Conditions: Hepatitis C, Chronic
Keywords: Hepatitis C, Chronic AL-335 Odalasvir Simeprevir ODV SMV ACH-3102 ACH-0143102 TMC435
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 365
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy (proportion of subjects with SVR12), safety, tolerability and pharmacokinetics of an 8- and 6-week treatment regimen of AL-335, odalasvir (ODV) and simeprevir (SMV) in chronic HCV genotype 1, 2, 4, 5 or 6 infected subjects without cirrhosis.

Detailed description:
This is a Phase 2b multicenter study. The study will include a screening period of maximum 6 weeks, a treatment period of 6 or 8 weeks and a 24-weeks post-treatment follow-up period. The total study duration for each subject will be 36 to 38 weeks. This study investigates a 3 direct-acting antiviral agent (DAA) combination of AL-335 (HCV NS5B inhibitor), odalasvir (ODV) (a second generation HCV NS5A inhibitor) and simeprevir (SMV) (HCV NS3A4 protease inhibitor). The results of this study will enable the selection of treatment and duration to be further developed.

Arms:
arm 1: AL-335 (800 mg), odalasvir (25 mg) and simeprevir (75 mg) once daily during 6 weeks. arm 2: AL-335 (800 mg), odalasvir (25 mg) and simeprevir (75 mg) once daily during 8 weeks.

Interventions: intervention 1: AL-335 intervention 2: Odalasvir intervention 3: Simeprevir
Intervention descriptions: intervention 1: AL-335 800 mg (2\*400) tablet will be administered once daily. intervention 2: Odalasvir 25 mg tablet will be administered once daily. intervention 3: Simeprevir 75 mg capsule will be administered once daily.

Protocol document:
Prot_000.pdf: 
1
Status: Approved,  Date: 10 April 2017
Janssen Research & Development *
Clinical Protocol
A Phase 2b, Multicenter, Randomized, Open-label Study to Investigate the Efficacy, Safety 
and Pharmacokinetics of Different Treatment Regimens of AL-335, Odalasvir, and 
Simeprevir in Treatment-naïve and Treatment-experienced Subjects With Chronic 
Hepatitis C Virus Genotype 1, 2, 4, 5 and 6 Infection Without Cirrhosis.
Protocol 64294178HPC2001; Phase 2b
AMENDMENT 4
AL-335, odalasvir, TMC435 (simeprevir)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Sciences Ireland UC; or Janssen 
Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these 
various legal entities; the sponsor is identified on the Contact Information page that accompanies the 
protocol.
EudraCT NUMBER: 2015-004200-38
Status:
Approved
Date:
10 April 2017
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-126421028
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.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
FIGURES ...................................................................................................................................................... 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 19
TIME AND EVENTS SCHEDULE .............................................................................................................. 29
ABBREVIATIONS ...................................................................................................................................... 35
DEFINITIONS OF TERMS.......................................................................................................................... 37
1.
INTRODUCTION................................................................................................................................ 38
1.1.
Background .................................................................................................................................... 38
1.1.1.
HCV Infection.............................................................................................................................. 38
1.1.2.
Treatment of HCV Infection ........................................................................................................ 39
1.1.3.
Background of AL-335................................................................................................................ 39
1.1.4.
Background of Odalasvir ............................................................................................................ 42
1.1.5.
Background of Simeprevir .......................................................................................................... 44
1.2.
Background to All-oral Combination Regimens ............................................................................. 46
1.3.
Risk Benefit Section....................................................................................................................... 53
1.3.1.
Known Benefits and Risks.......................................................................................................... 53
1.3.2.
Potential Benefits and Risks....................................................................................................... 56
1.3.2.1.
Potential Benefits..................................................................................................................... 56
1.3.2.2.
Potential Risks......................................................................................................................... 56
1.3.3.
Overall Benefit/Risk Assessment ............................................................................................... 62
1.4.
Overall Rationale for the Study...................................................................................................... 64
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 65
2.1.
Objectives ...................................................................................................................................... 65
2.2.
Hypothesis ..................................................................................................................................... 66
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 67
3.1.
Overview of Study Design.............................................................................................................. 67
3.2.
Study Design Rationale.................................................................................................................. 72
4.
SUBJECT POPULATION.................................................................................................................. 75
4.1.
Inclusion Criteria ............................................................................................................................ 76
4.2.
Exclusion Criteria ........................................................................................................................... 79
4.3.
Prohibitions and Restrictions ......................................................................................................... 81
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 82
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 82
6.1.
Timing of Doses ............................................................................................................................. 83
6.2.
Dose Adjustment and Treatment Interruption................................................................................ 83
6.3.
Treatment Stopping Rule (for Viral Breakthrough) ........................................................................ 84
6.4.
Study Treatment Stopping Rules ................................................................................................... 85
7.
TREATMENT COMPLIANCE............................................................................................................ 85
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8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 86
9.
STUDY EVALUATIONS .................................................................................................................... 88
9.1.
Study Procedures........................................................................................................................... 88
9.1.1.
Overview..................................................................................................................................... 88
9.1.2.
Screening Phase ........................................................................................................................ 89
9.1.3.
Open-label Treatment Phase ..................................................................................................... 90
9.1.4.
Post-treatment Phase (Follow-Up) ............................................................................................. 92
9.2.
Efficacy........................................................................................................................................... 93
9.2.1.
Evaluations ................................................................................................................................. 93
9.2.1.1.
HCV RNA Levels ..................................................................................................................... 93
9.2.1.2.
Alanine Aminotransferase and Aspartate Aminotransferase .................................................. 93
9.2.1.3.
Resistance Determinations...................................................................................................... 93
9.2.1.4.
Patient-reported Outcomes ..................................................................................................... 94
9.2.2.
Endpoints.................................................................................................................................... 96
9.2.2.1.
Primary Endpoints ................................................................................................................... 96
9.2.2.2.
Secondary Endpoints .............................................................................................................. 96
9.2.2.3.
Exploratory Endpoints ............................................................................................................. 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........................................................................ 100
9.5.
Pharmacogenomic (DNA) Evaluations ........................................................................................ 100
9.5.1.
Genotyping of IL28B................................................................................................................. 100
9.5.2.
Genotyping for Drug Metabolism and Transporter Genes ....................................................... 100
9.6.
Occupational/Employment Status................................................................................................ 100
9.7.
Medical Resource Utilization........................................................................................................ 101
9.8.
Safety Evaluations ....................................................................................................................... 101
9.8.1.
Adverse Events......................................................................................................................... 101
9.8.2.
Clinical Laboratory Tests .......................................................................................................... 101
9.8.3.
Electrocardiogram and Echocardiography ............................................................................... 104
9.8.4.
Vital Signs................................................................................................................................. 105
9.8.5.
Physical Examination................................................................................................................ 105
9.8.6.
Management of Specific Toxicities ........................................................................................... 105
9.8.6.1.
Rash (Including Photosensitivity Conditions) ........................................................................ 106
9.8.6.2.
Acute Allergic Reaction ......................................................................................................... 110
9.8.6.3.
Alanine Aminotransferase, Aspartate Aminotransferase and Bilirubin Elevations................ 111
9.8.6.4.
Clinical Hepatitis .................................................................................................................... 113
9.8.6.5.
Pancreatic Amylase or Lipase Elevations ............................................................................. 113
9.8.6.6.
Creatine Kinase ..................................................................................................................... 114
9.8.6.7.
Cardiac Safety Monitoring ..................................................................................................... 115
9.8.6.8.
Renal Safety Monitoring ........................................................................................................ 117
9.8.6.9.
Other Toxicities...................................................................................................................... 117
9.9.
Sample Collection and Handling.................................................................................................. 118
10.
SUBJECT COMPLETION/WITHDRAWAL..................................................................................... 118
10.1.
Completion ................................................................................................................................... 118
10.2.
Discontinuation of Study Treatment............................................................................................. 118
10.3.
Withdrawal From the Study.......................................................................................................... 119
11.
STATISTICAL METHODS............................................................................................................... 120
11.1.
Subject Information ...................................................................................................................... 120
11.2.
Sample Size Determination ......................................................................................................... 120
11.3.
Efficacy Analyses ......................................................................................................................... 121
11.3.1.
Criteria for Endpoints................................................................................................................ 122
11.3.2.
Resistance Determination Analyses......................................................................................... 123
11.3.3.
Patient-reported Outcomes Analyses....................................................................................... 123
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11.4.
Pharmacokinetic Analyses........................................................................................................... 124
11.5.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 124
11.6.
Pharmacogenomic Analyses ....................................................................................................... 125
11.7.
Occupational/Employment Status Analysis ................................................................................. 125
11.8.
Medical Resource Utilization........................................................................................................ 125
11.9.
Safety Analyses ........................................................................................................................... 125
11.10.
Interim Analysis............................................................................................................................ 127
11.11.
Data Review Committee .............................................................................................................. 127
12.
ADVERSE EVENT REPORTING .................................................................................................... 128
12.1.
Definitions .................................................................................................................................... 128
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 128
12.1.2.
Attribution Definitions................................................................................................................ 129
12.1.3.
Severity Criteria ........................................................................................................................ 130
12.2.
Special Reporting Situations........................................................................................................ 130
12.3.
Procedures................................................................................................................................... 130
12.3.1.
All Adverse Events.................................................................................................................... 130
12.3.2.
Serious Adverse Events ........................................................................................................... 131
12.3.3.
Pregnancy................................................................................................................................. 132
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 132
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 132
13.1.
Procedures................................................................................................................................... 133
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 133
14.
STUDY DRUG INFORMATION....................................................................................................... 133
14.1.
Physical Description of Study Drug(s) ......................................................................................... 133
14.2.
Packaging .................................................................................................................................... 133
14.3.
Labeling........................................................................................................................................ 133
14.4.
Preparation, Handling, and Storage............................................................................................. 134
14.5.
Drug Accountability ...................................................................................................................... 134
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 134
16.
ETHICAL ASPECTS ....................................................................................................................... 135
16.1.
Study-specific Design Considerations ......................................................................................... 135
16.2.
Regulatory Ethics Compliance..................................................................................................... 135
16.2.1.
Investigator Responsibilities ..................................................................................................... 135
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 135
16.2.3.
Informed Consent ..................................................................................................................... 137
16.2.4.
Privacy of Personal Data .......................................................................................................... 138
16.2.5.
Long-term Retention of Samples for Additional Future Research............................................ 138
16.2.6.
Country Selection ..................................................................................................................... 139
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 139
17.1.
Protocol Amendments.................................................................................................................. 139
17.2.
Regulatory Documentation .......................................................................................................... 139
17.2.1.
Regulatory Approval/Notification .............................................................................................. 139
17.2.2.
Required Prestudy Documentation........................................................................................... 140
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 140
17.4.
Source Documentation................................................................................................................. 141
17.5.
Case Report Form Completion .................................................................................................... 142
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 142
17.7.
Record Retention ......................................................................................................................... 142
17.8.
Monitoring .................................................................................................................................... 143
17.9.
Study Completion/Termination..................................................................................................... 144
17.9.1.
Study Completion ..................................................................................................................... 144
17.9.2.
Study Termination..................................................................................................................... 144
17.10.
On-site Audits............................................................................................................................... 144
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17.11.
Use of Information and Publication.............................................................................................. 144
REFERENCES.......................................................................................................................................... 147
ATTACHMENTS....................................................................................................................................... 150
INVESTIGATOR AGREEMENT ............................................................................................................... 174
LAST PAGE.............................................................................................................................................. 174
LIST OF ATTACHMENTS
Attachment 1:
WHO Scale for Determining the Severity of Adverse Events...................................... 150
Attachment 2:
Cardiovascular Safety – Abnormalities........................................................................ 155
Attachment 3:
CLDQ-HCV Questionnaire........................................................................................... 156
Attachment 4:
5-level EuroQol 5-Dimension Questionnaire (EQ-5D-5L)............................................ 162
Attachment 5:
Fatigue Severity Scale (FSS)....................................................................................... 165
Attachment 6:
SF-36v2 Questionnaire................................................................................................ 166
Attachment 7:
Visit Schedule for Rash Management ......................................................................... 172
Attachment 8:
Anticipated Events ....................................................................................................... 173
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1:
Disallowed Medication .............................................................................................................. 87
Table 2:
Concomitant Medication to be Used With Caution................................................................... 88
Table 3:
Guidelines for Subjects Developing Rash Grade 1 to Grade 4 .............................................. 107
Table 4:
Guidelines for Subjects Developing Allergic Reactions.......................................................... 110
Table 5:
Treatment-emergent Grade 1 to Grade 4 Alanine Aminotransferase (ALT) or 
Aspartate Aminotransferase (AST) Elevation and Grade 1 to Grade 4 Total Bilirubin 
Elevation ................................................................................................................................. 111
Table 6:
Guidelines for Subjects Developing Alanine Aminotransferase (ALT) and/or Aspartate 
Aminotransferase (AST) Elevations........................................................................................ 112
Table 7:
Guidelines for Subjects Developing Bilirubin Elevations ........................................................ 113
Table 8:
Proposed Threshold Values Indicating Clinically Important Improvement or Worsening 
in Individual Subject’s PRO Scores ........................................................................................ 123
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 70
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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
18 March 2016
Amendment 1
17 June 2016
Amendment 2
12 August 2016
Amendment 3
3 February 2017
Amendment 4
This document
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (10 April 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment is being written to implement study treatment stopping 
rules upon Health Authority feedback. In addition, as more subjects have been recruited than originally planned for, 
the actual number of subjects enrolled in the study is added and statistical considerations for safety are adjusted 
accordingly. Language with regard to HBV DNA assessments in subjects who are anti-HBc positive at baseline is 
added, references to a re-treatment study are deleted, changes are made to the statistical methods section and to the 
definitions of on-treatment failure and relapse.
Rationale: Following Health Authority 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 dosing in all subjects in the current study if the event is adjudicated by the DRC to have met the 
above criteria and 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.
1.3.2.2
Potential Risks
1.3.3
Overall Benefit/Risk Assessment
6.4
Study Treatment Stopping Rules
9.8.6.7
Cardiac Safety Monitoring
10.2
Discontinuation of Study Treatment
11.11 Data Review Committee
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Rationale: Recruitment for this Phase 2 HPC2001 study started in November 2016 and was completed as planned 
on 14 March 2017. Screening of new patients was stopped on 23 February 2017. As the screening failure rate 
towards the end of recruitment was significantly lower as compared to earlier observations, 365 patients were 
enrolled versus the approximately 300 patients planned. Per Sponsor’s policy, patients still in screening at the time 
of reaching the target enrollment in the study are allowed to enroll when proven eligible after completion of the 
screening procedures. The Sponsor confirms the overall risk benefit balance of the study, the study hypothesis and
the integrity of the study data in terms of both efficacy and safety remain unaltered.
As the actual subject recruitment exceeds 10% of the number of subjects planned for in the protocol dated 3 
February 2017, it was deemed appropriate to report this subject number and to update the statistical methods section 
for safety to reflect the actual number of enrolled subjects. 
SYNOPSIS
3.1 Overview of Study Design
4
SUBJECT POPULATION
11.2
Sample Size Determination
Rationale: References to possible re-treatment with AL-335 + ODV + SMV + ribavirin (RBV) for 12 weeks has 
been removed from the protocol since recently published robust data on re-treatment of DAA failures using soon-to-
be-approved regimens have led to the decision not to conduct this re-treatment study. For all subjects who do not 
achieve SVR, the sponsor will reimburse one treatment regimen with the standard of care for this population in the 
respective country.
1.3.2.2
Potential Risks
1.3.3
Overall Benefit/Risk Assessment
3.1
Overview of Study Design
Rationale: Following the recent review of direct-acting antivirals carried out by the European Medicines Agency’s 
(EMA’s) Pharmacovigilance Risk Assessment Committee (PRAC) on returning signs and symptoms of previously 
inactive hepatitis B infection (re-activation) when patients were treated with direct-acting antivirals (DAAs) for 
hepatitis C, the PRAC recommended to include a warning in the prescribing information about hepatitis B 
reactivation and how to minimize it. This recommendation has now been endorsed by EMA’s Committee for 
Medicinal Products for Human Use (CHMP).
HBsAg positive subjects are excluded from the current study. At baseline an anti-HBc test is performed in all 
subjects, but subjects with a positive test can be included in the study. In order to better monitor the risk of HBV 
reactivation during or following short-term HCV DAA treatment, language is added to the protocol indicating the 
need to measure HBV DNA in subjects with a clinically relevant ALT flare as defined in Section 9.8.6.3.
TIME AND EVENTS SCHEDULE
9.8.6.3
Alanine Aminotransferase, Aspartate Aminotransferase and Bilirubin Elevations
Rationale: Since the sponsor’s clinical development strategy aims to establish the shortest efficacious treatment 
duration, a fixed sequence procedure for adjusting for multiple confidence intervals will be used to determine 
non-inferiority of the treatment regimens compared to a historical control and not the Dunnett’s test as indicated in 
Section 11.3 of the protocol (dated 3 February 2017). The 6-week treatment will be tested first (at two-sided alpha 
of 5%) and only if this is statistically non-inferior, the 8-week treatment will be tested for non-inferiority also at 
two-sided alpha of 5%. The protocol has been adjusted accordingly.
11.3
Efficacy Analyses
Rationale: The definition of on-treatment failure and viral relapse are adjusted to align with Health Authority 
guidance on the development of direct-acting antivirals (DAAs) for the treatment of HCV infection.
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DEFINITIONS OF TERMS
Rationale: Minor errors were corrected.
SYNOPSIS
ABBREVIATIONS
TIME AND EVENTS SCHEDULE
3.1
Overview of Study Design
4.1
Inclusion Criteria
9.8.6.6
Creatine Kinase
9.8.6.7
Cardiac Safety Monitoring
11.2
Sample Size Determination
Amendment 3 (3 February 2017)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment is being written to adjust the concomitant medication 
section of the protocol.
Rationale: The protocol dated 12 August 2016 disallows the use of concomitant medication with a potential to 
prolong QT interval. Reference is made to the comprehensive list of 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)37 from screening until the end of the study. This amendment is being written to update Section 8 
PRESTUDY AND CONCOMITANT THERAPY in order to incorporate the possibility to enroll subjects on stable 
treatment with a drug that has the potential to prolong QT interval under specified conditions. 
Available data from 26-week nonclinical studies showed that dose levels at which there were no cardiac findings
corresponded to safety margins of ~6-fold for a 25-mg qd dose at steady state (6,930 ng·h/mL) in humans (predicted 
for the combination with 800 mg AL-335 and 75 mg SMV). In addition, available clinical data have not indicated 
an effect of AL-335, ODV or SMV on QTc. Hence, the sponsor does not consider the risk-benefit of the study 
altered by allowing eligible HCV infected patients on a stable concomitant drug with a potential to increase QT 
interval under specified conditions.
The protocol will continue to disallow the start of medications with the potential to prolong QT interval from 
screening until the end of the study unless the medication is necessary to protect subject safety and it has been 
discussed with the sponsor.
1.3.2.2
Potential Risks
8
PRESTUDY AND CONCOMITANT THERAPY
Amendment 2 (12 August 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: Change in design of the Phase 2b study with focus on treatment-naïve and 
treatment-experienced HCV genotype 1, 2, 4, 5 or 6 infected subjects without cirrhosis.
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Rationale: Following Health Authority feedback, the sponsor has decided to focus this Phase 2b study on HCV 
genotype 1, 2, 4, 5 and 6 infected subjects without cirrhosis for the evaluation of the efficacy, safety and 
pharmacokinetics of 6- and 8-week treatment with AL-335, odalasvir (ODV) and simeprevir (SMV). 
In addition, stratification factors are adjusted. Randomized subjects will be stratified by HCV treatment history 
(treatment-naïve versus treatment-experienced) and HCV geno/subtype (genotypes 1a or 2 versus genotypes 1b, 4, 5 
or 6). In the stratification by HCV geno/subtype, subjects with a genotype 1 non-specifiable subtype at screening 
will be assigned to the genotype 1b, 4, 5 or 6 stratification group.
The sample size remains unchanged, ie, 300 subjects (150 subjects/arm).
TITLE PAGE
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.1.2
Treatment of HCV Infection
1.4
Overall Rationale for the Study
2.1
Objectives
3.1
Overview of Study Design
3.2
Study Design Rationale
4
SUBJECT POPULATION
4.1
Inclusion Criteria
4.2
Exclusion Criteria
5
TREATMENT ALLOCATION AND BLINDING
9.1.2
Screening Phase
9.2.2.3Exploratory Endpoints
Rationale: Following Health Authority feedback, more detail on nonclinical cardiac toxicology data is added. In 
addition, preliminary data from an 8-week mechanistic oral gavage toxicity and toxicokinetic study with ODV in 
telemetered dogs are added. Based on the nonclinical cardiac toxicity data, the potential risk section for ODV 
described in Section 1.3.2.2 is updated.
1.1.4
Background of Odalasvir
1.3.1
Known Benefits and Risks
1.3.2.2
Potential Risks
1.3.3
Overall Benefit/Risk Assessment
Rationale: Data of studies AL-335-602 and AL-335-604 are updated with final data from study AL-335-602 and 
preliminary data from study AL-335-604, in line with the AL-335 Investigator’s Brochure Edition 2, Addendum 243
and the ODV Investigator’s Brochure Edition 6, Addendum 4.44 The preliminary data from study AL-335-604 are 
based on a snapshot analysis, ie, no formal database lock was performed. 
ABBREVIATIONS
1
INTRODUCTION
1.1.3
Background of AL-335
1.1.4
Background of Odalasvir
1.2
Background to All-oral Combination Regimens
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1.3.2.2
Potential Risks
1.4
Overall Rationale for the Study
3.2
Study Design Rationale
REFERENCES
Rationale: It is clarified in the protocol that safety, efficacy, and/or pharmacokinetic data from this study may be 
pooled with data from the Phase 2a AL-335-604 study and potentially other similarly performed studies to assess 
the combination regimen of AL-335, ODV and SMV. This will increase the sample size for the different 
subgroups/duration groups and provide for more accurate estimates for safety and efficacy endpoints. The details of 
this combined analysis will be outlined in a separate analysis plan.
3.1
Overview of Study Design
11
STATISTICAL METHODS
Rationale: Following Health Authority feedback, the recommendations regarding the concomitant use of calcium 
channel blockers are modified, ie, these drugs are disallowed from screening until the end of the study. Per the 
protocol Amendment 1, dated 17 June 2016, the concomitant use of calcium channel blockers without known 
impact on QT interval was to be used with caution. The sponsor in addition decided to disallow the use of sodium 
and potassium channel blockers from screening until the end of the study.
The list of proton-pump inhibitors, antifungals and antiretrovirals was extended.
It was clarified that consumption of large quantities of grapefruit juice (>1 liter/day) is disallowed from baseline till 
the end of treatment.
8
PRESTUDY AND CONCOMITANT THERAPY
Rationale: Following recent publications on the reactivation of HBV infection after short duration DAA-
containing HCV treatmenta, the sponsor decided to add anti-HBc testing at baseline to the protocol. For anti-HBc 
positive subjects, anti-HBs will be determined. 
TIME AND EVENTS SCHEDULE
9.8.2
Clinical Laboratory Tests
Rationale: The protocol is aligned with the recently updated sponsor’s internal protocol template with regard to the 
prohibitions and restrictions, including location of contraceptive requirement. In addition, the language of the 
contraceptive requirements is being aligned across the planned/ongoing JNJ-64294178 studies and adjusted in this 
protocol accordingly.
                                                
