imaging thoracic 
abnormal 
 
 
 
 
Broad 
Oedema 
 
 
 
 
Broad 
Orthostatic hypotension 
 
 
 
 
Broad 
Palpitations 
 
 
 
 
Broad 
Papillary muscle disorder 
 
 
 
 
Broad 
Papillary muscle haemorrhage 
 
 
 
 
Broad 
Radiation myocarditis 
 
 
 
 
Broad 
Right atrial dilatation 
 
 
 
 
Broad 
Right atrial enlargement 
 
 
 
 
Broad 
Right atrial pressure increased 
 
 
 
 
Broad 
Right ventricle outflow tract obstruction 
 
 
 
 
Broad 
Right ventricular dilatation 
 
 
 
 
Broad 
Right ventricular enlargement 
 
 
 
 
Broad 
Right ventricular heave 
 
 
 
 
Broad 
Right ventricular systolic pressure decreased 
 
 
 
 
Broad 
Scan myocardial perfusion abnormal 
 
 
 
 
Broad 
Sudden cardiac death 
 
 
 
 
Broad 
Sudden death 
 
 
 
 
Broad 
Surgical ventricular restoration 
 
 
 
 
Broad 
Syncope 
 
 
 
 
Broad 
Systolic anterior motion of mitral valve 
 
 
 
 
Broad 
Systolic dysfunction 
 
 
 
 
Broad 
Ultrasound Doppler abnormal 
 
 
 
 
Broad 
Vascular resistance pulmonary increased 
 
 
 
 
Broad 
Ventricular arrhythmia 
 
 
 
 
Broad 
Ventricular assist device insertion 
 
 
 
 
Broad 
Ventricular dysfunction 
 
 
 
 
Broad 
Ventricular dyskinesia 
 
 
 
 
Broad 
Ventricular dyssynchrony 
NCT02993250


AL-335, Odalasvir, TMC435(simeprevir)   
 
 
 
Statistical Analysis Plan 64294178HPC2003  
41 
Approved, Date: 8 June 2018  
 
Narrow/Broad 
PT Term 
 
 
 
 
Broad 
Ventricular hyperkinesia 
 
 
 
 
Broad 
Ventricular hypertrophy 
 
 
 
 
Broad 
Ventricular hypokinesia 
 
 
 
 
Broad 
Ventricular remodelling 
 
 
 
 
Broad 
Viral myocarditis 
Ischaemic heart disease (SMQ) 
 
Myocardial infarction (SMQ) 
 
 
 
 
Narrow 
Acute coronary syndrome 
 
 
 
 
Narrow 
Acute myocardial infarction 
 
 
 
 
Narrow 
Angina unstable 
 
 
 
 
Narrow 
Blood creatine phosphokinase MB abnormal 
 
 
 
 
Narrow 
Blood creatine phosphokinase MB increased 
 
 
 
 
Narrow 
Coronary artery embolism 
 
 
 
 
Narrow 
Coronary artery occlusion 
 
 
 
 
Narrow 
Coronary artery reocclusion 
 
 
 
 
Narrow 
Coronary artery thrombosis 
 
 
 
 
Narrow 
Coronary bypass thrombosis 
 
 
 
 
Narrow 
Coronary vascular graft occlusion 
 
 
 
 
Narrow 
Kounis syndrome 
 
 
 
 
Narrow 
Myocardial infarction 
 
 
 
 
Narrow 
Myocardial necrosis 
 
 
 
 
Narrow 
Myocardial reperfusion injury 
 
 
 
 
Narrow 
Myocardial stunning 
 
 
 
 
Narrow 
Papillary muscle infarction 
 
 
 
 
Narrow 
Post procedural myocardial infarction 
 
 
 
 
Narrow 
Postinfarction angina 
 
 
 
 
Narrow 
Silent myocardial infarction 
 
 
 
 
Narrow 
Troponin I increased 
 
 
 
 
Narrow 
Troponin increased 
 
 
 
 
Narrow 
Troponin T increased 
 
 
 
 
Broad 
Blood creatine phosphokinase abnormal 
 
 
 
 
Broad 
Blood creatine phosphokinase increased 
 
 
 
 
Broad 
Cardiac ventricular scarring 
 
 
 
 
Broad 
ECG electrically inactive area 
 
 
 
 
Broad 
ECG signs of myocardial infarction 
 
 
 
 
Broad 
Electrocardiogram Q wave abnormal 
 
 
 
 
Broad 
Electrocardiogram ST segment abnormal 
 
 
 
 
Broad 
Electrocardiogram ST segment elevation 
 
 
 
 
Broad 
Electrocardiogram ST-T segment elevation 
 
 
 
 
Broad 
Infarction 
 
 
 
 
Broad 
Myocardial necrosis marker increased 
 
 
 
 
Broad 
Scan myocardial perfusion abnormal 
 
 
 