a
Ende AR, Kim NH, Yeh MM, Harper J, Landis CS. Fulminant hepatitis B reactivation leading to liver 
transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. 
Journal of Medical Case Reports. 2015;9: 1-4.
Collins JM, Rapael KL, Terry C, et al. Hepatitis B virus reactivation during successful treatment of hepatitis C 
virus with sofosbuvir and simeprevir. Clinical Infectious Diseases. 2015;61(8): 1304-1306.
Kimura H, Ohkawa K, Sakakibara M et al. Sustained hepatitis C virus RNA clearance accompanied by 
elevation of hepatitis B virus DNA after short-term peginterferon-alpha, ribavirin and simeprevir therapy in 
chronic hepatitis patient having dual infection with hepatitis B and C viruses. Acta Hepatologica Japonica. 
2015;56(8): 422-427.
Balagopal A, Thio CL. Another call to cure Hepatitis B. Clinical Infectious Disease. 2015;61(8): 1307-1309.
Sato T. A case of superinfection of HBV/HCV in which therapy with daclatasvir and asunaprevir was done. 
The 103rd Cyugoku Regional Meeting of the Japanese Society of Gastroenterology. 2015;56.
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AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
11
Approved, Date: 10 April 2017
1.3.2.2
Potential Risks
4.1
Inclusion Criteria
4.3
Prohibitions and Restrictions
8
PRESTUDY AND CONCOMITANT THERAPY
Rationale: A sentence was added to the protocol to clarify that all efforts need to be made to enroll as many HCV 
genotype 2, 4, 5 and 6 infected subjects as possible.
SYNOPSIS
3.1
Overview of Study Design
4
SUBJECT POPULATION
Rationale: The list of anticipated events included in Attachment 8 has been updated.
ATTACHMENTS
Rationale: The time window for the Fibroscan confirming absence of cirrhosis has been adjusted from within 3 
months prior to baseline/Day 1 to within 6 months prior to baseline/Day 1.
SYNOPSIS
TIME AND EVENTS SCHEDULE
4.1 Inclusion Criteria
Rationale: Minor errors and inconsistencies were noted and corrected and clarifications were added where required.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.1.2
Treatment of HCV Infection
1.1.3
Background of AL-335
1.1.4
Background of Odalasvir
1.1.5
Background of Simeprevir
1.2 Background to All-oral Combination Regimens
1.3.1
Known Benefits and Risks
1.3.2.2Potential Risks
1.3.3
Overall Benefit/Risk Assessment
1.4
Overall Rationale for the Study
3.1
Overview of Study Design
3.2
Study Design Rationale
4.2
Exclusion Criteria
4.3
Prohibitions and Restrictions
8
PRESTUDY AND CONCOMITANT THERAPY
9.3.1
Evaluations
9.3.3
Pharmacokinetic Parameters
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Approved, Date: 10 April 2017
9.8.2
Clinical Laboratory Tests
9.8.6.7Cardiac Safety Monitoring
11.11 Data Review Committee
REFERENCES
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
13
Approved, Date: 10 April 2017
Amendment 1 (17 June 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: Change in design of the Phase 2b study with focus on evaluating the 
3-DAA treatment regimen comprising of AL-335+ODV with SMV.
Rationale: In treatment of chronic HCV infection, a combination of potent direct-acting antivirals (DAAs) with a 
different mechanism of action and non-overlapping resistance profiles is required to maximize the likelihood of 
achieving sustained virologic response (SVR) or cure. Currently, a Phase 2a study, AL-335-604, to evaluate the 
safety, pharmacokinetics and efficacy of the combination of AL-335, ODV and SMV in treatment-naïve subjects 
with genotype 1 and genotype 3 CHC is ongoing. In this Phase 2a study different treatment regimens of AL-
335+ODV with or without SMV (2-DAA and 3-DAA regimen) are being studied with the aim to determine the 
optimal dose of each component. Preliminary data from the ongoing Phase 2a study AL-335-604 (refer to Section 
1.2 for details) provide support for the use of the 3-DAA combination of AL-335+ODV with SMV to maximize 
SVR when evaluating short treatment durations of 6 and 8 weeks.
Based on the above data, the sponsor has made an informed decision to focus only on the 3-DAA combination. The 
updated study design of study 64294178HPC2001 aims to evaluate the combination of a 3-DAA regimen (AL-335
800 mg qd + ODV 25 mg qd + SMV 75 mg qd) in a regimen that shortens treatment duration compared to currently 
available treatment regimens, regardless of genotype or the presence or absence of compensated cirrhosis, to 8 or 
6 weeks without compromising efficacy, or the subject’s compliance and safety.
The 3-DAA regimen will be investigated for both 6 and 8 weeks (arms A and B). An increase in sample size per 
study arm from 100 to 150 patients will allow for more robust subgroup analysis. Sample size calculations were 
adjusted accordingly. The aim remains to have 30% of the subjects overall with compensated cirrhosis who are 
restricted to having genotype 1 or 3 infection. In addition, proportionally to the aim in the protocol dated 18 March 
2016, per treatment arm, approximately 30 HCV genotype 3 infected subjects, including approximately 15 subjects 
with cirrhosis, are aimed to be enrolled.
As per the initial protocol of 18 March 2016, 20 subjects from the 2-DAA (arms C and D combined) and 20 subjects 
from the 3-DAA (arms A and B combined) arms were planned to be included in the sparse PK and rich PK 
substudies each. In correspondence with the initial protocol, 20 subjects from arms A and B combined will be 
included in the sparse and rich PK substudies, each. However, since the 2-DAA combination will not be studied 
(arms C and D) the total number of subjects in the sparse and rich PK substudies will be 20 subjects each compared 
to 40 subjects in the initial protocol.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.1.2
Treatment of HCV Infection
1.2
Background to All-oral Combination Regimens
1.4
Overall Rationale for the Study
2.1
Objectives
3.1
Overview of Study Design
3.2
Study Design Rationale
4
SUBJECT POPULATION
4.3
Prohibitions and Restrictions
5
TREATMENT ALLOCATION AND BLINDING
6
DOSAGE AND ADMINISTRATION
6.1
Timing of Doses
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AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
14
Approved, Date: 10 April 2017
8
PRESTUDY AND CONCOMITANT THERAPY
9.1.3
Open-label Treatment Phase
9.1.4
Post-treatment Phase (Follow-Up)
9.3.1
Evaluations
9.3.2
Analytical Procedures
9.3.3
Pharmacokinetic Parameters
9.8.6
Management of Specific Toxicities
11.2
Sample Size Determination
11.3
Efficacy Analyses
11.4
Pharmacokinetic Analyses
11.7
Occupational/Employment Status Analysis
11.8
Medical Resource Utilization
11.9
Safety Analyses
Rationale: Given the long half-life of ODV and to ensure close monitoring of patients for late relapse during 
follow-up an additional visit will be scheduled 18 weeks after the EOT to collect samples for HCV RNA 
determination and viral sequencing.
SYNOPSIS
TIME AND EVENTS SCHEDULE
9.2.2.2Secondary Endpoints
Rationale: Following Health Authorities recommendation, it is clarified in the protocol that substantial changes to 
the study conduct other than the possible treatment prolongation triggered by the DRC which is clearly specified in 
the protocol, will lead to a protocol amendment which is to be submitted to ECs/IRBs for approval. In addition it is 
clarified that DRC also take emerging data of other completed and ongoing studies, including the Phase 2a study 
AL-335-604, into account in making informed recommendations on the continuation of the current study.
SYNOPSIS
1.3.3
Overall Benefit/Risk Assessment
3.1
Overview of Study Design
6.3
Treatment Stopping Rule (for Viral Breakthrough)
11.11 Data Review Committee
Rationale: Per the initial protocol of 18 March 2016, from the W4 FU visit until the subject’s last study related 
procedure, only SAEs, AEs at least possibly related to the study drugs by the investigator and AEs leading to study 
discontinuation had to be reported. Following Health Authority feedback, the protocol is adjusted to indicate that all 
AEs, irrespective of severity or causality, need to be reported from signing of the ICF until the subject’s last study 
visit. In addition, the assessment of AEs at Week 10 visit (if applicable) was missing in the Time and Events 
Schedule and has been added.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.3.3
Overall Benefit/Risk Assessment
9.1.4
Post-treatment Phase (Follow-Up)
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Clinical Protocol 64294178HPC2001 Amendment 4
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Approved, Date: 10 April 2017
9.8
Safety Evaluations
9.8.2
Clinical Laboratory Tests
9.8.3
Electrocardiogram and Echocardiography
9.8.4
Vital Signs
9.8.5
Physical Examination
12.3.1 All Adverse Events
Rationale: For female subjects of childbearing potential, a urine pregnancy test will be performed on Day 1 and at 
least every 4 to 6 weeks up to the W24 FU visit. The urine pregnancy test to be performed on Day 1 was not 
consistently mentioned throughout the protocol. This inconsistency is corrected. In addition, given the long half-life 
of ODV, urine pregnancy tests will be performed every 4 to 6 weeks up to the W24 FU visit and not up to the 
W12 FU visit as indicated in the initial protocol dated 18 March 2016. 
TIME AND EVENTS SCHEDULE
4.3
Prohibitions and Restrictions
9.1.3
Open-label Treatment Phase
Rationale: Following Health Authority feedback, recommendations with regard to concomitant therapy with 
amiodarone has been changed, disallowing amiodarone within 3 months prior to screening until the end of the study 
rather than EOT as per the initial protocol, dated 18 March 2016. In addition, a note is added to indicate that all 
concomitant medications with a potential to prolong QT interval, including digoxin, are disallowed from screening 
until the end of the study. Reference is made to the comprehensive list of 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.39 Consequently, medications with the potential to prolong QT interval were removed 
from the list of medications ‘to be used with caution’. Finally, recommendations with regard to the use of grapefruit 
juice are added: consumption of large quantities of grapefruit juice (>1 liter/day) should be avoided from baseline 
till EOT.
8
PRESTUDY AND CONCOMITANT THERAPY
REFERENCES
Rationale: Following Health Authority recommendations, B-type natriuretic peptide (BNP) testing is added to the 
protocol. The addition of testing with BNP increases the possibility for early detection of impaired cardiac function 
in between evaluation with echocardiography. To this end, BNP assessment will be performed at baseline, Week 2, 
Week 4, Week 6, the EOT and Week 4 FU. 
TIME AND EVENTS SCHEDULE
ABBREVIATIONS
8
PRESTUDY AND CONCOMITANT THERAPY
9.8.2
Clinical Laboratory Tests
Rationale: Following Health Authority feedback, more information is provided with regard to the potential risk of 
development of drug resistance. 
1.3.2.2Potential Risks
REFERENCES
Rationale: Following Health Authority feedback, the goal of the efficacy analyses is further clarified. 
11.3
Efficacy Analyses
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AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
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Approved, Date: 10 April 2017
Rationale: Following Health Authority feedback, it is clarified that in case 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 should ensure the subject signs a revised consent, if applicable. In addition, it is clarified that the sponsor will 
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 ADVERSE EVENT REPORTING
16.2.3 Informed Consent
Rationale: Following Health Authority feedback, the individual stopping criteria in response to changes in the EF 
described in Section 9.8.6.7 Cardiac Safety Monitoring of the protocol have been clarified. Asymptomatic patients 
with no clinical evidence of congestive failure: (1) if the absolute change (decrease) from baseline in LVEF ≥10% 
(eg, 59% to 49%) should discontinue AL-335, ODV and SMV if the change results in an LVEF of <50%. If the 
change is >10% but resulting in an LVEF >50%, an assessment of the subject’s clinical status including symptoms, 
physical exam, and other clinical parameters should be made before deciding whether to stop or continue study 
drugs. In both cases a mandatory assessment and urgent cardiology referral should be planned; 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.
9.8.6.7Cardiac Safety Monitoring
Rationale: Taking into account the normal physiological variations that can be observed with regard to PR 
intervals, and considering that an isolated ECG finding of increased PR interval does not necessarily indicate an 
underlying pathological condition that impacts the overall benefit-risk assessment, the individual stopping criteria in 
response to changes in PR interval (described in Section 9.8.6.7 Cardiac Safety Monitoring) have been clarified:
(1) If the PR interval is >200 milliseconds but <240 milliseconds, study drugs can be continued. Close 
monitoring with weekly ECGs is recommended; 
(2) If the PR interval >240 milliseconds but <300 milliseconds (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 exam, and other clinical parameters should be made and study drugs can be continued. 
Close monitoring with weekly ECG is recommended; 
(3) If the PR interval is >300 milliseconds43 or 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.
Furthermore, it is specified in the protocol that, in case the QTc value is >500 milliseconds (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 milliseconds from baseline, thorough evaluation of the clinical case and discussion
with the sponsor is required to assess further treatment strategy.
9.8.6.7Cardiac Safety Monitoring
Rationale: In the footnotes to the Time and Events Schedule, the timing of Fibroscan, liver biopsy and ultrasound 
were incorrect and inconsistent with the body text of the protocol. This is corrected to indicate that, in subjects with 
cirrhosis, cirrhosis should be confirmed by a Fibroscan or liver biopsy performed prior to or during the screening 
period. For subjects without cirrhosis, absence of cirrhosis should be confirmed by Fibroscan performed within 3 
months or liver biopsy within 6 months of baseline (Day 1). Subjects with cirrhosis have to receive an ultrasound 
scan within 3 months prior to baseline/Day 1.
TIME AND EVENTS SCHEDULE
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
17
Approved, Date: 10 April 2017
Rationale: According to the initial protocol, dated 18 March 2016, in certain cases of abnormal CK values all study 
medication had to be discontinued (see Section 9.8.6.6). However, since some subjects, depending on their baseline 
characteristics, may have a high chance of achieving SVR when they continue treatment with ODV and SMV, the 
sponsor considers it more appropriate to discontinue AL-335 and for the investigator to discuss ODV and SMV 
continuation with the sponsor on a case-by-case basis. Only 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.
9.8.6.6Creatine Kinase
Rationale: It is specified that, if thyroid stimulating hormone (TSH) is not within the normal range, testing of free 
triiodothyronine (fT3) and free thyroxine (fT4) will be performed.
TIME AND EVENTS SCHEDULE
ABBREVIATIONS
9.8.2
Clinical Laboratory Tests
Rationale: For clarity, the terminology with regard to the PK sampling is made consistent throughout the protocol, 
ie, PK blood sampling for the samples taken in all subjects, rich serial PK substudy (N=20 subjects) and sparse PK 
substudy (N=20 subjects). In addition, the body of the protocol was made consistent with regard to the 
documentation of food intake on the days of PK assessments and the previous day, ie, on the day prior to the PK 
assessments (all PK samples) it will be recorded whether study drugs were taken with food (ie, during or no later 
than 15 minutes after a meal). In case of the PK sampling in all subjects and the sparse PK substudy, on the day of 
the PK sampling it will be recorded whether study drugs were taken with food (ie, during or no later than 15 
minutes after a meal). In the rich serial PK substudy on the day of the PK sampling, the start and end time of the 
meal will be recorded.
SYNOPSIS
6.1
Timing of Doses
7
TREATMENT COMPLIANCE
9.1.3
Open-label Treatment Phase
9.1.4
Post-treatment Phase (Follow-Up)
9.3.1
Evaluations
11.4
Pharmacokinetic Analyses
Rationale: The protocol is aligned with the recently updated sponsor’s internal protocol template.
4.1
Inclusion Criteria
16.2.2 Independent Ethics Committee or Institutional Review Board
17.5
Case Report Form Completion
Rationale: In Attachment 2, the toxicity grading table for vital sign parameters was erroneously copied where the 
table for the PR interval toxicity grading scale had to be provided. This error is corrected.
Attachment 2:
Cardiovascular Safety - Abnormalities
Rationale: Minor errors were noted and corrected and minor clarifications were added where considered needed.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.1.2
Treatment of HCV Infection
1.1.3
Background of AL-335
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AL-335, odalasvir, TMC435 (simeprevir)
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Approved, Date: 10 April 2017
1.3.1
Known Benefits and Risks
1.3.3
Overall Benefit/Risk Assessment
1.4
Overall Rationale for the Study
2.1
Objectives
3.1
Overview of Study Design
3.2
Study Design Rationale
4.1
Inclusion Criteria
4.3
Prohibitions and Restrictions
8
PRESTUDY AND CONCOMITANT THERAPY
9.1.2
Screening Phase
9.1.3
Open-label Treatment Phase
9.1.4
Post-treatment Phase (Follow-Up)
9.2.1.1HCV RNA Levels
9.2.1.3Resistance Determinations
9.3.1
Evaluations
9.8.3
Electrocardiogram and Echocardiography
9.8.6
Management of Specific Toxicities
9.8.6.1Rash (Including Photosensitivity Conditions)
9.8.6.7Cardiac Safety Monitoring
10.2
Discontinuation of Study Treatment
11.4
Pharmacokinetic Analyses
REFERENCES
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
19
Approved, Date: 10 April 2017
SYNOPSIS
A Phase 2b, Multicenter, Randomized, Open-label Study to Investigate the Efficacy, Safety and 
Pharmacokinetics of Different Treatment Regimens of AL-335, Odalasvir, and Simeprevir in Treatment-
naïve and Treatment-experienced Subjects With Chronic Hepatitis C Virus Genotype 1, 2, 4, 5 and 6 
Infection Without Cirrhosis.
AL-335 (also known as JNJ-64146212) is a uridine based nucleoside monophosphate prodrug (or 
nucleotide analog) targeting hepatitis C virus (HCV) non-structural protein (NS)5B polymerase being 
developed for the treatment of chronic HCV (in clinical development).
Odalasvir (ODV, also known as ACH-0143102 and ACH-3102) is an HCV NS5A inhibitor being 
developed for the treatment of chronic HCV infection (in clinical development). 
Simeprevir (SMV, also known as TMC435) is an HCV NS3/4A protease inhibitor approved for the 
treatment of chronic HCV genotype 1 and 4 infection.
OBJECTIVE AND HYPOTHESES
Primary Objective
To evaluate the efficacy, ie, sustained virologic response 12 weeks after the end of treatment (SVR12), of
a combination treatment with AL-335, ODV, and SMV for 6 and 8 weeks in chronic HCV genotype 1, 2, 
4, 5 and 6 infected subjects without cirrhosis.
Secondary Objectives

To evaluate the safety and tolerability of a 6- and 8-week treatment regimen containing AL-335, 
ODV, and SMV in subjects without cirrhosis,

To evaluate SVR4 and SVR24 of a 6- and 8-week treatment regimen containing AL-335, ODV, 
and SMV in subjects without cirrhosis,

To evaluate on-treatment viral kinetics in a 6- and 8-week treatment regimen containing AL-335, 
ODV, and SMV in subjects without cirrhosis,

To evaluate the incidence of on-treatment failure during a 6- and 8-week treatment regimen 
containing AL-335, ODV, and SMV in subjects without cirrhosis,

To evaluate the incidence of viral relapse after an 6- and 8-week treatment regimen containing 
AL-335, ODV, and SMV in subjects without cirrhosis,

To assess changes from baseline in HCV NS3/4A, NS5A, and NS5B sequence in subjects not 
achieving SVR,

To evaluate the effect of the presence or absence of baseline HCV NS3/4A polymorphisms 
(including Q80K), NS5A polymorphisms and/or NS5B polymorphisms on treatment outcome 
(SVR12, on-treatment failure, viral relapse, and emergence of resistance), 

To evaluate concordance between SVR4, SVR12, and SVR24,

To evaluate the pharmacokinetics (PK) of AL-335 (and its 2 metabolites ALS-022399 and 
ALS-022227; AL-335 and its metabolites ALS-022399 and ALS-022227 are further referred to as 
AL-335 [and metabolites]), ODV, and SMV, in plasma,
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
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Approved, Date: 10 April 2017

To evaluate the relationship between the population-derived exposure parameters of AL-335 (and 
metabolites), ODV, and SMV (ie, area under the plasma concentration-time curve from time 0 
until 24 hours post dosing [AUC24h] and predose plasma concentrations [C0h]) with SVR12 and 
safety,

To explore the impact of HCV and its treatment with AL-335+ODV+SMV on the Fatigue 
Severity Scale (FSS) total score and the 5-level EuroQol 5-Dimension (EQ-5D-5L) Visual 
Analog Scale (VAS) score.
Exploratory Objectives

To explore the effect of prior HCV treatment history, baseline host and disease related characteristics 
including but not limited to HCV geno/subtype, baseline HCV ribonucleic acid (RNA) level, genetic 
factors (eg, interleukin-28B [IL28B] genotype), race, sex and age on treatment outcome,

To explore the impact of HCV and its treatment with AL-335+ODV+SMV on symptoms,
functioning and health-related quality of life (HRQoL), using patient-reported outcomes (PROs), ie, 
EQ-5D-5L domain scores, Short Form 36 version 2 (SF-36v2) Physical Component Summary and 
Mental Component Summary scores, and Chronic Liver Disease Quality of Life Questionnaire –
HCV (CLDQ-HCV) summary and domain scores,

To explore the impact of HCV treatment with AL-335+ODV+SMV on occupational/employment 
status,

To describe the impact of HCV treatment on medical resource utilization (MRU).
Hypothesis
The SVR12 rate is non-inferior in at least one treatment arm to the performance benchmark of 98% 
(based on historical interferon [IFN]-free, direct-acting antiviral [DAA] regimens) with a non-inferiority 
margin of 10%.
Statistical testing will be conducted using null hypothesis H0: C-T≥10% vs. Ha: C-T<10% at a 
significance level of 0.05, 2-sided, where C is the historical control rate of 98% and T is the expected 
SVR rate in the treatment arm.
OVERVIEW OF STUDY DESIGN
This is a Phase 2b multicenter, randomized, open-label, study to investigate the efficacy, safety and PK of 
a 6- and 8-week treatment regimen with AL-335, ODV, and SMV followed by a 24-week post-treatment 
follow-up in treatment-naïve and treatment-experienced subjects with chronic HCV genotype 1, 2, 4, 5 or 
6 infection without cirrhosis.
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 phase can be extended if discussed with and 
approved (documented) by the sponsor. Thereafter, if eligible, subjects will be randomized to receive
AL-335, ODV, and SMV for either 6 or 8 weeks. A post-treatment follow-up until 24 weeks after the 
actual end of treatment (EOT) is included to assess SVR12 and SVR24. The total study duration for each 
subject will be approximately 36 to 38 weeks (including the 6-week screening period, the 6- or 8-week 
treatment period, and the 24-week post-treatment follow-up period). The study is considered completed 
with the last visit of the last subject participating in the study.
The dose of SMV will be 75 mg once daily (qd), the dose of ODV will be 25 mg qd, and the dose of 
AL-335 will be 800 mg qd.
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
21
Approved, Date: 10 April 2017
Approximately 300 treatment-naïve or -experienced (to [pegylated {Peg}] IFN ± ribavirin [RBV])
chronic HCV genotype 1, 2, 4, 5 and 6 infected subjects without cirrhosis will be randomized (in a 1:1
ratio) to one of the following treatment arms:

Arm A (N=150): AL-335 800 mg qd + ODV 25 mg qd + SMV 75 mg qd for 6 weeks

Arm B (N=150): AL-335 800 mg qd + ODV 25 mg qd + SMV 75 mg qd for 8 weeks
Patients still in screening at the time of reaching the target enrollment in the study were allowed to enroll 
when proven eligible after completion of the screening procedures, leading to the enrollment of an 
additional 65 subjects in the study (365 subjects in total: 183 subjects in Arm A and 182 subjects in Arm 
B).
Randomized subjects in arms A and B will be stratified by HCV treatment history (treatment-naïve versus 
treatment-experienced) and HCV geno/subtype (genotype 1a or 2 versus genotype 1b, 4, 5, or 6). In the 
stratification by HCV geno/subtype, subjects with a genotype 1 non-specifiable subtype at screening will 
be assigned to the 1b, 4, 5 or 6 stratification group. All efforts need to be made to enroll as many HCV 
genotype 2, 4, 5 and 6 subjects as possible.
HCV RNA levels will be processed in real time and continuously monitored by the sponsor and 
communicated to the investigator throughout the study. Subjects will be monitored from Day 1 through 
end of follow-up for viral breakthrough or relapse. Study drugs will be discontinued for subjects with 
viral breakthrough (ie, confirmed >1.0 log10 increase in HCV RNA from nadir or confirmed HCV RNA 
>100 IU/mL in subjects who had previously achieved HCV RNA <lower limit of quantification [LLOQ]).
A Data Review Committee (DRC) will be established to monitor data on a regular basis to ensure the 
continuing safety, efficacy, and well-being of the subjects enrolled in this study. The DRC is a committee 
within the sponsor’s organization that is independent of the sponsor’s study team. Virologic failures will 
be communicated immediately to the DRC to trigger efficacy review. Emerging safety and efficacy data 
from this study will be reviewed at predetermined intervals. As a part of the safety evaluations, the DRC
will also review adverse events (AEs) considered as anticipated events for this patient population.
Upon review of the HCV RNA data from this study and/or consideration of data from other completed 
and ongoing studies, including the Phase 2a study AL-335-604, the DRC will make study conduct 
recommendations, which may include but are not limited to, continuing the study without modifications 
and/or implementation of treatment extension as described below. The sponsor’s decision based on the 
recommendation will be communicated to the investigator. Details will be specified in a separate charter.
In case a treatment extension is recommended by the DRC, treatment duration of the arms will be 
extended up to a maximum of 12 weeks (ie, the 6-week arm will be extended to 8 weeks, or both arms 
will be extended to 12 weeks). All subjects will continue to attend study visits every 2 weeks. In case of 
treatment extension to 8 weeks, the subjects should follow the visit schedule of subjects initially included 
in the 8-week treatment arm, with an EOT visit at Week 8. In case of treatment extension to 12 weeks, 
subjects should follow the schedule for the 12-week treatment extension arm with an EOT visit at 
Week 12 (see Time and Events Schedule).
In case of substantial changes to the study conduct, other than the treatment extension described above, an 
amendment to the current protocol will be submitted for approval by the competent authorities.
If study drug treatment 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 early 
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 (W4 FU) visit need to be performed. Any subject who withdraws consent during 
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
22
Approved, Date: 10 April 2017
the follow-up phase and/or notifies the site 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 (W24 FU) visit. However, all possible efforts should be made to ensure that
subjects complete the study.
SUBJECT POPULATION
Approximately 300 subjects were planned to be enrolled in the study and in total 365 subjects have been 
enrolled. The first screening assessment will be performed within 6 weeks before the first administration 
of study drugs. The key inclusion and exclusion criteria are summarized below.
Key Inclusion Criteria
Description 
Age and sex
Man or woman, 18 to 70 years of age, inclusive.
Body Mass Index
Body Mass Index (BMI) of 18.0 to 35.0 kg/m2, inclusive.
HCV genotype
All subjects must have HCV genotype 1, 2, 4, 5 or 6 infection, determined
at screening. 
Plasma HCV RNA 
>10,000 IU/mL (determined at screening).
HCV treatment history
Subjects can either be HCV treatment-naïve, defined as not having 
received treatment with any approved or investigational drug (including 
DAAs, IFN-based treatments, and vaccines) for chronic HCV infection, or 
HCV treatment-experienced, defined as having received HCV therapy 
consisting of IFN (pegylated or non-pegylated) with or without RBV.
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).

Note: liver biopsy should only be considered as an alternative in subjects 
where Fibroscan is not feasible.
Key Exclusion Criteria
Description 
Infection/co-infection
HCV genotype 3 infection
HCV co-infection with multiple genotypes
Human immunodeficiency virus (HIV) co-infection
Presence of cirrhosis
Exposure to a DAA
Prior exposure to an HCV DAA, either in combination with PegIFN or 
IFN-free.
Liver disease of non-HCV etiology
Any evidence of liver disease of non-HCV etiology. This includes, but is 
not limited to, acute hepatitis A infection (immunoglobulin M), hepatitis B 
infection (hepatitis B surface antigen positive), drug- or alcohol-related 
liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease, 
alpha-1 antitrypsin deficiency, primary biliary cirrhosis, or any other 
non-HCV 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 or 
hair transplant or skin graft).
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
23
Approved, Date: 10 April 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% or any other echocardiogram finding suggestive of clinically 
relevant cardiomyopathy;

abnormal electrocardiogram (ECG) findings such as: significantly 
abnormal PR [PR interval >200 milliseconds], QRS intervals or 
corrected QT interval [QTc] >450 milliseconds for male subjects and 
>470 milliseconds for female subjects (based on the average of the 
3 QTc values used to determine the subject’s eligibility);

evidence of any heart block;

evidence of right bundle branch block or left bundle branch block;

history or family history of prolonged QT syndrome (torsade de 
pointes) or sudden cardiac death.
Key laboratory values
Any of the following laboratory abnormalities at screening:

Platelet count <75 x 10³/µL or <75 x 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 x 10³/µL or <1.00 x 109/L;

Alanine 
aminotransferase 
(ALT)
and/or 
aspartate 
aminotransferase (AST) >10 x upper limit of normal (ULN);

Total serum bilirubin >1.5 x ULN;

Albumin <3.5 g/dL or <35 g/L;

estimated glomerular filtration rate (eGFR) of <50 mL/min/1.73 
m².
Hepatocellular carcinoma
Subjects who 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 for 6 weeks (arm A) or 
8 weeks (arm B).
All study drugs (AL-335, ODV, and SMV) should be taken once daily together in the morning at 
approximately the same time every day throughout the treatment phase and should be taken with food 
(ie, during or no later than 15 minutes after a meal). 
EFFICACY EVALUATIONS
All evaluations will be performed as specified in the Time and Events Schedule.
HCV RNA Levels
Blood samples for the determination of HCV RNA levels will be taken at all scheduled visits, processed 
in real time and results closely monitored by the sponsor. The results will be communicated to the 
investigator throughout the study. 
ALT and AST
ALT and AST levels will be determined as part of the biochemistry panel of the clinical laboratory tests. 
Samples for biochemistry will be taken at predefined time points and will be processed in real time.
Resistance Determinations
Sequencing of the HCV NS3/4A, NS5A and NS5B regions will be performed to identify pre-existing 
sequence polymorphisms and characterize emerging HCV variants. The NS3/4A, NS5A and NS5B 
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
24
Approved, Date: 10 April 2017
regions will be sequenced pre-treatment (from the baseline sample) by default in all subjects and 
post-baseline in subjects not achieving SVR. Sequencing of additional samples may be triggered by the 
sponsor virologist.
Patient-reported Outcomes
The impact of HCV and its treatment (safety and efficacy) on patient-reported symptoms, functioning and 
HRQoL will be evaluated, in all subjects at selected sites where appropriate translations are available, at 
predefined time points. The following PRO assessments will be used: CLDQ-HCV, EQ-5D-5L, FSS, and
SF-36v2 questionnaire.
PHARMACOKINETIC EVALUATIONS
All subjects will undergo PK blood sampling at the Week 4 visit, the Week 6 visit (arm B), and at the 
EOT visit at any time during the visit for the measurement of plasma concentrations of AL-335 (and 
metabolites), ODV, and SMV (see the Time and Events Schedule). At the EOT visit, subjects should still 
be on treatment at the time of the PK assessment. In case of treatment extension to 8 weeks or 12 weeks,
no additional PK assessments will be done.
In the rich serial PK substudy and sparse PK substudy, performed at selected study sites, PK blood 
sampling for the measurement of plasma concentrations of AL-335 (and metabolites), ODV, and SMV
will be performed in approximately 20 subjects in the rich PK substudy and 20 subjects in the sparse PK 
substudy, as indicated in the Time and Events Schedule: PK Assessments in PK Substudies.
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure parameters (C0h
and AUC24h) with SVR12 and with safety endpoints will be explored graphically.
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. Where locally permitted 
and upon consent of the subject (in addition to the consent for the main part of the study) an additional 
optional blood sample will be collected at baseline for exploratory host deoxyribonucleic acid (DNA)
research related to AL-335 (and metabolites), ODV, and SMV, and limited to genes involved in the 
metabolism of the study drugs as well as drug transporter genes.
OCCUPATIONAL/EMPLOYMENT STATUS
Information regarding occupational/employment status will be collected for all subjects at predefined time 
points.
MEDICAL RESOURCE UTILIZATION
MRU data will be collected at all scheduled visits from baseline until the W24 FU visit. Data collected
may be used to conduct exploratory economic analyses.
SAFETY EVALUATIONS
Safety and tolerability will be evaluated throughout the study from signing of the informed consent form 
(ICF) onwards until the end of the study. The evaluations of safety and tolerability will include 
monitoring of adverse events (AEs), clinical laboratory tests, ECGs, echocardiograms, vital sign 
measurements and physical examinations at predefined time points.
All AEs, whether serious or non-serious as well as pregnancies, will be reported from the time a signed 
ICF is obtained until the subject’s last study visit. 
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
25
Approved, Date: 10 April 2017
Specific toxicity management plans in line with the known pharmacological profile of the study drugs
(and the drug class) evaluated in this study are incorporated in this protocol.
STATISTICAL METHODS
The description of the sizing for the study based on 300 subjects is provided below.
The sample size consideration is based on non-inferiority testing against performance benchmark 98% 
based on historical data (ASTRAL 1-3 studies) in an IFN-free, 2-DAA (SOF/velpatasvir [VEL]) regimen 
for 12 weeks of treatment. Statistical hypothesis will be tested per arm using the confidence interval (CI)
approach with the lower bound of CI excluding a predefined threshold for non-inferiority of SVR12. The 
SVR performance benchmark is chosen to be 98% based on ASTRAL 1-3 studies, in which, across 
genotypes 1-6, SVR was observed to be 98% with 95% CI: 97% to 98.8%. In a subgroup of cirrhosis 
(F4), the SVR was 96% with 95% CI: 92.8% to 98.4%. Non-inferiority margin 10% was determined by 
referencing the most recent data from the ASTRAL-2 study, where 10% non-inferiority margin was used 
to compare 2-DAA (SOF/VEL) to active control SOF+RBV for non-inferiority. Additionally, recent data 
from a 3-DAA regimen plus RBV (Abt-450/r + ombitasvir + dasabuvir + RBV) in comparison to the 
historical control in a DAA with PegIFN/RBV used 10.5% non-inferiority margin for the non-inferiority 
testing. Therefore, a 10% non-inferiority margin was chosen for this Phase 2b study for the 
non-inferiority testing against historical control. Using a 2-sided 95% CI and assuming an expected SVR 
rate of 98% for each arm, a sample size of 150 subjects per arm will provide at least 90% power to reject 
the inferiority hypothesis by showing that the lower limit of the 2-sided 95% CI on the observed SVR will 
exceed 88% (the upper boundary of the 95% CI for the control rate minus 10%).
In addition, with a total sample size of 150 subjects in each treatment arm (300 subjects in total), the 
probability to observe an adverse event (AE) with an incidence of 0.1%, 0.5%, 0.8%, and 1% are 13.9% 
(25.9%), 52.9% (77.8%), 70.0% (91.0%), and 77.9% (95.1%), respectively.
To aid in the evaluation of efficacy of the 3-DAA regimens, Bayesian posterior probabilities on the true 
SVR will be calculated using uninformative prior (Jeffreys prior) and provided to the DRC. The posterior 
probability that the true SVR exceeds certain thresholds (eg, 90%, 95%) will be generated. Posterior 
probabilities associated with alternative thresholds may also be provided and are intended to aid the DRC 
in the interim evaluations of efficacy. Similar computations may also be provided for safety endpoints of 
interest.
In conclusion, a total sample size of 300 subjects in the study is considered sufficient to explore the 
efficacy, safety, tolerability and PK of the 3-DAA regimen in this study.
Note that the 65 additional subjects enrolled does not meaningfully affect the power considerations 
reported above to demonstrate non-inferiority of SVR12. Additionally, 182 subjects enrolled per arm (365 
in total) will provide a probability to observe an AE with an incidence of 0.1%, 0.5%, 0.8%, and 1% of 
16.6% (30.6%), 59.8% (84.0%), 76.8% (94.7%), and 83.9% (97.4%), respectively.
The primary efficacy analyses will be performed on the intent-to-treat (ITT) population, defined as all 
subjects who received at least one dose of study drugs (AL-335, ODV, or SMV).
Additional sensitivity analyses on efficacy may be performed after excluding subjects with early 
treatment discontinuation due to non-virologic reasons or missing data at the SVR12 time point, as well 
as on the per-protocol population, defined as the ITT population excluding subjects with a pre-specified
major protocol deviation.
An interim analysis is planned at the SVR4 time point, ie, when all subjects have reached the SVR4 
(Week 4 follow-up visit [W4 FU visit]) time point or discontinued earlier.
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
26
Approved, Date: 10 April 2017
The primary analysis will be performed when all subjects have reached the SVR12 time point (W12 FU
visit) or discontinued earlier. Additional interim analyses may be conducted if needed to support clinical 
development.
The final analysis will be performed when all subjects have completed the last study-related visit (SVR24 
time point; W24 FU visit) or discontinued earlier.
A DRC will be established to monitor data of the current study on a regular basis to ensure the continuing 
safety, efficacy and well-being of the subjects enrolled in the study. The DRC will take into consideration 
the data from the current study as well as data from completed and ongoing studies, including the 
Phase 2a study AL-335-604 in their recommendations regarding the continuation of the study. 
Efficacy Analyses
The primary efficacy endpoint is:

The proportion of chronic HCV infected subjects who achieve SVR12.
For the definition of SVR12, see the Definitions of Terms.
The secondary efficacy endpoints are:

The proportion of subjects with SVR4 and SVR24,

The proportion of subjects with viral relapse,

The proportion of subjects with on-treatment failure,

The proportion of subjects with virologic response:
o
HCV RNA <lower limit of quantification (LLOQ) undetectable,
o
HCV RNA<LLOQ,

Time to achieve undetectable HCV RNA and HCV RNA <LLOQ,

The effect of the presence or absence at baseline of NS3/4A, NS5A, or NS5B polymorphisms on 
treatment outcome,

The changes from baseline in amino acid sequence in the HCV NS3/4A, NS5A and NS5B regions in 
subjects not achieving SVR,

The relationship between the population-derived exposure parameters of SMV (AUC24h and C0h)
with SVR12 and safety,

Change from baseline over time in mean score for each of the following PRO scores:
o
EQ-5D-5L: VAS score,
o
FSS: Total score,

The proportion of subjects with clinically important improvement from baseline during study drug 
treatment and at follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L VAS scores,

The time to clinically important improvement from baseline during study drug treatment and at 
follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L VAS,

The proportion of subjects with clinically important worsening from baseline during study drug 
treatment and at follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L VAS,

The duration (weeks) of clinically important worsening from baseline during study drug treatment 
and at follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L VAS,
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
27
Approved, Date: 10 April 2017

Change from baseline over time in EQ-5D-5L VAL score and Domain scores.
For definitions of on-treatment virologic response, SVR4, SVR24, on-treatment failure and viral relapse, 
see the Definitions of Terms.
For the primary endpoint, for each treatment arm, the proportion of subjects who achieve SVR12 will be 
calculated. A 2-sided 95% CI will be constructed around the SVR12. The lower limit of the 95% CI of the 
SVR12 rate will be compared against the performance benchmark for non-inferiority. A lower bound of 
the 2-sided 95% CI 88% will satisfy the hypothesis for non-inferiority in at least one treatment arm.
Additional sensitivity analysis may be performed by applying different imputation rules for missing data. 
Missing data patterns will be analyzed and described in detail.
To aid in the evaluation of efficacy of the 3-DAA regimens, Bayesian posterior probabilities on the true 
SVR will be calculated using uninformative prior.
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment arm.
The potential association between treatment outcome and baseline factors such as stratification factors, 
geno/subtype, and baseline HCV RNA levels will be explored by subgroup analysis.
Resistance Determination Analyses
The results of viral sequencing will be evaluated by the sponsor virologist. Pre-treatment 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 
pre-treatment NS3/4A, NS5A and NS5B polymorphisms on treatment outcome will be explored.
Patient-reported Outcomes Analyses
Patient-reported outcomes scores will be analyzed descriptively by treatment arm as mean scores over 
time, and evaluated based on the proportion of subjects experiencing a clinically important improvement 
or worsening in PRO scores from baseline during study drug treatment and follow-up. Time and duration 
of clinically important significant improvement or worsening in PRO scores will be analyzed and 
reported.
Pharmacokinetic Analyses 
The PK samples taken from all subjects in the study (see Time and Events Schedule), as well as the sparse 
and rich PK samples collected in the PK substudies (Time and Events Schedule: PK Assessments in PK 
Substudies) will be used for population PK (popPK) model development and/or popPK model update. 
PopPK analysis of plasma concentration-time data of AL-335 (and its metabolites), ODV, and SMV from 
all subjects (including those of sparse and rich PK substudies) will be performed using nonlinear mixed-
effects modeling. Population PK modeling will be used to describe the concentration-time profiles and 
estimate the exposure parameters (AUC24h and C0h) of AL-335 (and its metabolites), ODV, and SMV. 
Available baseline subject characteristics (demographics, body weight, laboratory variables, genotype, 
etc.) may be explored as potential covariates affecting PK parameters of AL-335, ODV, or SMV. Details 
will be given in a popPK analysis plan and the results of the popPK analysis will be presented in a 
separate popPK report.
For the intensive PK samples of the rich PK substudy, non-compartmental PK analysis of AL-335 (and its 
metabolites), ODV, and SMV will be performed using actual sampling time and plasma concentrations 
obtained from rich serial PK blood sampling at Week 4 for approximately 20 subjects (arms A and B
combined). Descriptive statistics will be provided for the PK parameters derived, including graphical 
analyses of the data.
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
28
Approved, Date: 10 April 2017
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure parameters 
(AUC24h and C0h) with SVR12 and with safety endpoints will be explored. These relationships will be 
presented in a graphical display.
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.
The statistical approach for analyzing the exploratory host DNA research may depend on the objective of 
the analyses (treatment response, side effects, metabolism) and possibly relevant genes at the time of 
analysis.
Occupational/Employment Status Analysis
Occupational/employment status will be descriptively summarized by treatment arm over time.
Medical Resource Utilization
MRU data will be descriptively summarized by treatment arm over time.
Safety Analyses
The incidence of AEs will be summarized for each treatment arm by body system and preferred term. 
Changes from baseline in clinical laboratory values,
vital signs, ECG parameters, and key 
echocardiography parameters (including LVEF) will be presented descriptively. The percentage of 
subjects with abnormal clinical laboratory, vital sign, ECG parameter, and LVEF values will be presented 
by treatment arm. Physical examination findings will be listed.
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
29
Approved, Date: 10 April 2017
TIME AND EVENTS SCHEDULE
Phase
Screeninga
Baselineb
Treatment Phasec,d
Post-Treatment
Follow-Up Phase
Week/Day
W-6
D1
D2
D3
W1
W2
W3
W4
W6f
(W8)g,ff (W10)ff
EOTh
Early 
treatment 
withdrawal 
visite
W4 
FU
W8 
FU
W12 
FU
W18 
FU
W24 
FUi
Study Procedures
Screening/Administrative
Informed consent form 
(ICF)j
X
Demographics
X
Medical/surgical history
X
Prestudy therapies
X
Concomitant diseases
X
Inclusion/exclusion 
criteria
X
Xk
Hepatitis C virus (HCV)
geno-/subtyping
X
Fibroscan/biopsyl
X
Echocardiographym
X
X
X
Electrocardiogram 
(ECG)m
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testn
X
X
X
X
Xo
X
X
X
X
X
X
Follicle-stimulating 
hormone (FSH)p
X
Hepatitis A, B and C 
serologyii
X
X
Human immunodeficiency 
virus (HIV)
type 1 and 2 serology
X
Study Drug Administration
Provision of study drugs 
for daily use at home
X
X
Xff
Study drugs to be taken 
X
X
X
X
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
30
Approved, Date: 10 April 2017
Phase
Screeninga
Baselineb
Treatment Phasec,d
Post-Treatment
Follow-Up Phase
Week/Day
W-6
D1
D2
D3
W1
W2
W3
W4
W6f
(W8)g,ff (W10)ff
EOTh
Early 
treatment 
withdrawal 
visite
W4 
FU
W8 
FU
W12 
FU
W18 
FU
W24 
FUi
Study Procedures
on-site
Provision 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 determinationr
X
Xq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral sequencings
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient-reported outcomes 
(PROs)t
X
X
X
Xu
X
X
X
Occupational/Employment Status
Occupational/employment 
status
X
X
X
X
X
X
X
X
X
Medical Resource Utilization (MRU)
MRU
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics (PK)
Plasma concentrations of 
AL-335 (and metabolites),
odalasvir (ODV), and
simeprevir (SMV)v
X
Xf
Xw
Sparse PK substudy -
plasma concentrations of 
AL-335 (and metabolites), 
ODV, and SMV
See Time and Events Schedule: PK Assessments in PK Substudies
Rich PK substudy -
plasma concentrations of 
AL-335 (and metabolites),
See Time and Events Schedule: PK Assessments in PK Substudies
NCT02765490


AL-335, odalasvir, TMC435 (simeprevir)
Clinical Protocol 64294178HPC2001 Amendment 4
31
Approved, Date: 10 April 2017
Phase
Screeninga
Baselineb
Treatment Phasec,d
Post-Treatment
Follow-Up Phase
Week/Day
W-6
D1
D2
D3
W1
W2
W3
W4
W6f
(W8)g,ff (W10)ff
EOTh
Early 
treatment 
withdrawal 
visite
W4 
FU
W8 
FU
W12 
FU
W18 
FU
W24 
FUi
Study Procedures
ODV, and SMV
Safety Assessments
Physical examinationx
X
X
X
X
X
X
X
X
Vital signsy
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Assessments
Hematology, 
biochemistryjj
Xbb
Xz,aa,gg
X
Xz,gg
Xz,gg
Xhh
X
Xz,aa,bb,gg
Xbb
Xz,gg
Xz,aa
X
Urinalysis
Xcc
X
X
X
X
X
X
X
X
X
X
Pharmacogenomics (blood sample)
Host interleukin-28B
(IL28B) genotyping
X
Host DNA researchdd
X
Ongoing Subject Review
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events (AEs)ee
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FU: follow-up
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 phase to assess eligibility. Any potential delays in the screening phase 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, except for a second blood sample on Day 1 for post-dose HCV RNA determination, 
which should be taken within 4 hours after dosing. 
c
Subjects should ensure intake of study drugs exactly up to 6 weeks (43 days) or 8 weeks (57 days) of treatment (or 12 weeks [85 days] of treatment in case of 
treatment extension to 12 weeks), depending on the treatment arm they are in, in order to complete the indicated treatment duration.
d
In case a treatment extension is recommended by the DRC, subjects will continue to attend study visits every 2 weeks. In case of treatment extension to 8 weeks, 
the subjects should follow the visit schedule of subjects initially included in the 8-week treatment arm, with an EOT visit at Week 8. In case of treatment 
extension to 12 weeks, subjects should follow the schedule for the 12-week treatment extension arm. Subjects should ensure intake of study drugs exactly up to 
8 weeks (57 days) or 12 weeks (85 days) of treatment, depending on the extended treatment duration, in order to complete the indicated treatment duration.
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e
If study drug treatment 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 early 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.
f
The Week 6 assessments should not be performed if the Week 6 is the EOT visit (arm A); in that case only the EOT assessments should be performed.
g
The Week 8 assessments should not be performed if the Week 8 is the EOT visit (arm B); in that case only the EOT assessments should be performed.
h
In case of the treatment extension of the 6-week treatment arm to 8 weeks, the EOT assessments will be performed at Week 8. In case of treatment extension of 
the 6-week and/or 8-week treatment arms to 12 weeks, the EOT assessments will be performed at Week 12.
i
Any subject who withdraws consent during the follow-up phase and/or notifies the site 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.
j
Signing of the ICF can be done before the screening visit but needs to be done before the first study-related activity.
k
Investigator to confirm eligibility based on the overall clinical picture.
l
Absence of cirrhosis confirmed by Fibroscan performed within 6 months or liver biopsy within 6 months of baseline (Day 1). A biopsy should only be considered 
in subjects who do not have access to Fibroscan at the study site or at a referral site.
m
Additional ECG, echocardiography or cardiac monitoring 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.
n
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 to 6 weeks up to the W24 FU visit. 
o
A urine pregnancy test is not needed at the EOT visit for female subjects in the 6-week treatment arm, since they had a urine pregnancy test within 2 weeks prior 
to the EOT visit, ie, at Week 4. 
p
FSH will be tested for female subjects who are postmenopausal for less than 2 years.
q
Two blood samples need to be taken: a first sample pre-dose and a second sample post-dose but within 4 hours after dosing. The time when the pre- and
post-dose blood sample is obtained as well as the timing of the dosing at baseline should be recorded.
r
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.
s
Viral sequencing will be performed on baseline samples by default in all subjects and on post-baseline samples in subjects not achieving sustained virologic 
response (SVR). Sequencing of additional samples may be triggered by the sponsor virologist.
t
PRO assessments will be performed by all subjects at sites where appropriate translations are available. Subjects will complete the Chronic Liver Disease Quality 
of Life Questionnaire - HCV (CLDQ-HCV), 5-level EuroQol 5-Dimension (EQ-5D-5L), Fatigue Severity Scale (FSS), and Short Form 36 version 2 (SF-36v2)
questionnaires on an electronic device during the specified clinic visits. The ePRO assessments are to be completed before any tests, procedures or other 
consultations for that visit to prevent influencing the subject’s perceptions.
u
No PRO assessments need to be performed if a PRO assessment was performed within 2 weeks prior to the withdrawal visit.
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v
A PK sample for popPK analysis will be collected in all subjects at any time during the visit. A PK sample is not needed at Week 4 for subjects participating in 
the rich serial PK substudy and at Week 6 for subjects participating in the sparse PK substudy (see Time and Events Schedule: PK Assessments in PK 
Substudies). For these subjects a PK sample is taken as part of the PK substudies. 
w
At the EOT visit, subjects should still be on treatment at the time of the PK assessment (the last dose is expected to be taken on the morning of the visit).
x
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.
y
Systolic and diastolic blood pressure and pulse/heart rate need to be taken supine after at least 5 minutes of rest.
z
Biochemistry samples must be taken after fasting for at least 8 hours. Lipid profile is only to be assessed during visits with fasting samples. 
aa
An additional blood sample for biochemistry should be taken for assessment of insulin and glucose. 
bb
Thyroid stimulating hormone (TSH) is to be assessed at screening and EOT or early withdrawal. In case TSH is not within the normal range, testing of free 
triiodothyronine (fT3) and free thyroxine (fT4) will be performed.
cc
Includes a urine drug screening test.
dd
An optional blood sample for exploratory host DNA research limited to genes involved in the metabolism of the study drugs as well as drug transporter genes
may be taken where locally permitted and upon consent of the subject (in addition to the consent for the main part of the study).
ee
All adverse events (AEs), whether serious or non-serious, and pregnancies will be reported from the time a signed ICF is obtained until the subject’s last study 
visit. 
ff
Only applicable in case of treatment extension to 12 weeks.
gg
Includes assessment of B-type natriuretic peptide (BNP).
hh
Assessment of BNP only.
ii
At screening, determination of HBsAg should be performed to determine eligibility of the subjects. At baseline, a blood sample should be taken for determination 
of anti-HBc. For anti-HBc positive subjects, anti-HBs will be determined. Hepatitis A and C serology will only be determined at screening. 
jj
Any significant ALT flare during the conduct of the study, defined as either: (1) ALT of >2X ULN and >2X the lowest previous ALT value measured during the 
study, OR (2) any treatment-emergent grade 3 ALT elevation (>5X ULN), will trigger a thorough clinical work-up of the case by the investigator. This 
evaluation should include the assessment of serum HBV DNA (mandatory in subjects that are anti-HBc antibody positive at baseline).
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Time and Events Schedule: PK Assessments in PK Substudies
Rich serial PK substudya (N~20)
Time of Visit
Sampling Time (hours)
pre-dose
dosing
1h
2h
3h
4h
6h
8h
10h
12h
24h
Week 4b,c
X
(-0.5h)
X
X
X
X
X
X
X
X
X
a
This may require an overnight stay in the hospital. 
b
Study drugs should be taken on site.
c
One of the assessments can be used as the PK assessment scheduled at Week 4 (to be taken anytime during the visit) indicated in the main Time and Events 
Schedule; no additional sample is needed.
Sparse PK substudy (N~20a)
Time of Visit
Sampling Time (hours)
pre-dose
dosing
1h
2h
3h
4h
6h
8h
10h
12h
24h
Week 2b
X
X (anytime between 2h and 4h post-dose)
After 6 weeks of treatmente
EOT visitc,d (arm A)
Week 6d (arm B)
X (anytime between 6h and 12h post-dose)
After 8 weeks of treatmente
EOT visitb,c (arm B)
X
X (anytime between 2h and 4h post-dose)
W4 FU, W12 FU, W 24 FU
Any time during the visit for ODV only
a
Sparse PK sampling for AL-335 (and metabolites), ODV, and SMV will be performed in approximately 20 subjects (arms A and B combined) not participating
in the rich serial PK substudy. At least 5 subjects are to be included from each arm.
b
Study drugs should be taken on site.
c
Subjects should still be on treatment at the time of the PK assessment.
d
This assessment can be used as the PK assessment scheduled at Week 6 (to be taken anytime during the visit) indicated in the main Time and Events Schedule;
no additional PK blood sample is needed.
e
In case of treatment extension to 8 weeks or 12 weeks, no additional PK assessments will be done.
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ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve 
AUC24h
area under the plasma concentration-time curve from time 0 to 24 hours after dosing
AV
atrioventricular
BCRP
breast cancer resistance protein 
BMI
body mass index
BNP
B-type natriuretic peptide
BSEP
bile salt export pump 
C0h
predose (trough) plasma concentration
CI
confidence interval
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CK-MB
creatine kinase muscle-brain
CLDQ-HCV
Chronic Liver Disease Quality of Life Questionnaire – HCV
Cmax
maximum plasma concentration 
Cmin
minimum plasma concentration
Ctrough
trough plasma concentration
CYP
cytochrome P450
DAA
direct-acting antiviral agent
DCV
daclatasvir
DDI
drug-drug interaction
DNA
deoxyribonucleic acid
DRC
Data Review Committee
EC50/90
50%/90% effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
EF
ejection fraction
(e)GFR
(estimated) glomerular filtration rate
EOT
end of treatment
(e)PRO
(electronic) patient-reported outcome
EQ-5D-5L
5-level EuroQol 5-Dimension
fT3
free triiodothyronine
fT4
Free thyroxine
FC
fold change
FSH
follicle-stimulating hormone
FSS
Fatigue Severity Scale
GCP
Good Clinical Practice
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HIV
human immunodeficiency virus
HOMA-IR
homeostatis model assessment insulin resistance
HRQoL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
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IEC
Independent Ethics Committee
IFN
interferon
IL28B
interleukin-28B
IRB
Institutional Review Board
ITT
intent-to-treat
IUD
intrauterine device
IVRS
interactive voice response system
IWRS
interactive web response system
LFC
liquid-filled capsule
LLOQ
lower limit of quantification
LVEF
left ventricular ejection fraction
MAD
multiple ascending dose
MCS
mental component summary
MedDRA
Medical Dictionary for Regulatory Activities
MRP
multidrug resistance-associated protein
MRU
Medical Resource Utilization
NS
non-structural (protein)
OAT
organic anion transporter
OATP
organic anion transporting polypeptide 
OCT2
organic cation transporter 2
ODV
odalasvir
PCS
physical component summary
PegIFN
pegylated interferon
P-gp
P-glycoprotein
pH
power of hydrogen
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
qd
once daily
QTc
corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RAV
resistance-associated variant
RBC
red blood cell
RBV
ribavirin
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SE
standard error
SF-36v2
Short Form 36 version 2
SMV
simeprevir
SOF
sofosbuvir
SUSAR
suspected unexpected serious adverse reaction
SVR
sustained virologic response
SVRx
sustained virologic response x weeks after the end of treatment
t1/2,term
terminal elimination half-life
tmax
time to reach maximum plasma concentration 
TMC
Tibotec Medicinal Compound
TSH
thyroid stimulating hormone
ULN
upper limit of normal
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VAS
Visual Analog Scale
VEL
velpatasvir
VI
Valuation Index
WBC
white blood cell
WHO
World Health Organization
WX FU
Week X Follow-up
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 <lower limit of quantification 
(LLOQ) undetectable or <LLOQ (detectable or undetectable) at specified time 
points during treatment.
Sustained Virologic
Response (SVRX)
Subjects achieve SVRX if HCV RNA <LLOQ (detectable or undetectable) 
X weeks after EOT.
Failure (no SVR12)
Subjects who do not achieve SVR12, including:

on-treatment failure (see below)

post-treatment 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 log10 in HCV 
RNA from nadir, or confirmed HCV RNA >100 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).
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.
East-Asian subjects
East-Asian subjects are defined as subjects whose parents and maternal and 
paternal grandparents are Japanese, Chinese, Taiwanese or Korean, as 
determined by subject’s verbal report.
The following definition characterizes subject’s HCV treatment experience:
Treatment-naïve
Subjects are considered treatment-naïve if they have never received treatment 
with any approved or investigational drug (including direct-acting antivirals 
[DAAs], interferon [IFN]-based treatments and vaccines) for chronic HCV 
infection.
Treatment-experienced
Subjects who have received at least one previous course of interferon (IFN; 
pegylated or non-pegylated) with or without ribavirin (RBV). Note that subjects 
with a history of treatment with an approved or investigational anti-HCV DAA 
are excluded.
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1.
INTRODUCTION
AL-335 (also known as JNJ-64146212) is a uridine based nucleoside monophosphate prodrug (or 
nucleotide analog) targeting hepatitis C virus (HCV) non-structural protein (NS)5B polymerase 
being developed for the treatment of chronic HCV (in clinical development).
Odalasvir (ODV, also known as ACH-0143102 and ACH-3102) is an HCV NS5A inhibitor 
being developed for the treatment of chronic HCV infection (in clinical development). 
Simeprevir (SMV, also known as TMC435) is an HCV NS3/4A protease inhibitor approved for 
the treatment of chronic HCV genotype 1 and 4 infection.
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, if applicable,
for AL-335, ODV, and SMV, respectively.15,16,17,18,42,43,44
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
HCV infection is a leading cause of liver disease worldwide. An estimated 130-150 million 
people (about 2% of the global population) are currently infected with HCV,33 with an incidence 
of 3 to 4 million new infections per year.34 Between 70% and 90% of acute HCV infections 
become chronic and may lead to liver cirrhosis, chronic liver failure, hepatocellular carcinoma, 
liver transplantation and death.7,23,34 Complications of HCV infection are currently the most 
common indication for liver transplantation. In the United States 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.6 The risk of hepatic decompensation in 
subjects with cirrhosis is approximately 5% per year and the 5-year survival rate after 
decompensation is around 50%.3
HCV has been classified into at least 6 major genotypes (designated 1 to 6) and many subtypes 
(a, b, c, etc.).6 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%), followed by 
genotype 3 (30%), genotype 2 (9%), genotype 4 (8%), genotype 6 (5%), and genotype 5 (<1%).26
Genotype 1b is the most common subtype, accounting for 22% of all infections. Infections in 
North America, Latin America, and Europe were predominantly genotype 1. North Africa and 
the Middle East were found to have a large genotype 4 population (71%), which is related to the 
high prevalence of genotype 4 in Egypt. Asia has predominantly genotype 3 (39%), largely 
driven by the HCV infections in India and Pakistan, followed by genotype 1 (36%).12
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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.27,28,30 Since 2014, additional DAAs, including 
daclatasvir (DCV; Daklinza5),
dasabuvir (Exviera8) and the fixed-dose combinations
SOF/ledipasvir (Harvoni13) and ombitasvir/paritaprevir/ritonavir (Viekirax and Technivie31,32), 
have been approved for use in the United States, European Union and/or in other regions.
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 non-responsiveness to PegIFN by increasing antiviral 
activity and reducing the risk of developing resistance-associated variants. 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 anti-HCV 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.21
The current open-label Phase 2b study is designed to investigate efficacy, safety and tolerability, 
and pharmacokinetics of a once daily (qd) treatment with AL-335, ODV, and SMV for 6 and 
8 weeks (3-DAA regimen) in HCV genotype 1, 2, 4, 5 or 6 infected subjects without cirrhosis.
1.1.3.
Background of AL-335
AL-335 is a uridine based nucleoside monophosphate prodrug (or nucleotide analog) being 
developed as an orally administered anti-HCV 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.16,42,43,
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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 genotype 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 5ʹ-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% and 36% of the administered radioactivity 
was recovered in urine. Oral administration of (non-labelled) AL-335 revealed that AL-335 was 
recovered mainly as the metabolites in urine with only 0.0006%-0.17% of AL-335 excreted in 
urine in rats and dogs. In contrast, 0.02%-2% of ALS-022399 (metabolite) and 4%-18% of 
ALS-022227 (metabolite) is excreted in urine in rats and dogs, respectively.
AL-335 and metabolites (ALS-022399 and ALS-022227; AL-335 and its metabolites 
ALS-022399 and ALS-22227 are further referred to as AL-335 [and metabolites]) are not 
expected to cause drug-drug interaction (DDI) 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 its 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.
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%) and body temperature (<1°C) were observed at the 
1,000 mg/kg dose. All of these findings are monitorable and reversible and all were considered 
non-adverse.
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.
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Clinical Experience
Up to 28 August 2015, forty (40) healthy volunteers have received single doses up to 1,200 mg 
(single ascending dose [SAD]) or multiple ascending doses (MAD) of AL-335 of 400 mg and 
800 mg for 7 days (AL-335-601). This study also evaluates 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 1-4) 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] 30-45 minutes) and converted to ALS-022399. The terminal elimination 
half-life (t1/2,term) of AL-335 was 30-60 minutes. In healthy volunteers, 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.
Efficacy and Safety
In the 40 healthy subjects of Study AL-335-601, there were no serious AEs (SAEs), and no 
clinically relevant laboratory, electrocardiogram (ECG), Holter, vital sign, or physical exam 
safety signals have been identified. Three subjects reported four AEs, one of which emerged 
prior to dose administration. For the treatment-emergent AEs, one 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 study drug. The second treatment-emergent AE, moderate dental pain 
(2 events), occurred 9 hours post-dose and again 6 days after dosing. These events were assessed 
as unrelated to study drug. 
In the same Phase 1b study, multiple ascending doses of AL-335 (400 or 800 mg) over 7 days 
were evaluated in twenty (20), ten (10), and ten (10) subjects with genotype 1, 2, or 3 chronic 
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HCV infection, respectively. Thirty-two (32) subjects received active study medication 
(400 or 800 mg AL-335 [genotype 1], or 800 mg only [genotypes 2 and 3]) and eight (8) 
received placebo. In Study AL-335-601, monotherapy with AL-335 800 mg 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 also 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 two subjects 
≥10 days after the conclusion of dosing and were similar in magnitude to baseline (pre-dosing) 
levels. Three AEs occurred one time each: fatigue, common cold, and increased bilirubin. All 
AEs were mild (8 events) or moderate (8 events) in severity with the exception of one 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 exam safety signals have been identified to date.
1.1.4.
Background of Odalasvir
ODV is an HCV NS5A inhibitor being developed as an orally administered anti-HCV 
therapeutic.
A summary of in vitro, nonclinical, and clinical data for ODV is provided below; more details
can be found in the Investigator’s Brochure (IB) and its addendum.15,44
For details on the IFN-free studies including ODV, see Section 1.2.
In Vitro/Nonclinical Data
ODV is a highly potent HCV NS5A inhibitor with a mean EC50 of 5.3 pM and 26 pM against 
genotype 1b and 1a HCV replicons, respectively, and 6.4 to 27 pM and 9.0 to 20 pM against 
chimeric replicons carrying NS5A from genotype 1b and 1a clinical isolates, respectively. The 
EC50 values of ODV against chimeric replicons carrying the N-terminus of NS5A from 
representative strains of genotype 2a, 2b, 3a, 4a, 5a, and 6a are 25, 215, 48, 8.0, 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 terminal half-life in plasma (rat: up to 55 hours; dog: up to 114 hours; 
monkey: 65.8 hours). The t1/2 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% or greater in rat, dog, and 
human plasma.
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Preclinical data indicate that 91% to 98% of the administered oral dose of ODV is recovered in 
excreta by 168 hours post-dose 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 
OATP1B1/3, and is neither a substrate nor an inhibitor of transporters such as breast cancer 
resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), MRP3, and bile 
salt export pump (BSEP). 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 cardiovascular safety 
pharmacology studies in the dog, repeated dosing of ODV in dogs was associated with ECG 
changes (prolonged PR and/or 1st-degree AV block, prolonged QRS, QT and 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.
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. Pharmacokinetic and 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, with or 
without 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 
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a rapid phase, followed by a more prolonged, slower phase of decline. In the rapid phase, plasma 
concentrations generally decline to 10% of Cmax values by 4-5 days after dose administration. 
The pharmacokinetic (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 4-5 weeks. Plasma sampling beyond a 12-week dose period 
suggested that it would take approximately 20-24 weeks after the end of dosing to achieve 
effective clearance of the drug.
No clinically significant DDI was 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 anti-viral 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 
atrioventricular (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 4 days after study drug discontinuation, and no further 
investigations were considered needed. In Study ACH102-005 a treatment-emergent PR 
prolongation was observed; this event evolved to a transient type 1 second-degree 
atrioventricular (AV) block. The cardiologist assessed the subject's second-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 Simeprevir
SMV is an HCV NS3/4A protease inhibitor approved in 2013 in the United States, 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 multiple other countries and regions globally for 
the treatment of chronic HCV genotype 1 and 4 infection with and without human 
immunodeficiency virus (HIV) co-infection. Additional registration procedures are ongoing 
worldwide. The marketed SMV formulation is an oral capsule. Each hard capsule contains SMV 
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sodium equivalent to 150 mg (globally except Japan) or 100 mg (Japan only). The estimated 
cumulative post-authorization 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.17,18 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 EC90 values 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. Genotype 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 genotype 4a, 4d, and 4other 
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 ongoing. In 
addition, data are available from 30 Phase 1 studies, during which 1,027 non-HCV infected 
subjects were exposed to SMV and 8 studies conducted in Japan (4 Phase 3, 1 Phase 2 and 
2 Phase 1 studies) including 434 HCV infected treatment-naïve and treatment-experienced 
subjects who received SMV.
Pharmacokinetics
The blood: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, 
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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% after a high-fat, high-caloric breakfast (928 kcal) and by 69% 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 that 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 -experienced subjects with chronic HCV genotype 1 with or 
without HIV-1 co-infection and in subjects with chronic HCV genotype 4 infection, with no 
clinically relevant additional toxicity.27,28
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 C202, treatment-naïve subjects with HCV genotypes 2, 3, 4, 5, and 6 
infection 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 genotype 2, 4, 5, and 6. 
For the primary endpoint at Day 8, the mean (±SE) 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 HPC3011.
In Phase 2 study HPC2002 and Phase 3 studies HPC3017 and HPC3018, high SVR12 rates were 
observed in HCV infected subjects treated with SMV and SOF; for more details, refer to 
Section 1.2.
1.2.
Background to All-oral Combination Regimens
A summary of available data for AL-335, ODV, and SMV containing all-oral regimens in 
HCV infected subjects is provided below.
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NS3/4A Protease Inhibitor and Nucleotide NS5B Polymerase Inhibitor (SMV/SOF)
In a Phase 2 study (HPC2002) 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 SVR 12 weeks after 
the end of treatment (SVR12) rates (≥90%) 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%. Similar 
SVR12 rates were observed for HCV genotype 1a infected subjects with and without baseline 
Q80K polymorphism.
In Phase 3 studies HPC3017 and HPC3018 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. 