 
Broad 
Vascular graft occlusion 
 
 
 
 
Broad 
Vascular stent occlusion 
 
 
 
 
Broad 
Vascular stent thrombosis 
Shock (SMQ) 
 
Shock-associated circulatory or cardiac conditions (excl torsade de pointes) (SMQ) 
 
 
 
 
Narrow 
Acute left ventricular failure 
 
 
 
 
Narrow 
Adams-Stokes syndrome 
 
 
 
 
Narrow 
Atrial parasystole 
 
 
 
 
Narrow 
Cardiac arrest 
 
 
 
 
Narrow 
Cardiac arrest neonatal 
 
 
 
 
Narrow 
Cardiac death 
 
 
 
 
Narrow 
Cardiac fibrillation 
NCT02993250


AL-335, Odalasvir, TMC435(simeprevir)   
 
 
 
Statistical Analysis Plan 64294178HPC2003  
42 
Approved, Date: 8 June 2018  
 
Narrow/Broad 
PT Term 
 
 
 
 
Narrow 
Cardiac flutter 
 
 
 
 
Narrow 
Cardiogenic shock 
 
 
 
 
Narrow 
Cardio-respiratory arrest 
 
 
 
 
Narrow 
Cardio-respiratory arrest neonatal 
 
 
 
 
Narrow 
Cardiovascular insufficiency 
 
 
 
 
Narrow 
Circulatory collapse 
 
 
 
 
Narrow 
Obstructive shock 
 
 
 
 
Narrow 
Pulse absent 
 
 
 
 
Narrow 
Pulseless electrical activity 
 
 
 
 
Narrow 
Shock 
 
 
 
 
Narrow 
Shock symptom 
 
 
 
 
Narrow 
Sudden cardiac death 
 
 
 
 
Narrow 
Ventricular asystole 
 
 
 
 
Narrow 
Ventricular fibrillation 
 
 
 
 
Narrow 
Ventricular flutter 
 
 
 
 
Narrow 
Ventricular parasystole 
 
 
 
 
Broad 
Acute kidney injury 
 
 
 
 
Broad 
Acute prerenal failure 
 
 
 
 
Broad 
Acute respiratory failure 
 
 
 
 
Broad 
Anuria 
 
 
 
 
Broad 
Blood pressure immeasurable 
 
 
 
 
Broad 
Cerebral hypoperfusion 
 
 
 
 
Broad 
Grey syndrome neonatal 
 
 
 
 
Broad 
Hepatic congestion 
 
 
 
 
Broad 
Hepatojugular reflux 
 
 
 
 
Broad 
Hepatorenal failure 
 
 
 
 
Broad 
Hypoperfusion 
 
 
 
 
Broad 
Jugular vein distension 
 
 
 
 
Broad 
Myocardial depression 
 
 
 
 
Broad 
Neonatal anuria 
 
 
 
 
Broad 
Neonatal multi-organ failure 
 
 
 
 
Broad 
Neonatal respiratory failure 
 
 
 
 
Broad 
Organ failure 
 
 
 
 
Broad 
Prerenal failure 
 
 
 
 
Broad 
Propofol infusion syndrome 
 
 
 
 
Broad 
Renal failure 
 
 
 
 
Broad 
Renal failure neonatal 
 
 
 
 
Broad 
Respiratory failure 
Torsade de pointes/QT prolongation (SMQ)
 
 
 
 
Narrow 
Electrocardiogram QT interval abnormal 
 
 
 
 
Narrow 
Electrocardiogram QT prolonged 
 
 
 
 
Narrow 
Long QT syndrome 
 
 
 
 
Narrow 
Long QT syndrome congenital 
 
 
 
 
Narrow 
Torsade de pointes 
 
 
 
 
Narrow 
Ventricular tachycardia 
 
 
 
 
Broad 
Cardiac arrest 
 
 
 
 
Broad 
Cardiac death 
 
 
 
 
Broad 
Cardiac fibrillation 
 
 
 
 
Broad 
Cardio-respiratory arrest 
 
 
 
 
Broad 
Electrocardiogram repolarisation abnormality 
 
 
 
 
Broad 
Electrocardiogram U-wave abnormality 
 
 
 
 
Broad 
Loss of consciousness 
 
 
 
 
Broad 
Sudden cardiac death 
 
 
 
 
Broad 
Sudden death 
NCT02993250


AL-335, Odalasvir, TMC435(simeprevir)   
 
 
 
Statistical Analysis Plan 64294178HPC2003  
43 
Approved, Date: 8 June 2018  
 
Narrow/Broad 
PT Term 
 
 
 
 
Broad 
Syncope 
 
 
 
 
Broad 
Ventricular arrhythmia 
 
 
 
 
Broad 
Ventricular fibrillation 
 
 
 
 
Broad 
Ventricular flutter 
 
 
 
 
Broad 
Ventricular tachyarrhythmia 
 
NCT02993250