For chronic HCV genotype 1 infected subjects without cirrhosis who were HCV 
treatment-naïve or treatment-experienced superiority of the 12-week treatment regimen 
of SMV+SOF to a historical control (ie, composite of approved DAA/PegIFN/RBV 
regimens) was concluded based on the primary analysis of study HPC3017. The SVR12 
rate of the 12-week treatment regimen was 96.8% versus 87% for the historical control.
High SVR12 rates were observed for the 12-week regimen, regardless of the subgroup 
analyzed.
The 8-week SMV+SOF regimen in study HPC3017 was not superior to a historical 
control. The SVR12 rate of the 8-week regimen was 82.6% versus 83% for the historical
control. Higher SVR12 rates were observed among those subjects with more favorable 
demographic and baseline disease characteristics.

For chronic HCV genotype 1 infected subjects with cirrhosis who were HCV 
treatment-naïve or treatment-experienced superiority of the 12-week treatment regimen 
of SMV+SOF to a historical control was concluded based on the primary analysis of 
study HPC3018. The SVR12 rate of the 12-week treatment regimen in study HPC3018 
was 83.5% versus 70% for the historical control.
Pooled data from HPC2002, HPC3017, and HPC3018 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 AEs and AEs leading to discontinuation of study drugs were rare in these studies.
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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 group. 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 of clinical interest in cirrhotic subjects.
NS3/4A Protease Inhibitor and NS5A Inhibitor (SMV/DCV, ODV/sovaprevir)
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).35 SVR12 was achieved in 
74.5% and 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% (9/92) 
and 5% (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 
study drug). SAEs occurred in 4% (4/92) and 9% (7/76) of subjects treated with SMV and DCV 
with and without RBV, respectively. SAEs were related to study drug in 2 subjects 
(neurotoxicity, liver disorder). AEs leading to early discontinuation were reported in 2% (2/92) 
and 3% (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, insomnia/sleep terror). Grade 3 or 4 hyperbilirubinemia occurred in 15% (14/92) 
and 4% (3/76) of subjects treated with SMV and DCV with and without RBV, respectively.
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 Group 1 and Group 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 two 
weeks of study drugs. There have been three viral breakthroughs in Groups 1 and 2 each, all 
occurring in subjects with the genotype 1a HCV subtype. In contrast, no subjects with HCV 
genotype 1b infection have had viral breakthrough or relapse to date. Both combination dosing 
regimens were well tolerated with no drug-related SAEs and no discontinuations for safety. 
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Trough concentrations of ODV concentrations were similar in Group 1 (200 mg sovaprevir) and 
Group 2 (400 mg sovaprevir), suggesting no effect of sovaprevir dose on ODV concentrations.
Nucleotide NS5B Polymerase Inhibitor and NS5A Inhibitor (ODV/SOF)1,15
ACH102-017 is 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 formulation of 
ODV given in the fasted condition without a loading dose plus 400 mg of SOF for 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). Preliminary PK 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%) subjects in Group 1 and all 12 (100%) subjects in Group 2 
achieved 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, 4/6 had interleukin-28B (IL28B) genotype non-CC (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%) subjects achieved SVR12.
The dosing regimen was well tolerated in both groups with no SAEs or discontinuations for 
safety. No significant ECG findings or lab abnormalities were observed during treatment. 
3-DAA Combination (SMV/DCV/SOF, SMV/ODV/AL-335)
At the time of the initial protocol writing, interim results from the Phase 2 IMPACT (HPC2010)
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%) 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. Co-administration 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) 
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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 in this study. All treatment emergent AEs (N=20) 
were assessed as mild (N=14) or moderate (N=6; oropharyngeal pain, tooth abscess, alkaline 
aminotransferase [ALT] increase, and fatigue [3 events]), in severity by the investigator. The 
most commonly reported treatment emergent AEs (≥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 adverse event (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 are available from an analysis with cut-off date 22 June 2016
which is 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 3 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 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 patients 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) have completed dosing. No cases of viral breakthrough or viral relapse
are known to have occurred in any cohorts including 3-DAA treatment as of the 3 August 2016 
data cut-off.
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In Cohort 1b, HCV genotype 1 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 
visit 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 resistance-associated variants (RAVs) were 
observed at baseline in the 2 subjects with viral relapse, both infected with HCV genotype 1a. At 
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; 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 have completed treatment and reached the 
follow-up Week 4 visit as of the 3 August 2016 cut-off, 1 further subject infected with HCV 
genotype 1a is known to have experienced viral relapse. This viral relapse was identified on 
2 August 2016 and viral sequencing is pending. No other cases of viral relapse or viral 
breakthrough are known to have occurred in any cohorts including 2-DAA treatment as of the 
3 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 is 
generally safe and well tolerated. No clear safety signals have been identified in terms of 
treatment-emergent AEs, 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 treatment-emergent 
AEs have been reported. All treatment-emergent AEs were mild (N=162 events) or moderate 
(N=11 events) in severity; no severe or life-threatening AEs were reported. The most commonly 
reported treatment-emergent AEs (≥5% of the subjects) are 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 re-educated about dosing instructions and subsequently 
completed their treatment course. None of the reported treatment-emergent AEs are 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 I 2nd degree 
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atrioventricular (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 I 2nd degree AV block (SAE) described above. The 
second subject had an elevated PR interval (mean: 234 milliseconds) at baseline which did not 
change significantly post-baseline (maximum mean: 257 milliseconds). This was not considered 
a treatment-emergent AE, however, in light of the second 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 3 August 2016, no additional treatment-emergent SAEs, serious/life 
threatening treatment-emergent AEs, or treatment-emergent AEs 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 creatine kinase 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 post-baseline ECGs were 
considered to have an overall interpretation which is 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.
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1.3.
Risk Benefit Section
1.3.1.
Known Benefits and Risks
Known Benefits and Risks for AL-335
Please see Section 1.1.3.
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 (ADR) analysis has not yet been conducted for AL-335.
Known Benefits and Risks for ODV 
Please see Section 1.1.4 and Section 1.2.
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 2-6. 
For the majority of mutations associated with resistance to first generation NS5A inhibitors the 
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 a treatment 
duration of 6 weeks has shown an efficacy of 100% SVR 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 with genotype 1a.
A formal ADR analysis has not yet been conducted for ODV. However, an internal assessment 
of all pre-clinical and clinical information available at the time of the protocol writing has 
identified the effect of ODV on cardiac conduction as a potential risk. Details are discussed in 
Section 1.3.2.
Known Benefits and Risks for SMV
Please see Section 1.1.5 and Section 1.2.
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 genotype 1a and 1b 
HCV NS3/4A proteases, with median kinetic inhibition constant values of 0.5 nM and 1.4 nM, 
respectively.
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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 good efficacy 
and a favorable safety/tolerability profile in Japanese and Caucasian HCV genotype 1 
treatment-naïve and treatment-experienced subjects. 
HPC3005, 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 SMV150 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 SMV150/PegIFN/RBV in Asian subjects from China and South 
Korea was similar to the known safety profile of SMV 150 mg in Caucasian 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%) 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 controla 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%]), it is recommended that patients HCV genotype 1 
infected patients are treated with SMV/SOF for 24 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.
                                                
a The SVR12 historical control considered the most appropriate was a composite of the historical SVR12 rates of 
approved DAA/PegIFN/RBV-based regimens (ie, the best SVR of any approved regimen at the time of study 
conception) in the subpopulations depending on the proportion of treatment-naïve, prior relapser, prior 
nonresponder, IFN-intolerant, and “other” subjects enrolled in this study. This was the best SVR rate of an 
approved regimen at the time of study conception (ie, SMV or SOF + PegIFN/RBV) in the subpopulations with 
data available.
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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 co-infection.
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 (C208, C216, and 
HPC3007) 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 subjects on placebo 
were pruritus (21.9% vs 14.6%), rash (21.8% vs 16.6%), blood bilirubin increased (7.4% vs 
2.8%), photosensitivity reaction (4.7% vs 0.8%), and constipation (2.6% vs 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.
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 HPC2002, HPC3017, and HPC3018 (SMV+SOF). 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 co-administered 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).
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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 
treatment durations compared to currently available treatment regimens to achieve cure for all 
infected patients irrespective of genotypes or any other baseline factor, all without compromising
patient compliance and safety.
1.3.2.2.
Potential Risks 
Every medication can have undesirable effects.
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 9.8.6.6).
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. Odalasvir also 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).
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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 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.
For more information refer to the Investigator’s Brochure and its addendum.15,44
Evaluation of the results from an additional 8-week repeat dose (70 mg/kg orally) mechanistic 
study in the telemetered dog is currently ongoing with details to be included in the preclinical 
study report. In this study ODV was administered at a dose approximately 200 times higher than
the dose planned for the current study HPC2001. Preliminary data 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. Information of exposure levels achieved with this dose, biomarker data and 
histopathology are pending and will be included in the final study report. The clinical relevance 
of the above findings is not yet completely understood. Importantly, analysis of all available 
echocardiography assessments from clinical studies in humans has not shown safety signals to 
date (see below).
Summary of cardiac safety in humans
A total of 440 subjects, of whom 75 were HCV infected subjects and 365 were healthy subjects 
(ie, non-HCV 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 Fridericia (QTcF)11 values over time were noted and there were no clinically 
significant findings identified in the echocardiograms.
In these completed studies, in study ACH102-005 a treatment-emergent PR prolongation was 
observed; this event evolved to a transient type 1 second-degree AV block at Week 12. The 
cardiologist assessed the subject's second-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 considered 
acceptable to conduct the present study.
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 volunteers 
received AL-335+ODV±SMV. As of 22 June 2016, 97 subjects in Study AL-335-604 had been 
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enrolled and had received at least 1 dose of study medication. One SAE of asymptomatic second-
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 and possibly related to AL-335 and SMV 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 milliseconds) at baseline which did not change significantly post baseline (maximum 
mean: 257 milliseconds). This was not considered a treatment-emergent AE, 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.
Continued surveillance of cardiac safety will be done in this Phase 2b study via assessments of 
AEs and serial 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 9.8.6.7) and study treatment 
stopping rules (see Section 6.4) taking into account cardiac safety data of all ongoing studies 
including ODV as part of the regimen are included in the protocol. Finally, concomitant use of 
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 unless this regimen is chronically 
administered at a stable dose with no detectable prolonging effect on QT interval or initiation of 
the medication is necessary to protect subject safety and the case has been discussed with the 
sponsor (for details see Section 8).
Potential Risks for SMV

Hepatic Decompensation and Hepatic Failure:
Hepatic decompensation and hepatic failure, including fatal cases, have been reported 
post-marketing 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:
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
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. 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 12 weeks 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 co-administration of all 3 study drugs (SMV, ODV, and AL-335) 
resulted in a 7-9-fold, 2.5- to 2.7-fold, and 1- to 1.5-fold increase in AL-335, ALS-22399, 
and ALS-22227 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 
was observed when the 3 study drugs were co-administered 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.
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SMV is mainly metabolized by CYP3A enzymes. Co-administration of SMV and drugs that 
induce CYP3A enzymes may decrease SMV plasma concentrations and reduce its 
therapeutic effect. Conversely, co-administration 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:
Resistance mutations emerging during unsuccessful treatment with all oral DAA regimens 
have been associated with decreased susceptibility to drugs within the same DAA classes 
used in subsequent treatment regimens and may therefore have an impact on clinical 
outcome. Some subjects treated with the 3-DAA combination AL-335+ODV+SMV for a 
duration of 6 or 8 weeks may fail treatment due to viral relapse. Although published 
data38,39,40 from DAA combination regimens given for short durations like 6 or 8 weeks have 
shown that a substantial part of subjects with viral relapse fail without the emergence of 
resistance, there is a potential risk that subjects with virologic failure in this study may 
develop resistance to AL-335, ODV and/or SMV. Persistence of emergent AL-335-, ODV-, 
and/or SMV-resistant variants could potentially impair a subject’s future treatment options 
due to potential cross-resistance within the respective DAA class. For subjects not achieving 
SVR, the sponsor will reimburse one treatment regimen with the standard of care for this 
population in the respective country.
AL-335
In the multiple ascending dose part of Study AL-335-601, 16 HCV genotype 1, 
8 genotype 2, and 8 HCV genotype 3 infected subjects received AL-335 (400 mg or 800 mg) 
for 7 days and 4 genotype 1, 2 genotype 2 and 2 genotype 3 subjects received placebo for 
7 days. Population sequencing of the HCV NS5B region was performed for 20 genotype 1 
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 genotype 1 subjects at any time point during the study. No 
other potential AL-335 RAVs were observed in these subjects.
Odalasvir
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 pre-existing mutations 
associated with NS5A inhibitor resistance. In two 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 two subjects, multiple NS5A amino acid substitutions (3 up to 6) were 
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detected at baseline. Three out of 6 subjects who achieved HCV RNA levels < lower limit of 
quantification (LLOQ) target not detected 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. 
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.
Simeprevir
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 C205, C206, C208, C216, and HPC3007, 
emerging mutations at NS3 positions 80, 122, 155 and/or 168 were observed in 180 of 
197 (91%) 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. 
Follow-up of the subjects with emerging mutations at time of failure within the Phase 2b and 
3 studies showed that emerging resistant variants were no longer detectable by standard 
population sequencing in 50.0% (90/180 subjects) of subjects within the trial period (median 
follow-up time 28 weeks; range: 0 to 70 weeks).
In study HPC3011 in genotype 4 infected subjects, 28 out of 32 (88%) 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 out of 32 [75%] subjects), similar to the emerging 
mutations observed in genotype 1 infected subjects.
In study HPC3005, 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 (76.9% 
[10 of 13 subjects]). Nine out of the 10 subjects with emerging mutations had emerging 
D168V. 
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 
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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.
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: 
5/6 subjects in study HPC2002, 1/3 subjects in study HPC3017 and 11/13 subjects in 
HPC3018. The emerging NS3 amino acid substitutions were similar to those observed in 
subjects who did not achieve SVR following treatment with SMV in combination with 
PegIFN/RBV. 
In contrast, the majority of subjects experiencing viral relapse following 8 weeks of 
treatment with SMV and SOF in study HPC3017 had no emerging NS3 mutations reducing 
SMV activity in vitro at the time of failure.
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 available nonclinical and clinical data, cardiac monitoring is 
conducted through serial ECGs and regular echocardiograms throughout the treatment period 
and follow-up (see the Time and Events Schedule). In addition, a toxicity management plan 
for cardiac events is included in the protocol (see Section 9.8.6.7) 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.
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
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, ECG, echocardiography 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 upon in collaboration with the sponsor). Pregnancies will be reported until end of 
study.

Regular review of HCV RNA data by a Data Review Committee (DRC) is implemented to 
allow for prompt determination of suboptimal efficacy due to virologic failure (viral relapse 
and/or on-treatment virologic failure). The DRC will also review accumulating safety data 
from this study as well as emerging safety and efficacy data from other completed and 
ongoing studies, including the Phase 2a study AL-335-604.

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 9.8.6), 
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).
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o
For subjects who do not achieve SVR the sponsor will reimburse one treatment 
regimen with the standard of care for this population in the respective country.
o
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 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 Phase 2b study investigates a 3-DAA combination 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. 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. The aim of the study is to 
evaluate shorter treatment durations of 8 or 6 weeks AL-335+ODV+SMV in HCV genotype 1, 2, 
4, 5 and 6 infected subjects without cirrhosis without compromising efficacy, or the subject’s 
compliance and safety.
Available clinical data and nonclinical data for AL-335 have indicated that AL-335 has potent in 
vitro activity against all 6 HCV genotypes. Dosing with AL-335 for 7 days in subjects with 
chronic HCV genotype 1, 2, or 3 infection resulted in a rapid, consistent, dose-dependent decline 
in HCV RNA concentrations. ODV in combination with SOF for 6 weeks or 8 weeks resulted in 
high SVR rates in HCV genotype 1 infected subjects; 100% of the subjects (N=30, of which 
18 were treated for 6 weeks), including subjects with HCV genotype 1a and subjects with IL28B
genotype non-CC, achieved SVR12. Odalasvir has potent in vitro activity against all 6 HCV 
genotypes. SMV has antiviral activity against HCV genotypes 1, 2, 4, 5, and 6, and is approved 
in several countries/regions in combination with PegIFN/RBV and in combination with SOF for 
the treatment of HCV genotype 1 or 4 infected patients with or without HIV co-infection and 
with or without cirrhosis.
The toxicology profile for AL-335, established in multiple in vitro and in vivo studies and safety 
data from a Phase 1 study in healthy volunteers, provides evidence that AL-335 has an 
acceptable safety profile. The safety and tolerability of ODV has been and is being studied in 
Phase 2 (chronic HCV infected subjects) and Phase 1 studies (healthy volunteers) and these 
studies provide evidence that ODV is generally safe and well tolerated. The safety and 
tolerability of SMV in combination with PegIFN and RBV or with SOF has been established in 
HCV infected subjects with and without cirrhosis and in subjects co-infected with HIV. 
While in the Phase 2a study AL-335-604, the SVR12 was high in both the 3- and 2-DAA arms, 
preliminary data support the use of a 3-DAA regimen with AL335 800 mg + ODV 25 mg and 
SMV 75 mg to maximize SVR when evaluating short treatment durations of 6 and 8 weeks.
The present Phase 2b study is designed to evaluate the efficacy, safety, tolerability and PK of a 
6- and 8-week treatment regimen consisting of AL-335, ODV, and SMV in treatment-naïve and 
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treatment-experienced subjects with chronic HCV genotype 1, 2, 4, 5 or 6 infection without
cirrhosis. Data from the DDI study, AL-335-602, in 32 healthy volunteers, evaluating 800 mg 
AL-335 which was either administered alone or co-administered with 150 mg SMV and/or 
50 mg ODV, indicated that SMV when given on top of ODV led to a significant increase in 
AL-335 exposure (7- to 9-fold) and metabolite ALS-022399 exposure (2.5- to 2.7-fold), and 
a slight increase in metabolite ALS-022227 (1- to 1.5-fold). In vitro, AL-335 is a clear substrate 
for the intestinal P-gp efflux pump and SMV is a clinically confirmed P-gp inhibitor (increased 
exposure of digoxin in presence of SMV). The observed boosting effect of SMV on the plasma 
levels of AL-335 as well as the mechanism of P-gp inhibition could lead to an increase in the 
bioavailability of AL-335 and subsequently higher intrahepatic triphosphate levels in liver cells 
of HCV infected subjects and an enhanced antiviral activity of AL-335. In addition, at the 
selected dose of AL-335 800 mg, a rapid and consistent decline in HCV RNA concentrations has
been observed (multiple ascending dose cohorts in Study AL-335-601). 
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to evaluate the efficacy, ie, sustained virologic response 12 weeks after 
the EOT (SVR12), of a combination treatment with AL-335, ODV, and SMV for 6 and 8 weeks 
in chronic HCV genotype 1, 2, 4, 5 or 6 infected subjects without cirrhosis.
Secondary Objectives
The secondary objectives are:

To evaluate the safety and tolerability of a 6- and 8-week treatment regimen containing
AL-335, ODV, and SMV in subjects without cirrhosis,

To evaluate SVR4 and SVR24 of a 6- and 8-week treatment regimen containing AL-335, 
ODV, and SMV in subjects without cirrhosis,

To evaluate on-treatment viral kinetics in a 6- and 8-week treatment regimen containing 
AL-335, ODV, and SMV in subjects without cirrhosis,

To evaluate the incidence of on-treatment failure during a 6- and 8-week treatment
regimen containing AL-335, ODV, and SMV in subjects without cirrhosis,

To evaluate the incidence of viral relapse after a 6- and 8-week treatment regimen 
containing AL-335, ODV, and SMV in subjects without cirrhosis,

To assess changes from baseline in HCV NS3/4A, NS5A and NS5B sequence in subjects 
not achieving SVR,

To evaluate the effect of the presence or absence of baseline HCV NS3/4A
polymorphisms (including Q80K), NS5A polymorphisms and/or NS5B polymorphisms
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on treatment outcome (SVR12, on-treatment failure, viral relapse, and emergence of 
resistance),

To evaluate concordance between SVR4, SVR12, and SVR24,

To evaluate the PK of AL-335 (and metabolites), ODV , and SMV in plasma,

To evaluate the relationship between the population-derived exposure parameters of 
AL-335 (and metabolites), ODV, and SMV
(ie, AUC24h
and predose plasma 
concentrations [C0h]) with SVR12 and safety,

To explore the impact of HCV and its treatment with AL-335+ODV+SMV on the 
Fatigue Severity Scale (FSS) total score and the 5-level EuroQol 5-Dimension 
(EQ-5D-5L) Visual Analog Scale (VAS) score.
Exploratory Objectives
The exploratory objectives are:

To explore the effect of prior HCV treatment history, baseline host and disease related 
characteristics including but not limited to HCV geno/subtype, baseline HCV RNA level, 
genetic factors (eg, IL28B), race, sex, and age on treatment outcome,

To explore the impact of HCV and its treatment with AL-335+ODV+SMV on symptoms,
functioning and health-related quality of life (HRQoL), using patient-reported outcomes 
(PROs), ie, EQ-5D-5L domain scores, Short Form 36 version 2 (SF-36v2) Physical 
Component Summary (PCS) and Mental Component Summary (MCS) scores, and Chronic 
Liver Disease Quality of Life Questionnaire – HCV (CLDQ-HCV) summary and domain
scores,

To 
explore 
the 
impact 
of 
HCV 
treatment 
with
AL-335+ODV+SMV 
on 
occupational/employment status,

To describe the impact of HCV treatment on medical resource utilization (MRU).
2.2.
Hypothesis
The SVR12 rate is non-inferior in at least one treatment arm to the performance benchmark of 
98% (based on historical IFN-free, DAA regimens) with a non-inferiority margin of 10%.
Statistical testing will be conducted using null hypothesis H0: C-T≥10% vs. Ha: C-T<10% at a 
significance level of 0.05, 2-sided, where C is the historical control rate of 98% and T is the 
expected SVR rate in the treatment arm.
For more information, see Section 11.3.
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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a Phase 2b multicenter, randomized, open-label, study to investigate the efficacy, safety 
and PK of a 6- and 8-week treatment regimen with AL-335, ODV, and SMV followed by a 
24-week post-treatment follow-up in treatment-naïve and treatment-experienced subjects with 
chronic HCV genotype 1, 2, 4, 5 or 6 infection without cirrhosis.
The study will include a screening period of maximum 6 weeks starting from the time of first 
screening assessment. In exceptional cases, the screening phase can be extended if discussed 
with and approved (documented) by the sponsor. Thereafter, if eligible, subjects will be 
randomized to receive AL-335, ODV, and SMV for either 6 or 8 weeks. A post-treatment 
follow-up until 24 weeks after the actual EOT is included to assess SVR12 and SVR24. The total 
study duration for each subject will be approximately 36 to 38 weeks (including the 6-week 
screening period, the 6- or 8-week treatment periods and the 24-week post-treatment follow-up 
period); the 6- and 8-week treatment periods can be extended to treatment periods of maximum 
12 weeks upon recommendation by the DRC. The study is considered completed with the last 
visit of the last subject participating in the study.
A target of approximately 300 male or female subjects, aged 18 to 70 years (extremes included), 
with HCV genotype 1, 2, 4, 5 or 6 infection and with HCV RNA >10,000 IU/mL are planned to
be enrolled in the study. Subjects with cirrhosis or liver disease of non-HCV etiology, including 
hepatitis B co-infection will be excluded. 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).
The study will include treatment-naïve and treatment-experienced (to [Peg]IFN ± RBV) HCV 
genotype 1, 2, 4, 5 and 6 infected subjects without cirrhosis. Subjects who participate in this 
study will be classified as treatment-naïve, defined as not having received prior treatment with 
any approved or investigational drug (including DAAs, IFN-based treatments and vaccines) for 
chronic HCV infection or treatment-experienced, defined as having received HCV therapy 
consisting of IFN (pegylated or non-pegylated) with or without RBV. Subjects who have prior 
experience with any anti-HCV DAA-based regimen or all-oral DAA regimen are excluded from 
the study.
The dose of SMV will be 75 mg qd, the dose of ODV will be 25 mg qd and the dose of AL-335 
will be 800 mg qd. For more information on the dose selection, see Section 3.2.
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Approximately 300 treatment-naïve and –experienced (to [Peg]IFN ± RBV) chronic HCV 
genotype 1, 2, 4, 5 or 6 infected subjects without cirrhosis will be randomized (in a 1:1 ratio) to 
one of the following treatment arms:

Arm A (N=150): AL-335 800 mg qd + ODV 25 mg qd + SMV 75 mg qd for 6 weeks

Arm B (N=150): AL-335 800 mg qd + ODV 25 mg qd + SMV 75 mg qd for 8 weeks
Patients still in screening at the time of reaching the target enrollment in the study were allowed 
to enroll when proven eligible after completion of the screening procedures, leading to the 
enrollment of an additional 65 subjects in the study (365 subjects in total: 183 subjects in Arm A 
and 182 subjects in Arm B).
Randomized subjects in arms A and B will be stratified by HCV treatment history (treatment-
naïve versus treatment-experienced) and HCV geno/subtype (genotypes 1a or 2 versus genotypes
1b, 4, 5 or 6). In the stratification by HCV geno/subtype, subjects with a genotype 1 non-
specifiable subtype at screening will be assigned to the 1b, 4, 5 or 6 stratification group (see 
Section 5). All efforts need to be made to enroll as many HCV genotype 2, 4, 5 and 6 subjects as 
possible.
HCV RNA levels will be processed in real time and continuously monitored by the sponsor and 
communicated to the investigator throughout the study. Subjects will be monitored from Day 1
through end of follow-up for viral breakthrough or relapse. As described in Section 11.11, Data 
Review Committee, review of virologic response including viral relapse will be conducted to 
allow for any specific recommendation including extension of treatment duration if deemed 
necessary based on the accumulating data. If treatment extension is recommended for the 6-week 
treatment duration, the 6-week treatment arm will be extended to 8 weeks. If treatment extension
is recommended for the 8-week treatment duration, the 6- and 8-week arms will be extended to 
12 weeks. In case of observation of treatment failure, a thorough evaluation of each case will be 
performed to ensure that the treatment failure is not related to non-virologic reasons. For subjects 
who do not achieve SVR, the sponsor will provide the investigator
with available HCV 
sequencing data. For these subjects, the sponsor will reimburse one treatment regimen with the 
standard of care for this population in the respective country.
Study drugs will be discontinued for subjects with viral breakthrough (ie, confirmed >1.0 log10
increase in HCV RNA from nadir or confirmed HCV RNA >100 IU/mL in subjects who had 
previously achieved HCV RNA <LLOQ).
A DRC will be established to monitor data on a regular basis to ensure the continuing safety, 
efficacy and well-being of the subjects enrolled in this study (see Section 11.11). The DRC is a 
committee within the sponsor’s organization that is independent of the sponsor’s study team.
Virologic failures will be communicated immediately to the DRC to trigger efficacy review.
Emerging safety and efficacy data from this study will be reviewed at predetermined intervals. 
As a part of the safety evaluations, the DRC will also review AEs considered anticipated events
for this patient population (see Attachment 8).
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Upon review of the HCV RNA data from this study and/or consideration of data from other 
completed and ongoing studies, including the Phase 2a study AL-335-604, the DRC will make 
study conduct recommendations, which may include but are not limited to, continuing the study 
without modifications and/or implementation of treatment extension. The sponsor’s decision 
based on the recommendation will be communicated to the investigator. Details will be specified 
in a separate charter.
In case of treatment extension, subjects will continue to attend study visits every 2 weeks. In case 
of treatment extension to 8 weeks, the subjects should follow the visit schedule of subjects
initially included in the 8-week treatment arm, with an EOT visit at Week 8. In case of treatment 
extension to 12 weeks, subjects should follow the schedule for the 12-week treatment extension 
arm with an EOT visit at Week 12.
In case of substantial changes to the study conduct, other than the treatment prolongation
described above, an amendment to the current protocol will be submitted for approval by the 
competent authorities.
If study drug treatment 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 early 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 (W4 FU) visit need to 
be performed. Any subject who withdraws consent during the follow-up phase and/or notifies the 
site 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 (W24 FU) visit. However, all possible efforts should be made to ensure that subjects 
complete the study.
All study drugs (AL-335, ODV, and SMV) should be taken together in the morning at 
approximately the same time every day throughout the treatment phase and be administered with 
food (ie, during or no later than 15 minutes after a meal). Study drug intake should take place on 
site during visits when biochemistry samples are to be taken after fasting for at least 8 hours, and 
when pre-dose PK sampling is performed (see Time and Events Schedule: PK Assessments in 
PK Substudies). At visits where study drug dosing occurs on-site, study sites should have 
arrangements in place to offer the subjects a meal.
A diagram of the study design is provided in Figure 1.
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Figure 1:
Schematic Overview of the Study
* If DRC recommends treatment extension, treatment will be extended to 8 weeks.
** If DRC recommends treatment extension, treatment of this arm and the 6-week arm will be extended to 12 weeks.
*** Randomized subjects in arms A and B will be stratified by HCV treatment history (treatment-naïve versus treatment-experienced) and HCV geno/subtype 
(genotypes 1a or 2 versus genotypes 1b, 4, 5 or 6). 
Dosage: AL-335 800 mg qd, ODV 25 mg qd, SMV 75 mg qd
N: planned number of subjects; ODV: odalasvir, SMV: simeprevir, Wks: weeks
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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 (except for the second blood sample to be taken within 4 hours 
post dose for the post-dose HCV RNA determination).
Efficacy of the regimen will be assessed by means of HCV RNA levels (see Section 9.2.1.1) and
ALT/AST levels (part of biochemistry testing battery; see Section 9.2.1.2); samples will be
collected throughout the study. For resistance determination, blood samples will be collected 
throughout the study (see Section 9.2.1.3).
The impact of HCV and its treatment (safety and efficacy) on patient-reported symptoms, 
functioning and HRQoL (PRO, see Section 9.2.1.4) will be assessed at selected time points 
throughout the study. In addition occupational/employment status (see Section 9.6) and MRU 
(see Section 9.7) will be assessed.
Pharmacokinetic samples will be taken at any time during the visit for all subjects at the Week 4
visit, the Week 6 visit (arm B) and at the EOT visit. At the EOT visit, subjects should still be on 
treatment at the time of the PK assessments (the last dose is expected to be taken on the morning 
of the visit). In addition, at selected sites, a rich PK substudy and a sparse PK substudy will be 
performed in subsets of subjects (ie, 20 subjects from arms A and B combined in each of the PK 
substudies; 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). Where locally permitted and upon 
consent of the subject (in addition to the consent for the main part of the study), an additional 
optional blood sample may be collected preferentially at baseline for host DNA research (see 
Section 9.5) related to AL-335 (and metabolites), ODV, and SMV, and limited to genes involved 
in the metabolism of the study drugs as well as drug transporter genes.
The safety evaluations will include the monitoring of AEs, clinical laboratory tests, ECGs, 
echocardiograms, vital sign measurements, physical examinations, and specific toxicities (see 
Section 9.8). 
Subjects will complete all above mentioned assessments during study-related visits as specified 
in the Time and Events Schedule.
An interim analysis is planned at the SVR4 time point, ie, when all subjects have reached the 
SVR4 (W4 FU visit) time point or discontinued earlier.
The primary analysis will be performed when all subjects have reached the SVR12 time point 
(W12 FU visit) or discontinued earlier. The final analysis will be performed when all subjects 
have completed the last study-related visit (SVR24 time point; W24 FU visit) or discontinued 
earlier. Additional interim analyses may be conducted if needed to support clinical development.
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Safety, efficacy, and/or pharmacokinetic data from this study may be pooled with data from the
Phase 2a AL-335-604 study and potentially other similarly performed studies to assess the 
combination regimen of AL-335, ODV and SMV. This will increase the sample size for the 
different subgroups/duration groups and provide for more accurate estimates for safety and 
efficacy endpoints. The details of this combined analysis will be outlined in a separate analysis 
plan.
3.2.
Study Design Rationale
Dose and Treatment Duration
The present study will evaluate a 3-DAA regimen of AL-335 800 mg, ODV 25 mg, and SMV
75 mg, co-administered qd with food (as individual tablets/capsules) in the morning for 6 or 
8 weeks.
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 
anti-HCV 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. The study population of the current study will include (IFN-based) treatment-naïve 
and -experienced subjects without cirrhosis across HCV genotypes 1, 2, 4, 5 and 6. 
Selection of Doses
AL-335 dose selection
At the time of the AL-335 dose selection for the current study, preliminary PK 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.
The objective of the ongoing Phase 2a study AL-335-604 is to enable 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 evaluated. 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 pro-drug 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 showed in HCV genotype 1-infected 
patients a greater magnitude of HCV RNA decline from baseline at 800 mg qd compared to that 
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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 genotype 2- and genotype 3-infected 
patients 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 genotype 2 and genotype 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 2b 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). There were no related SAEs, and no clinically relevant 
laboratory, ECG, Holter, vital sign, or physical exam safety signals were identified when AL-335 
was administered as monotherapy. Preliminary safety evaluation of the first 97 subjects who
were dosed for 6 or 8 weeks (Cohort 1, 1b, 2 and 3; 20 subjects each) or received at least 1 dose 
of study medication (Cohorts 4 [N=5], 5 [N=5] and 6 [N=7]) with AL-335 and ODV with or 
without SMV in the ongoing Phase 2a study AL-335-604 revealed no safety signals in AE, 
laboratory, ECG, cardiac echo, vital signs, or physical examination. One cardiac-related SAE 
was reported in a patient with progressive prolongation of PR interval and development of type 1 
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 patients, potent antiviral activity was demonstrated for 
all doses.
At the time of the ODV dose selection for the current study, 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 liquid-filled capsule (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]) 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 50 mg every 
other day in the ongoing cohorts of Phase 2a study AL-335-604 and will be 25 mg qd in the 
current Phase 2b study.
SMV dose selection
Although SMV exposure was increased by 1.6-fold when administered in combination with 
ODV compared to SMV administered alone or ODV administered alone in the DDI study
AL-335-602 (preliminary data available at the time of the SMV dose selection in the current 
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study) in healthy volunteers, results from the ongoing Phase 2a study AL-335-604 indicated that 
there is no significant interaction when these compounds are administered to HCV patients. In 
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 along 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 well 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 the dose of 75 mg. 
Taking into account the dose selection rationale described above, the doses for AL-335, ODV,
and SMV in the current Phase 2b study will be 800 mg qd, 25 mg qd, and 75 mg qd, 
respectively.
Selection of Treatment Duration
This study investigates the safety and efficacy of two different treatment durations. The 3-DAA 
combination of AL-335, ODV, and SMV will be given for 8 or 6 weeks.
Ideally, an IFN-free regimen for treatment of chronic HCV infection combines agents with 
different mechanisms of action.
Available data suggest that addition of a third anti-HCV 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.
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 a 
treatment duration of 8 weeks (12 subjects) and 6 weeks (18 subjects). Given the high SVR rates 
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 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.
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Study Population
A number of IFN-free DAA combination regimens have been approved mainly for the treatment 
of HCV genotype 1 and 4 infected patients, and recently also for genotype 2, 3, 5, and 6 HCV 
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.
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 Section 1.1.4 and 1.1.3, respectively), is 
expected to provide in combination with SMV an effective treatment for HCV genotypes 
1-6 infected patients.
This study will include treatment-naïve and treatment-experienced subjects (received prior 
treatment consisting of IFN [pegylated or non-pegylated] with or without RBV) with HCV 
genotype 1, 2, 4, 5 and 6 without cirrhosis. 
Plasma levels of drugs are known to vary among races or ethnic subpopulations. Therefore we 
are collecting information on race upon voluntary consent of the subjects. Subjects of East-Asian 
origin are known to have higher plasma levels of SMV as compared to Caucasian subjects. No 
information is available yet on the PK of AL-335 and its metabolites and ODV in subjects of 
East-Asian origin. In order to accurately measure the impact of race and ethnicity on plasma 
exposures of AL-335 and its metabolites, ODV, and SMV when given in combination in this 
study, the present study will document whether subjects participating in the study are of 
East-Asian origin, defined as subjects whose parents and maternal and paternal grandparents are 
Japanese, Chinese, Taiwanese, or Korean, as determined by subject’s verbal report.
Stratification Factors
The randomization will be balanced by using randomly permuted blocks and will be stratified by
two 
important 
baseline
factors:
HCV 
treatment 
history 
(treatment-naïve 
versus 
treatment-experienced) and HCV geno/subtype (genotypes 1a or 2 versus genotypes 1b, 4, 5 or 
6). In the stratification by HCV geno/subtype, subjects with a genotype 1 non-specifiable 
subtype at screening will be assigned to the 1b, 4, 5 or 6 stratification group.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 6 weeks before administration of the 
study drug. In exceptional cases, the screening phase 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.
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 
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investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study.
Approximately 300 subjects were planned to be enrolled in the study and, in total, 365 have been 
enrolled. For a discussion of the statistical considerations of subject selection, refer to 
Section 11.2, Sample Size Determination. All efforts need to be made to enroll as many HCV 
genotype 2, 4, 5 and 6 subjects as possible.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Man or woman, 18 to 70 years of age, inclusive.
2.
Body mass index (BMI; 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.
4.1
All subjects must have HCV genotype 1, 2, 4, 5 or 6 infection, determined at screening.
5.1
Inclusion criterion 5 was removed per the HPC2001 protocol amendment 2.
6.
HCV RNA plasma levels >10,000 IU/mL for all subjects.
Note: genotype and HCV RNA plasma levels will be determined by the central lab at 
screening. In case of discrepancy between previously documented geno/subtype and the 
geno/subtype determined at screening, the screening results will be used.
7.1
HCV treatment-naïve, defined as not having received treatment with any approved or 
investigational drug (including DAAs, IFN-based treatments, and vaccines) for chronic 
HCV infection, or previously treated subjects (treatment-experienced) defined as having 
received HCV therapy consisting of IFN (pegylated or non-pegylated) with or without 
RBV.
8.
A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin) pregnancy test at screening.
9.2
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.
female subjects must either:
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
be not of childbearing potential:

postmenopausal for at least 12 months (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

be surgically sterile (have had a hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation/bilateral tubal clips without reversal operation), or 
otherwise be incapable of pregnancy, 
OR

be of childbearing potential and

not heterosexually active (eg, abstinence) from screening until 12 weeks after 
the EOT (or longer, if dictated by local regulations), OR

have a vasectomized partner (confirmed sterile per verbal account of the 
subject), OR

if heterosexually active, be participating an acceptable method of birth control 
from screening 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 4 weeks after the EOT. An IUD, 
being either hormonal (ie, IUS*) or non-hormonal, is considered highly 
effective and reliable, therefore subjects are not required to use additional 
contraceptive methods (no double barrier method required). Other non-oral 
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.
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.
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10.
Willing and able to comply with the protocol requirements, including the Prohibitions 
and Restrictions described in Section 4.3.
11.
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.
12.
Each subject must voluntarily sign an ICF as such indicating that he or she understands 
the purpose of and procedures required for the study and is willing to participate in the 
study.
13.1
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).
Note liver biopsy should only be considered as an alternative in subjects where 
Fibroscan is not feasible
14.
Female subject 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.
15.
Female subject must have a negative highly sensitive urine pregnancy test at Day 1.
16.
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.
Male subject must either:
be surgically sterile (had a vasectomy), or otherwise incapable of fathering a child,
OR
be not heterosexually active (eg, abstinence) from enrollment (Day 1) in the study 
until at least 12 weeks after the EOT, OR
if heterosexually active have a partner who is postmenopausal (2 years amenorrhea), 
surgically sterile (has had a hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation/bilateral tubal clips without reversal operation), or otherwise incapable of 
becoming pregnant OR
if heterosexually active with a woman of childbearing potential, be practicing an 
acceptable method of birth control from enrolment in the study (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 male subjects is a double-barrier method (eg, 
male condom + either diaphragm or cervical cap with or without spermicide). Male 
subjects with a female partner who uses hormonal contraceptives (oral, injectable, 
implants) or an hormonal (IUS) or non-hormonal IUD and male subjects who are 
vasectomized or otherwise incapable of fathering a child are not required to use 
additional contraceptive methods.
Note 1: Sexual abstinence is considered a highly effective method only if defined as 
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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.
17.
Male subjects must agree not to donate sperm during the study until 12 weeks after the 
EOT (or longer, if dictated by local regulations).
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.
3.1
Presence of cirrhosis.
4.
Prior exposure to an HCV DAA, either in combination with PegIFN or IFN-free.
5.
Any evidence of liver disease of non-HCV etiology. This includes, but is not limited to, 
acute hepatitis A infection (immunoglobulin M), hepatitis B infection (hepatitis B 
surface antigen positive), drug- or alcohol-related liver disease, autoimmune hepatitis, 
hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, primary biliary 
cirrhosis, or any other non-HCV liver disease that is considered clinically significant by 
the investigator.
6.
Evidence of hepatic decompensation (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 that 
in the opinion of the investigator, with concurrence of the sponsor's medical monitor, is 
considered cured with minimal risk of recurrence).
9.
Known allergies, hypersensitivity, or intolerance to AL-335, ODV, or SMV or their 
excipients (refer to the IBs of AL-335, ODV, and SMV, respectively).
10.
Presence of significant co-morbidities, 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 
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could prevent, limit, or confound the protocol-specified assessments.
11.
Organ transplant (other than cornea or 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% or any 
other echocardiogram finding suggestive of clinically relevant cardiomyopathy;

abnormal ECG findings such as: significantly abnormal PR [PR interval 
>200 milliseconds], 
QRS 
intervals 
or 
corrected 
QT 
interval 
[QTc] 
>450 milliseconds for male subjects and >470 milliseconds for female subjects 
(based on the average of the 3 QTc values);

Evidence of any heart block;

Evidence of right bundle branch block or left bundle branch block;

History or family history of prolonged QT syndrome (torsade de pointes) or 
sudden cardiac death.
13.1
Any of the following laboratory abnormalities at screening:

Platelet count <75 x 10³/µL or <75 x 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 x 10³/µL or <1.00 x 109/L;

ALT and/or AST >10 x ULN;

Total serum bilirubin >1.5 x ULN;

Albumin <3.5 g/dL or <35 g/L;

Estimated glomerular filtration rate (eGFR) of <50 mL/min/1.73 m².
14.
Other abnormal screening laboratory results that are considered clinically significant by 
the investigator.
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15.
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.
16.
Pregnant, planning on becoming pregnant (during treatment and up to 12 weeks after 
the EOT), or breast-feeding female subject, or male subject whose female partner is 
pregnant or planning on becoming pregnant (during treatment and up to 12 weeks after 
the EOT).
17.
Subject 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.
18.1
Subject has findings suggestive of hepatocellular carcinoma.
19.
Subjects with HCV genotype 3 infection.
NOTE:
o
Retesting of laboratory values that lead to exclusion will be allowed once during the 
screening phase to assess eligibility.
o
Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including 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.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions:
1.1
Agree to follow all requirements that must be met during the study as noted in the 
inclusion (Section 4.1) and exclusion criteria (Section 4.2; eg, contraceptive 
requirements).
2.
Prohibitions and restrictions criterion 2, 3.1, 4, 5, and 6.1 were removed per the 
HPC2001 protocol amendment 2.
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3.1
4.
5.
6.1
7.1
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. 
8
Refer to Section 8 PRESTUDY AND CONCOMITANT THERAPY for details 
regarding prohibited and restricted therapy during the study.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of the 2 treatment arms in a 1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The interactive voice 
response system (IVRS) or interactive web response system (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment and matching study drug kit for the 
subject. The requestor must use his or her own user identification and personal identification 
number when contacting the IVRS/IWRS, and will then give the relevant subject details to 
uniquely identify the subject. Randomized subjects in arms A and B will be stratified by HCV 
treatment history (treatment-naïve versus treatment-experienced) and HCV geno/subtype 
(genotypes 1a or 2 versus genotypes 1b, 4, 5 or 6).
Blinding
As this is an open 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). 
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All subjects will receive AL-335, ODV, and SMV at the selected dose for 6 weeks (arm A) or
8 weeks (arm B).
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 all subjects. In case of treatment extension to
12 weeks, study drugs will also be dispensed at the Week 8 visit. Subjects will be instructed to 
continue intake of study drugs exactly up to 6 (43 days) or 8 (57 days) weeks of treatment (or 
12 weeks [85 days] in case of treatment extension to 12 weeks), depending on the treatment arm 
they are in, 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. All subjects should take the study drugs (AL-335, ODV, and SMV) 
orally, qd and with food, starting on Day 1 after the baseline assessments have been completed 
(except for the second blood sample for post-dose HCV RNA determination which is to be taken 
within 4 hours after dosing). Thereafter, all study drugs should be taken together, qd, in the 
morning at approximately the same time each day with food (ie, during or within 15 minutes 
after completion of a meal). Study drug intake should take place on site during visits when 
biochemistry samples are to be taken after fasting for at least 8 hours, and when pre-dose PK 
sampling is performed (see the Time and Events Schedule and Time and Events Schedule: PK 
Assessments in PK Substudies). 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 
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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 
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 early treatment discontinuation is withdrawal of consent. Additional 
unscheduled visits may be performed for safety/tolerability reasons, if needed. Subjects who 
withdraw consent during the treatment or follow-up phase will be offered an optional safety 
follow-up visit.
All treatment modifications, interruptions, and discontinuations will be recorded in the eCRF.
6.3.
Treatment Stopping Rule (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 >100 IU/mL in subjects 
who had previously achieved HCV RNA <LLOQ. 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 study drug is necessary, an early 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. In the eCRF, the data will be captured on separate pages (early treatment 
withdrawal visit pages) and not on the scheduled visit pages.
For details on the assessments during the early treatment withdrawal visit, see the Time and 
Events Schedule.
Upon review of the HCV RNA data from this study and/or consideration of data from other 
completed and ongoing studies, including the Phase 2a study AL-335-604, the DRC will make 
study conduct recommendations, which may include but are not limited to, continuing the study 
without modifications and/or implementation of treatment prolongation. The sponsor’s decision 
based on the recommendation will be communicated to the investigator.
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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 dosing in all subjects in the current study if the event is adjudicated by the 
DRC to have met the above criteria and 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. For more 
information on the reporting of SAEs, see Section 12.3.2.
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 and 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). On the day 
of PK assessments which are part of the rich PK substudy, the start and end times of the meal 
accompanying the drug intake should be documented; on the previous day it should be recorded 
if the study drugs were taken with food (ie, during or no later than 15 minutes after a meal). 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. Study-site personnel is to review 
the medication diary for adherence and perform adherence counseling at each on-treatment study 
visit. Given the short treatment duration, 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).
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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) is 
disallowed from baseline till EOT.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) used during the study different from the study drug (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.
For study-specific rules on the use of contraceptive methods, refer to Section 4.3.
AL-335 is metabolized by esterases and is not a substrate of any CYP enzymes. AL-335 (and the 
metabolites ALS-022399 and ALS-022227) 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. Co-administration 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 OATP1B3, BCRP, MRP2, MRP3, and BSEP. 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. Co-administration 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. Co-administration 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. Co-administration of SMV with 
inhibitors of CYP3A may increase SMV plasma concentrations. Clinically, SMV inhibits uptake 
transporters OATP1B1/3 and the efflux transporters P-gp/multidrug resistance protein 1 and 
MRP2. Co-administration of SMV with drugs that are substrates for OATP1B1/3, and P-gp 
transport may result in increased plasma concentrations of such drugs.
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An overview of disallowed concomitant medication is presented in Table 1. An overview of 
concomitant medication that should be used with caution follows after the table.
Table 1:
Disallowed Medication
Disallowed at any time prior to screening and during the study period, including post treatment follow-up:

Previous treatment with any approved or investigational anti-HCV drug (including vaccines) other than 
(Peg)IFN/RBV.
Note: Prior hepatic treatment with herbal or nutritional products is allowed but should be stopped at screening
Disallowed within 30 days of screening, during screening and during the entire treatment period:

All non-HCV investigational drugs or invasive investigational medical devices.

Experimental non-HCV vaccines.
Note: Approved non-HCV vaccines are allowed
Disallowed within 3 months prior to screening until the end of the study:

The antiarrhythmic amiodarone.
Disallowed from screening onwards until the EOT:

Immunomodulators (eg, cyclosporine, interleukins, or systemic corticosteroids in immunosuppressive dose).

Any herbal or nutritional products for HCV treatment including silibinin, silybin, silymarin (milk thistle).

Antiarrhythmics: disopyramide, flecainide, mexiletine, systemic lidocaine, propafenone, quinidine.

Beta-blockers.

Proton-pump inhibitors (eg, [dex]lansoprazole, [es]omeprazole, rabeprazole).
Disallowed from screening onwards until the end of the study

Ca-channel blockers (eg, amlodipine, bepridil, diltiazem, felodipine, nifedipine, nisoldipine,verapamil, 
nicardipine).

Na-channel blockers (eg, disopyramide, flecainide, lidocaine, mexiletine, moricizine, procainamide, 
propafenone, quinidine, tocainide)

K-channel blockers (eg, bretylium, dronedarone, sotalol, ibutilide, dofetilide) 
Disallowed from 2 weeks before baseline and during the treatment period: 

Potent and moderate CYP3A4 inducers, such as:
-
The anti-epileptics: carbamazepine, oxcarbazapine, (fos)phenytoin,phenobarbital.
-
The anti-tuberculosis drugs: rifabutin, rifampin, and rifapentine.
-
Systemic dexamethasone (if more than a single dose).
-
Miscellaneous: products containing Hypericum perforatum (St. John’s Wort).

P-gp inhibitors (eg, clarithromycin, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, 
ketoconazole, quinidine, ritonavir verapamil).
Disallowed from baseline onwards until the EOT:

Potent and moderate CYP3A4 inhibitors, such as:
-
The antifungals (systemic): ketoconazole, itraconazole, voriconazole.
-
The antibiotics (systemic): clarithromycin, erythromycin, troleandomycin, and telithromycin.
-
The antiretrovirals: (fos)amprenavir, atazanavir, delavirdine, darunavir, efavirenz, etravirine, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, 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 W4 FU:

Oral contraceptives.
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 interfer with BNP measurement, sacubitril-containing products are disallowed from screening
until W4 FU.
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In addition to the disallowed medications outlined in Table 1, drugs which are known to prolong 
the QTc interval (refer to the list of drugs provided by the Arizona Center for Education and 
Research on Therapeutics37) may not be newly initiated once a subject has begun study drug 
treatment unless the medication is necessary to protect subject safety and it has been discussed 
with the sponsor. An ECG should be performed prior to initiating any drugs which may prolong 
the QTc interval. Drugs which prolong the QTc (eg, methadone, citalopram) are permitted as 
prior/concomitant medications if they have been administered chronically with an unchanged 
dose (at least 2 months prior to screening) and the subject’s QTc interval is normal (see in- and 
exclusion criteria in Section 4).
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 AEs and desired efficacy
Analgesics: ergaloid mesylates, ergotamine tartrate, dihydroergotamine and methylergonovine.
Lipid-lowering drugs: atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin.
Phosphodiesterase 5 inhibitors: sildenafil, tadalafil.
Sedatives/anxiolytics: midazolam, 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 IB 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 AE 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.
All visit-specific PRO assessments should be conducted/completed before any tests, procedures, 
or other consultations for that visit to prevent influencing subject’s perceptions.
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.
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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
For all subjects, less than 500 mL of blood will be drawn during each 60-day interval throughout 
the study, which is within the limits of standard blood donation.
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 phase 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 phase: -1 to +1 day.

For visits at Weeks 2 and 3 of the treatment phase: -2 to +2 days.

For visits at Weeks 4, 6, 8 and 10 and 12 (if applicable) of the treatment phase: -2 to +2 days 
(only applicable when the respective visits are not the EOT visit)

For the EOT visit: no time window allowed.

For visit at W4 FU: -3 to +3 days.

For all other scheduled visits during the 24-week follow-up phase: -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 Phase
Within 6 weeks prior to the baseline visit and after signing and dating the ICF, the first screening 
assessment should be performed. Screening assessment as indicated in the Time and Events 
Schedule may be split over more than one visit. 
A complete physical examination (including body weight, height 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 disease, and 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 
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.
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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, for whom the date 
of last menses will be recorded in the eCRF. 
Absence of cirrhosis will be determined by the methods described in Section 4.1.
Occurrence of clinical events related to AEs and pregnancies 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 values (eg, safety laboratory or HCV RNA) that lead to 
exclusion will be allowed once using an unscheduled visit during the screening phase to assess 
eligibility. In exceptional cases, the screening phase 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 Phase
If eligible, subjects to be enrolled in the study will be randomly assigned in a 1:1 ratio to 
treatment arms A or B and all subjects will come for the baseline visit. Investigators should 
ensure that all study enrollment criteria have been met during screening. If, after screening but 
prior to the first dose of study drugs, 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.
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, except for the second 
blood sample on Day 1 for HCV RNA determination, which should be taken post-dose but 
within 4 hours after dosing. The time when the pre- and post-dose blood sample is obtained as 
well as the timing of the baseline dosing should be recorded in the eCRF.
From the baseline visit onwards, at sites where appropriate translations are available, PRO 
assessments (CLDQ-HCV, EQ-5D-5L, FSS, and SF-36v2) are to be completed before any tests, 
procedures or other consultations for that visit, and at the time points indicated in the Time and 
Events Schedule.
MRU data will be collected at all scheduled visits.
A pharmacogenomic blood sample for host IL28B genotyping and, where locally permitted, and 
upon consent of the subject (in addition to the consent for the main part of the study) an optional 
additional blood sample will be collected at baseline for exploratory host DNA research related 
to AL-335 (and metabolites), ODV, and SMV, and limited to genes involved in the metabolism 
of the study drugs as well as drug transporter genes.
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Targeted physical examinations (ie, physical examinations directed at specific body systems as 
required based on the clinical presentation) (including body weight), vital sign measurements 
and blood and urine sampling 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 Day 1 
and at least every 4 to 6 weeks up to the W24 FU visit as indicated in the Time and Events 
Schedule. 
Blood sampling for determination of the HCV RNA level (2 samples taken on Day 1; 1 pre-dose 
and 1 post-dose but within 4 hours after dosing) and for viral sequencing will be performed at all 
scheduled visits. Viral sequencing will be performed on pre-treatment (baseline) samples of all 
subjects by default and on post-baseline samples of subjects not achieving SVR. Sequencing of 
additional samples may be triggered by the sponsor’s virologist. A retest sample for confirmation 
of the HCV RNA result will be needed in case viral breakthrough is suspected. At the time of the 
retest sample for HCV RNA, a sample for viral sequencing will also be collected.
Occurrence of clinical events related to all AEs, whether serious or non-serious, pregnancies and 
use of concomitant medication will be reported throughout the treatment phase.
Echocardiography and triplicate ECG (central reading) will be performed at the time points 
indicated in the Time and Events Schedule. Additional ECG, echocardiography or cardiac 
monitoring may be done at any time during the study if clinically indicated in the opinion of the 
investigator. 
Pharmacokinetic blood samples to determine the plasma concentrations of AL-335 (and 
metabolites), ODV, and SMV will be collected at any time during the visit for all subjects at the
Week 4 visit, the Week 6 visit (arm B) and at the EOT visit. At the EOT visit, subjects should 
still be on treatment at the time of the PK assessment. In addition, at selected sites, a rich PK 
substudy and a sparse PK substudy will be performed in subsets of subjects (ie, 20 subjects each
for the rich PK substudy and sparse PK substudy) as indicated in the Time and Events Schedule: 
PK Assessments in PK Substudies. For PK sampling in the sparse PK substudy, at least 
5 subjects are to be included from each treatment arm.
From baseline onwards, subjects’ occupational/employment status will be checked throughout 
the treatment phase as indicated in the Time and Events Schedule.
In case a treatment extension is recommended by the DRC, treatment duration of the arms will 
be extended up to a maximum of 12 weeks (ie, the 6-week arm will be extended to 8 weeks, or 
both arms will be extended to 12 weeks). All subjects will continue to attend study visits every 
2 weeks. In case of treatment extension to 8 weeks, the subjects should follow the visit schedule 
of subjects initially included in the 8-week treatment arm, with an EOT visit at Week 8. In case 
of treatment extension to 12 weeks, subjects should follow the schedule for the 12-week 
treatment extension arm with an EOT visit at Week 12.
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If study drug treatment 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 early 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.
9.1.4.
Post-treatment Phase (Follow-Up)
All subjects will enter the 24-week follow-up phase, except for subjects who withdraw consent. 
The latter subjects will be offered an optional safety follow-up visit, at which the assessments of 
the W4 FU visit need to be performed. If applicable, PRO assessments (CLDQ-HCV, 
EQ-5D-5L, FSS, and SF-36v2) are to be completed at visits as indicated in the Time and Events 
Schedule before any tests, procedures or other consultations for that visit.
Any subject who withdraws consent during the follow-up phase and/or notifies the site 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 W24 FU visit. However, all 
possible efforts should be made to ensure that subjects complete the study.
Patient-reported outcomes assessments (CLDQ-HCV, EQ-5D-5L, FSS, and SF-36v2) are to be 
completed before any tests, procedures or other consultations for that visit at the time points 
indicated in the Time and Events Schedule.
MRU data will be collected at all scheduled visits.
Targeted physical examinations (including body weight) and vital sign measurements will be 
performed at the W4 FU and W24 FU visit.
Subjects’ occupational/employment status will be checked at each of the follow-up visits.
Echocardiography and triplicate ECG will be performed at the W4 FU visit.
Blood and urine samples for clinical laboratory assessments and a urine pregnancy test will be 
performed at the time points indicated in the Time and Events Schedule.
Blood samples for PK assessment of ODV will be collected, in approximately 20 subjects who 
are participating to the sparse PK substudy, at the time points indicated in the Time and Events 
Schedule: PK Assessments in PK Substudies.
Blood sampling for determination of the HCV RNA level and for viral sequencing will be 
performed at all scheduled visits.
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 
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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 non-serious, and pregnancies will be reported until the subject’s last 
study visit. The use of concomitant medication will be reported throughout the follow-up phase.
9.2.
Efficacy 
9.2.1.
Evaluations
9.2.1.1.
HCV RNA Levels
Blood samples for the determination of HCV RNA levels will be taken at all scheduled visits,
processed in real time and results closely monitored by the sponsor. 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 procedures for sample collection, processing and storage will 
be provided in the laboratory manual.
On Day 1, 2 blood samples should be taken: the first one pre-dose and the second one post-dose 
but within 4 hours after dosing. The time when the pre- and post-dose blood sample is obtained 
as well as the timing of the dosing at baseline should be recorded in the eCRF.
Results of the HCV RNA measurements will be communicated to the investigator and the 
sponsor. 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 (please see 
Section 6.3, Treatment Stopping Rule [for Viral Breakthrough]).
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.
Changes in HCV RNA levels will not be reported as AEs or SAEs.
9.2.1.2.
Alanine Aminotransferase and Aspartate Aminotransferase
Alanine aminotransferase and AST levels will be determined as part of the biochemistry panel of 
the clinical laboratory tests (see Section 9.8.2). Samples for biochemistry will be taken at the 
time points indicated in the Time and Events Schedule and will be processed in real time.
9.2.1.3.
Resistance Determinations
Sequencing of the HCV NS3/4A, NS5A and NS5B regions will be performed to identify 
pre-existing sequence polymorphisms and characterize emerging HCV variants. 
Samples for viral sequencing will be taken at all scheduled visits except at screening.
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The NS3/4A, NS5A and NS5B regions will be sequenced pre-treatment (at baseline) by default 
in all subjects and post-baseline in subjects not achieving SVR. Sequencing of additional
samples may be triggered by the sponsor virologist.
Changes in viral genotype will be evaluated by the sponsor 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.
9.2.1.4.
Patient-reported Outcomes
The impact of HCV and its treatment (safety and efficacy) on patient-reported symptoms, 
functioning and HRQoL will be evaluated at the time points indicated in the Time and Events 
Schedule, using the PRO assessments CLDQ-HCV, EQ-5D-5L, FSS,
and
SF-36v2. 
Patient-reported outcomes assessments will be performed by all subjects at sites where 
appropriate translations are available. Subjects should complete these assessments in their native 
language or if there is no version available in their native language, a version in a language in 
which the subject is fluent and literate. It is preferable that subjects are able to read and write to 
complete the assessments by themselves. If a subject is unable to read or has visual or other 
physical limitations that make it difficult to read or complete the assessments, trained study-site
personnel may read the questions and responses aloud exactly as they appear on the assessment 
and record the subject’s responses.
Study-site personnel will instruct subjects how to self-administer the PRO tools and will record 
in the eCRF whether the PRO assessments were performed during the study visit.
Subjects will complete the PRO assessments electronically during study site visits on a 
touch-screen tablet provided for this study. The subject should be provided a quiet place to 
complete the PRO assessments, and instructed how to complete the PRO assessment on the 
tablet. When deciding which answer to report, subjects should not receive any help from anyone 
accompanying them (such as family members and friends) or study-site personnel; the responses 
should reflect the subject’s interpretation and response.
Subjects’ responses to the PRO questionnaires will not be reported as AEs or SAEs.
Chronic Liver Disease Quality of Life Questionnaire
The CLDQ-HCV questionnaire is a fully validated disease-specific HRQoL instrument to assess 
health-related quality of life in patients with chronic hepatitis C. The questionnaire is supposed 
to capture HRQoL impairments such as (fatigue, activity, emotional function, abdominal 
symptoms, systemic symptoms and worry). CLDQ-HCV includes four HRQoL domains: activity 
and energy (AE), emotional (EM), worry (WO), and systemic (SY). There are domain scores and 
a total CLDQ-HCV score which ranges from 1 to 7 with higher values representing better 
HRQoL. The answers to each of the questions are from 1-7 on a Likert scale which are then 
averaged to the total CLDQ total score. The CLDQ-HCV questionnaire is comprised of 
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29 questions which is short, easy to administer and produces both a summary score and domain 
scores.
It takes 10 minutes to complete the CLDQ-HCV questionnaire. See Attachment 3 for a 
representative example of the CLDQ-HCV questionnaire.
Health Status and Quality of Life
The EQ-5D-5L questionnaire is a brief, 2-page, generic HRQoL assessment that evaluates a 
subject’s self-rated health state on 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). Additionally, a VAS records the subject’s self-rated health 
on a vertical VAS where the endpoints are labelled ‘best imaginable health state’ (100) and 
‘worst imaginable health state’ (0). This information can be used as a quantitative measure of 
health outcome as judged by the subject. EQ-5D scores include the following:

EQ-5D Valuation Index (VI) score (a weighted scoring of the 5 dimension scores with a 
possible range from 0 to 1);

EQ-5D VAS score (with a possible range from 0 [worst imaginable health] to 100 [best 
imaginable health]);

EQ-5D descriptive system scores (5 scores reflecting each of the 5 dimensions ranging from 
0 [no limitation] to 4 [incapacity]).
It takes 5 minutes to complete the EQ-5D-5L questionnaire. See Attachment 4 for a 
representative example of the EQ-5D-5L.
Fatigue Severity Scale
The FSS is a questionnaire with 9 items developed to assess the impact of fatigue on subjects and 
has been used extensively in studies of chronic HCV infection in which it has shown good 
internal consistency, test-retest reliability, and content and construct validity.20 Item responses 
are measured on a 7-point Likert scale ranging from strongly disagree (1 point) to strongly agree 
(7 points). The 9 items are averaged to produce a total score; a lower total score indicates less 
effect of fatigue on everyday life. The recall period of the FSS used in this study is 2 weeks (the 
past 14 days). It takes 5 minutes to complete the FSS questionnaire. See Attachment 5 for a 
representative example of the FSS.
SF-36v2
SF-36v2 is a generic 36-item questionnaire measuring HRQoL that can be interpreted using 
2 summary scores – PCS and MCS – as well as domain subscales. The SF-36v2 consists of 
8 subscales. Although SF-36v2 PCS and MCS scores include information from all 8 SF-36 
domains, the PCS score gives more weight to physical aspects of HRQoL as represented in the
Physical functioning, Physical role limitations, Pain, and General health perception domain 
scores. The MCS score gives more weight to the emotional and social aspects of HRQoL as 
assessed by the Vitality, Social function, Social role limitations, and Mental health domain 
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scores. Participants self-report on items in a subscale that have between 2-6 choices per item 
using Likert-type responses (eg, none of the time, some of the time, etc.). Summations of item 
scores of the same subscale give the subscale scores, which are transformed into a range from 
0 to 100; 0=worst HRQoL, 100=best HRQoL. Physical component summary and MCS scores 
are constructed as a T-score with a mean of 50 and standard deviation of 10 and no minimum or 
maximum score; higher scores indicate better health status.
It takes 5 minutes to complete the SF-36v2 questionnaire. See Attachment 6 for a representative
example of the SF-36v2.
9.2.2.
Endpoints
9.2.2.1.
Primary Endpoints
The primary efficacy endpoint is:

The proportion of chronic HCV infected subjects who achieve SVR12.
For the definition of SVR12, see the Definitions of Terms.
9.2.2.2.
Secondary Endpoints
The secondary efficacy endpoints are:

The proportion of subjects with SVR4 and SVR24,

The proportion of subjects with viral relapse,

The proportion of subjects with on-treatment failure,

The proportion of subjects with virologic response:
o
HCV RNA <LLOQ undetectable,
o
HCV RNA <LLOQ,

Time to achieve undetectable HCV RNA and HCV RNA <LLOQ,

The effect of the presence or absence at baseline of NS5A, NS5B or NS3/4A
polymorphisms on treatment outcome,

The changes from baseline in amino acid sequence in the HCV NS3/4A, NS5A and NS5B 
regions in subjects not achieving SVR,

The relationship between the population-derived exposure parameters of SMV (AUC24h and 
C0h) with SVR12 and safety,

Change from baseline over time in mean score for each of the following PRO scores:
o
EQ-5D-5L: VAS score,
o
FSS: Total score,

The proportion of subjects with clinically important improvement from baseline during study 
drug treatment and at follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L 
VAS scores,
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
The time to clinically important improvement from baseline during study drug treatment and 
at follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L VAS,

The proportion of subjects with clinically important worsening from baseline during study 
drug treatment and at follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L
VAS,

The duration (weeks) of clinically important worsening from baseline during study drug 
treatment and at follow-up visits at Weeks 4, 12, and 24 in FSS total and EQ-5D-5L VAS,

Change from baseline over time in EQ-5D-5L VI score and Domain scores.
For definitions of on-treatment virologic response, SVR4, SVR24, on-treatment failure and viral 
relapse, see the Definitions of Terms.
9.2.2.3.
Exploratory Endpoints
The exploratory efficacy endpoints are:

Change from baseline over time in mean score for each of the following PRO scores:
o
SF-36v2 PCS and MCS scores,
o
CLDQ-HCV summary and domain scores,

The proportion of subjects with clinically important improvement from baseline during 
study drug treatment and at follow-up visits at Weeks 4, 12, and 24 in each of the PRO 
scores mentioned above,

The time to clinically important improvement from baseline during study drug treatment and 
at follow-up visits at Weeks 4, 12, and 24 in each of the PRO scores mentioned above,

The proportion of subjects with clinically important worsening from baseline during study 
drug treatment and at follow-up visits at Weeks 4, 12, and 24 in each of the PRO scores 
mentioned above,

The duration (weeks) of clinically important worsening from baseline during study drug 
treatment and at follow-up visits at Weeks 4, 12, and 24 in each of the PRO scores 
mentioned above,

Change from baseline over time in EQ-5D-5L Domain scores,

The effect of prior HCV treatment history, baseline host and disease related characteristics
including but not limited to HCV geno/subtype, baseline HCV RNA level, genetic factors 
(eg, IL28B, the presence of NS3/4A, NS5A and NS5B polymorphisms), race, sex and age on 
treatment outcome.
9.3.
Pharmacokinetics
9.3.1.
Evaluations
Blood samples for PK assessments of AL-335 (and metabolites), ODV, and SMV, will be 
collected from all subjects at the Week 4 visit, the Week 6 visit (arm B) and at the EOT visit
at any time during the visit. At the EOT visit, subjects should still be on treatment at the time of 
the PK assessment (the last dose is expected to be taken on the morning of the visit).
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The following times need to be recorded in the eCRF: date and time of study drug intake on the 
day of the PK blood sampling and the previous day, and date and time of PK blood sampling; it 
will be recorded whether study drugs were taken with food (ie, during or no later than 15 minutes 
after a meal) on the day of PK blood sampling and on the previous day. For details on study drug 
intake, see Section 6.
Rich Serial PK Substudy
In the rich serial PK substudy, performed at selected study sites, rich serial PK blood sampling 
for the measurement of plasma concentrations of AL-335 (and metabolites), ODV, and SMV
will be performed in approximately 20 subjects (arms A and B 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. 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 standardized 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. Subjects participating in the rich serial 
PK substudy will not participate in the sparse PK substudy.
A standardized breakfast will consist of (or its equivalent) 4 slices of bread, 2 slices of ham 
and/or cheese, butter, jelly, and 2 cups (up to 480 mL) of decaffeinated coffee or decaffeinated 
tea with milk and/or sugar, if desired (containing approx.: fat, 21 g; carbohydrates, 67 g; 
proteins, 19 g; calories, 533) and should be eaten completely within 30 minutes. The study drugs 
should be taken during or no later than 15 minutes after completing the breakfast.
The following times need to be recorded in the eCRF: actual dates and times of study drug intake 
on the day of the visit and the previous and the next day and actual dates and times of PK blood 
sampling. In addition, start and end times of accompanying meal on the day of the PK sampling 
need to be recorded and it should be documented whether 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. For 
details on study drug intake, see Section 6.
Sparse PK Substudy
In the sparse PK substudy, at selected sites, sparse PK sampling for AL-335 (and metabolites), 
ODV, and SMV will be performed for a subset of approximately 20 subjects (arms A and B 
combined) who are not participating in the rich serial PK substudy.
At least 5 subjects are to be included from each arm.
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Blood samples will be collected at the following time points (see also Time and Events 
Schedule: PK Assessments in PK Substudies):
o
At the Week 2 visit: pre-dose and 2-4 hours post-dose,
o
After 6 weeks of treatment (ie, EOT visit [arm A] and Week 6 visit [arm B]): 
6-12 hours post-dose,
Note: for subjects in the sparse PK substudy, this sample replaces the PK sample to 
be taken at any time during the visit at the EOT visit (arm A) and at the Week 6 visit 
(arm B).
o
After 8 weeks of treatment (ie, EOT visit [arm B]: pre-dose and 2-4 hours post-dose,
o
At W4 FU, W12 FU, and W24 FU: for ODV only, any time during the visit.
At the EOT visit, subjects should still be on treatment at time of the PK assessment (the last dose 
is expected to be taken on the morning of the visit). In case of treatment extension to 8 weeks or 
12 weeks, no additional PK assessments will be done.
The following times need to be recorded in the eCRF: date and time of study drug intake on the 
day of the PK blood sampling and the previous day, and date and time of PK blood sampling; it 
will be recorded whether study drugs were taken with food (ie, during or no later than 15 minutes 
after a meal) on the day of PK blood sampling and on the previous day. For details on study drug 
intake, see Section 6.
9.3.2.
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of AL-335 and its metabolites
ALS-022227 and ALS-022399, ODV, and 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.
9.3.3.
Pharmacokinetic Parameters
Based on the individual plasma concentration-time data from all subjects (including those of 
subjects in the PK substudies), exposure parameters of AL-335 and its metabolites ALS-022227 
and ALS-022399, ODV, and SMV will be derived using population PK (popPK) modeling. 
Potential baseline covariates (eg, demographics such as age, sex and race, body weight, 
laboratory variables such as creatinine clearance, genotype, etc.) may be included in the models, 
if relevant. The following exposure parameters for AL-335 (and metabolites), ODV, and SMV
will be derived using Bayesian feedback analysis: AUC24h and C0h.
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Rich serial PK sampling
For subjects participating in the rich serial PK substudy, the following PK parameters for
AL-335 (and metabolites), ODV, and SMV will be derived using non-compartmental methods: 
C0h, Cmax, tmax, Cmin, and AUC24h.
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations 
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure 
parameters (C0h and AUC24h) with SVR12 and with safety endpoints will be graphically
explored. 
9.5.
Pharmacogenomic (DNA) Evaluations
9.5.1.
Genotyping of IL28B
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. 
Determination of the subject’s IL28B genotype will be performed on human genomic DNA by 
techniques allowing amplification of the DNA and identification of the polymorphism.
9.5.2.
Genotyping for Drug Metabolism and Transporter Genes
Where locally permitted and upon consent of the subject (in addition to the consent for the main
part of the study), an additional optional blood sample will be collected for all subjects at the 
baseline visit for exploratory host DNA research related to AL-335, ODV, and SMV, providing 
the opportunity to explore the genetic basis of host factors that influence response to therapy, PK
and side effects. Only genes involved in the metabolism of the study drugs (eg, CYP2C19 and 
CYP3A5), as well as drug transporter genes (eg, OATP1B1, ABCG2, ABCB1, and MRP2) may be 
analyzed to potentially help in assessing the relationship between variants in these genes and 
drug efficacy, safety, and PK.
Both blood samples for pharmacogenomic evaluations will preferably be collected at the baseline
visit. However, if necessary eg, in case of a technical failure, they may be collected at a later 
time point without constituting a protocol deviation.
9.6.
Occupational/Employment Status
Occupational/employment status will be collected in the eCRF by the investigator and study-site 
personnel for all subjects at the time points indicated in the Time and Events Schedule.
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9.7.
Medical Resource Utilization 
MRU data, associated with medical encounters, will be collected in the eCRF by the investigator 
and study-site personnel for all subjects throughout the study. Protocol-mandated procedures, 
tests, and encounters are excluded from MRU data collection. The data collected may be used to
conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient),

Duration of hospitalization (total days length of stay, including duration by wards; 
eg, intensive care unit),

Number and character of diagnostic and therapeutic tests and procedures,

Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications).
9.8.
Safety Evaluations
Any clinically relevant changes occurring during the study must be recorded on the AE Section 
of the eCRF.
All AEs, whether serious or non-serious 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/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
Anticipated events will be recorded and reported as described in Attachment 8.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule.
9.8.1.
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.
9.8.2.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis 
will be collected. The investigator must review the laboratory report, document this review, and 
record in the Adverse Event Section of the eCRF any clinically relevant changes, occurring from 
signing of the ICF onwards until the subject’s last study visit. The laboratory reports must be 
filed with the source documents.
Biochemistry samples on Day 1, Week 2, Week 4, EOT, W4 FU, and W12 FU must be taken
after fasting for at least 8 hours. The lipid profile is to be assessed at these visits, ie, after fasting. 
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The following tests will be performed by the selected central laboratory:

Hematology Panel
- hemoglobin
- WBC differentialb
- hematocrit
- neutrophils
- red blood cell (RBC) counta
- lymphocytes
- RBC parametersa:
- monocytes
- mean corpuscular hemoglobin
- eosinophils
- mean corpuscular hemoglobin concentration
- basophils
- mean corpuscular volume
- platelet count
- white blood cell (WBC) countb
a RBC evaluation may include abnormalities in RBC count and/or RBC parameters and/or RBC 
morphology, which will then be reported by the laboratory.
b 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.
The samples will also be used for coagulation tests. Prothrombin time and activated partial 
thromboplastin time will be assessed, 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
- creatinine clearance
- BNPc
a The homeostasis model assessment insulin resistance (HOMA-IR) index will be derived from plasma insulin 
and plasma glucose (fasting) test results performed on the biochemistry sample taken after fasting at baseline, 
EOT and W12 FU.
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 W4 FU.
For each time point of the laboratory assessments, the selected central laboratory will also 
estimate the GFR according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) equation.24
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
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.

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. The results of the 
pregnancy test should be recorded in the eCRF and in the subject’s medical record.

FSH 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, hepatitis B 
surface antigen, 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.

An additional sample for anti-HBc testing will be taken at baseline. For anti-HBc positive 
subjects anti-HBs will be tested.

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 9.8.6.1, 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 9.8.6.6.
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9.8.3.
Electrocardiogram and Echocardiography
Electrocardiogram
Triplicate ECGs will be performed centrally 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 9.8.6.7). The mean of the triplicate ECGs need to be taken into account for decision 
making.
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.
The triplicate ECGs should be performed approximately 2 minutes apart over 10 minutes.
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 the measured QT/QTc value is >500 milliseconds or in case the QT/QTc value increases 
by >60 milliseconds from baseline, the sites need to check whether there is a technical problem 
with the ECG machine. It also needs to be checked if the ECG leads were correctly applied and 
if the tracing is free of artifacts that may interfere with QT measurements (see Section 9.8.6.7 for 
cardiac safety monitoring). 
In case of a technical problem, the ECG recording has to be repeated after fixing the problem. 
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. 
Echocardiography
The cardiac monitoring requirements outlined in the protocol are critical and must be followed 
for all subjects. Transthoracic echocardiography will be performed at study approved facility to 
establish parameters including but not limited to 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 9.8.6.7). 
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 
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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. 
9.8.4.
Vital Signs
Systolic and diastolic blood pressure and pulse/heart 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/heart 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 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. 
9.8.5.
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 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 neurological 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. 
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. 
9.8.6.
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 and known side effects of nucleotide analogs. Cardiac events and 
increased bilirubin are considered events of special interest for the AL-335+ODV+SMV
combination program. Photosensitivity is considered an event of clinical interest.
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9.8.6.1.
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 7). 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 (see Section 6.2) 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 x baseline 
value
- fever >38°C or 100°F
- eosinophils >1.00 x 103/µL
- serum sickness-like 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.
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 7).
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 7).
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, 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 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 non-study 
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. A copy of the dermatologist's report should be made 
anonymous and will be collected by the monitor.
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 x baseline value,

fever >38°C or 100°F,

eosinophils >1.00 x103/µL,

serum sickness-like 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 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 made anonymous and be collected by the monitor.
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 onset of rash. A copy of the dermatologist's 
report, and the biopsy if performed, should be made anonymous and be collected by the monitor.
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 Attachment 7.
9.8.6.2.
Acute Allergic Reaction
Oral antihistamines (eg, cetirizine, 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.
9.8.6.3.
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. 
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 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.22
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 Alanine Aminotransferase (ALT) or Aspartate 
Aminotransferase (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 x ULN
1.1 to 1.5 x ULN
Grade 2
>2.5 to ≤5.0 x ULN
>1.5 to ≤2.5 x ULN
Grade 3
>5.0 to ≤10.0 x ULN
>2.5 to ≤5.0 x ULN
Grade 4
>10.0 x ULN
>5.0 x ULN
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, 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.
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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).
Any significant ALT flare, defined as either:

ALT of >2X ULN and >2X the lowest previous ALT value measured during the study,
OR

any treatment-emergent grade 3 ALT elevation (>5X ULN) 
will trigger a thorough clinical work-up of the case by the investigator. This evaluation should 
include the assessment of serum HBV DNA (mandatory in subjects that are anti-HBc antibody 
positive at baseline). 
In case of a grade 4 bilirubin value, subjects should have a confirmatory measurement within 
72 hours after receipt of the results. If the grade 4 value is confirmed but not considered a sign of 
worsening liver disease, or if there is an identifiable cause for the value (eg, hereditary 
hyperbilirubinemia [Gilbert’s syndrome] or concomitant medication associated event), subjects 
may continue the study drugs at the investigator’s discretion (Table 7). Subjects who continue 
the study drugs should be carefully evaluated and close follow-up is recommended to monitor for 
progressive increase in bilirubin levels. If the grade 4 value is confirmed and is considered a sign 
of worsening liver disease, or if there is no identifiable explanation for the confirmed value, all 
study drugs should be discontinued.
For concurrent grade 4 ALT and/or AST elevations >2 times the baseline value and 
grade 4 bilirubin values, subjects should have a confirmatory measurement within 72 hours after 
receipt of the results. In case of confirmed grade 4 elevations, the study drugs should be 
discontinued. 
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 Alanine Aminotransferase (ALT) and/or Aspartate 
Aminotransferase (AST) Elevations
WHO Toxicity Grade 
Ranges
Investigator Action 
Grade 1
Grade 2
Grade 3
≥1.25 to 2.5 x ULN
>2.5 to 5.0 x ULN
>5.0 to 10.0 x 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.
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Table 6:
Guidelines for Subjects Developing Alanine Aminotransferase (ALT) and/or Aspartate 
Aminotransferase (AST) Elevations
WHO Toxicity Grade 
Ranges
Investigator Action 
Grade 4
>10.0 x 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.
Note: Any significant ALT flare, defined as either: (1) ALT of >2X ULN and >2X the lowest previous ALT value 
measured during the study, OR (2) any treatment-emergent grade 3 ALT elevation (>5X ULN), will trigger a 
thorough clinical work-up of the case by the investigator. This evaluation should include the assessment of 
serum HBV DNA (mandatory in subjects that are anti-HBc antibody positive at baseline).
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 x ULN
>1.5 to 2.5 x ULN
>2.5 to 5.0 x ULN
May continue intake of study drugs at the investigator’s 
discretion. Monitor for progressive increase in bilirubin levels.
Grade 4
>5.0 x ULN
A confirmatory measurement should be performed within 
72 hours after receipt of the results. If the value is confirmed 
and:
- Not considered a sign of worsening liver disease, or if there 
is an identifiable causea for the confirmed value, subjects may 
continue study drugs at the investigator’s discretion. 
- Considered a sign of worsening liver disease, or if there is 
no identifiable explanation for the confirmed value, all study 
drugs should be discontinued.
Monitor for progressive increase in bilirubin levels.
a Eg, hereditary hyperbilirubinemia (Gilbert’s syndrome) or concomitant medication associated event.
9.8.6.4.
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, 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.
9.8.6.5.
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, 
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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.
9.8.6.6.
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, 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 x 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.
If a study subject’s experiences treatment-emergent CK elevations (without a concomitant 
proportionate CK-MB elevation), the following treatment stopping criteria for CK elevations 
should be applied29:

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):
o
If CK is ≥20 × ULN, immediately re-draw and repeat the test. If the repeat 
remains ≥20 x ULN, discontinue AL-335. Continuation of ODV and SMV should 
be discussed with the sponsor on a case-by-case basis
o
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)
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
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,

if the third follow-up CK assessment (ie, ~9 days after CK elevation was 
first recognized) is ≥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,
o
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 non-study drug related etiology for a 
CK elevation (eg, recent exercise, other clinical comorbidities [eg, endocrinal, 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):
o
If initial CK is <5 × ULN, continue study medication unless follow-up CK 
assessments are increased to ≥20 × ULN,
o
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 ≥ 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, EKG, troponin) should be initiated.
If a subject who experiences CK elevations also demonstrates clinical or laboratory evidence of 
renal insufficiency/damage or clinically significant muscle signs or symptoms (eg, proximal 
weakness), all study medication should be stopped regardless of the magnitude of the CK 
elevation.
9.8.6.7.
Cardiac Safety Monitoring
Regular cardiac safety monitoring will be done in this study via assessments of AEs, serial ECGs 
and regular echocardiograms. 
For all subjects enrolled in this study, LVEF at screening must be ≥55% (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 criteria25:
A.
Asymptomatic patients with no clinical evidence of congestive heart failure: 
1.
If the absolute decrease from baseline in LVEF is ≥10% (eg, 59% to 49%) and resulting 
in an LVEF of <50%, discontinue AL-335, ODV, and SMV.
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2.
If the absolute decrease from baseline in LVEF is >5% and ≤10%, or >10% and
resulting in an LVEF ≥50%, an assessment of the subject’s clinical status, including 
symptoms, physical exam, and other clinical parameters should be made before 
deciding whether to stop or continue study drugs.
B.
For subjects with symptoms (eg, dyspnea, orthopnea) or signs of congestive heart failure 
(eg, S3 gallop, pedal edema, pulmonary edema):
1. If the absolute decrease from baseline in LVEF is ≥5%, 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, 

Chest X ray, 

Troponin I assessment, 

12 lead ECG, and 

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 first degree AV block is diagnosed and
a.
The PR interval is >200 milliseconds but ≤240 milliseconds, study drugs can be 
continued. Close monitoring with weekly ECG is recommended.
b. The PR interval is >240 milliseconds but ≤300 milliseconds (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 milliseconds (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.
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2. If a second 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 QTcF value is >500 milliseconds (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 milliseconds 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 milliseconds). 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.
9.8.6.8.
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, 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, 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.
9.8.6.9.
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 non-confirmed events.
Grade 1
Subjects who develop a grade 1 AE or grade 1 laboratory abnormality may continue the intake of 
study drugs.
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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 “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.
9.9.
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/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed the 
assessments at the W24 FU visit.
10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. 
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Study drug(s) should be discontinued if (see Section 9.8.6 for more details):

The investigator believes that for safety 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 9.8.6.1.

The subject has a grade 3 or 4 allergic reaction; see Section 9.8.6.2.

The subject has a confirmed grade 4 ALT and/or AST value that is >2 times the baseline 
value; see Section 9.8.6.3.

The subject has a confirmed grade 4 bilirubin value which is considered a sign of worsening 
liver disease, or for which there is no identifiable explanation; see Section 9.8.6.3.

The subject has severe worsening of hepatic disease; see Section 9.8.6.4.

The subject has a confirmed diagnosis of pancreatitis; see Section 9.8.6.5.

The subject has clinical signs suggestive of muscle injury; see Section 9.8.6.6.

The subject has evidence of cardiac toxicity, see Section 9.8.6.7.

The subject has a grade 4 AE at least possibly related to 1 of the study drugs; see 
Section 9.8.6.9.
Note: For laboratory abnormalities triggering treatment discontinuation, see the toxicity 
management plan described in Section 9.8.6.

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 follow-up phase. 
Additional unscheduled visits may be performed for safety/tolerability reasons, if needed.
10.3.
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.
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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 follow-up phase will be offered an 
optional safety follow-up visit, at which the assessments from the W4 FU visit need to be 
performed. Any subject who withdraws consent during the follow-up phase and/or notifies the 
site 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 W24 FU visit.
However, all possible efforts should be made to ensure that subjects complete the study.
Subjects who withdraw consent from the PK substudies or who withdraw their optional consent 
for the optional host DNA research (see Section 16.2.3) can still continue to participate in the 
main study.
If the subject enrolls in a clinical study with an investigational drug (including investigational 
vaccines), the subject will have to withdraw from the present study first.
Withdrawal of Consent for Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to 
Section 16.2.5). 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).
Safety, efficacy, and/or pharmacokinetic data from this study may be pooled with data from the
Phase 2a AL-335-604 study and potentially other similarly performed studies to assess the 
combination regimen of AL-335, ODV and SMV. This will increase the sample size for the 
different subgroups/duration groups and provide for more accurate estimates for safety and 
efficacy endpoints. The details of this combined analysis will be outlined in a separate analysis 
plan.
11.1.
Subject Information
For all subjects who receive at least one dose of study drug descriptive statistics will be 
provided.
11.2.
Sample Size Determination
The description of the sizing for the study based on 300 subjects is provided below.
The sample size consideration is based on non-inferiority testing against performance benchmark 
98% based on historical data (ASTRAL 1-3 studies)4,9,10
in an IFN-free, 2-DAA 
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(SOF/velpatasvir [VEL]) regimen for 12 weeks of treatment. Statistical hypothesis will be tested 
per arm using the CI approach with the lower bound of CI excluding a predefined threshold for 
non-inferiority of SVR12. The SVR performance benchmark is chosen to be 98% based on 
ASTRAL 1-3 studies, in which, across genotypes 1-6, SVR was observed to be 98% with 95% 
CI: 97% to 98.8%. In a subgroup of cirrhosis (F4), the SVR was 96% with 95% CI: 92.8% to 
98.4%). Non-inferiority margin 10% was determined by referencing the most recent data from 
the ASTRAL-2 study, where 10% non-inferiority margin was used to compare 2-DAA 
(SOF/VEL) to active control SOF+RBV for non-inferiority. Additionally, recent data from a
3-DAA regimen plus RBV (Abt-450/r + ombitasvir + dasabuvir + RBV) in comparison to the 
historical control in a DAA with PegIFN/RBV used 10.5% non-inferiority margin for the 
non-inferiority testing.36 Therefore, a 10% non-inferiority margin was chosen for this Phase 2b 
study for the non-inferiority testing against historical control. Using a 2-sided 95% CI and 
assuming an expected SVR rate of 98% for each arm, a sample size of 150 subjects per arm will 
provide at least 90% power to reject the inferiority hypothesis by showing that the lower limit of 
the 2-sided 95% CI on the observed SVR will exceed 88% (the upper boundary of the 95% CI 
for the control rate minus 10%).
In addition, with a total sample size of 150 subjects in each treatment arm (300 subjects in total), 
the probability to observe an AE with an incidence of 0.1%, 0.5%, 0.8%, and 1% are 13.9% 
(25.9%), 52.9% (77.8%), 70.0% (91.0%), and 77.9% (95.1%), respectively.
To aid in the evaluation of efficacy of the 3-DAA regimens, Bayesian posterior probabilities on 
the true SVR will be calculated using uninformative prior (Jeffreys prior) and provided to the 
DRC (see Section 11.11). The posterior probability that the true SVR exceeds certain thresholds 
(eg, 90%, 95%) will be generated. Posterior probabilities associated with alternative thresholds 
may also be provided and are intended to aid the DRC in the interim evaluations of efficacy. 
Similar computations may also be provided for safety endpoints of interest.
In conclusion, a total sample size of 300 subjects in the study is considered sufficient to explore 
the efficacy, safety, tolerability and PK of the 3-DAA regimen in this study.
Note that the 65 additional subjects enrolled does not meaningfully affect the power 
considerations reported above to demonstrate non-inferiority of SVR12. Additionally, 182 
subjects enrolled per arm (365 in total) will provide a probability to observe an AE with an 
incidence of 0.1%, 0.5%, 0.8%, and 1% of 16.6% (30.6%), 59.8% (84.0%), 76.8% (94.7%), and 
83.9% (97.4%), respectively.
11.3.
Efficacy Analyses
The primary efficacy analyses will be performed on the intent-to-treat (ITT) population, defined 
as all subjects who received at least one dose of study drug (AL-335, ODV, or SMV). Additional 
sensitivity analyses on efficacy may be performed after excluding subjects with early treatment 
discontinuation due to non-virologic reasons or missing data at SVR12 time point, as well as on 
the per-protocol population, defined as the ITT population excluding subjects with a 
pre-specified major protocol deviation.
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An interim analysis is planned at the SVR4 time point, ie, when all subjects have reached the 
SVR4 (W4 FU visit) time point or discontinued earlier.
The primary analyses will be performed when all subjects have reached the SVR12 time point or 
discontinued earlier. Additional interim analyses may be conducted if needed to support clinical 
development.
The final analysis will be performed when all subjects have completed the last study-related visit 
(SVR24 time point; W24 FU visit) or discontinued earlier.
For the primary endpoint, for each treatment arm, the proportion of subjects who achieve SVR12 
will be calculated. A 2-sided 95% CI will be constructed around the SVR12. The lower limit of 
the 95% CI of the SVR12 rate will be compared against the performance benchmark for 
non-inferiority. A lower bound of the 2-sided 95% CI 88% will satisfy the hypothesis for 
non-inferiority in at least one treatment arm. Since this is a Phase 2 study, the primary goal in 
efficacy analyses is to obtain a reliable estimation of SVR12 and then compare it to the historical 
control for non-inferiority in order to select the optimum regimen for further evaluation in 
Phase 3.. A fixed sequence procedure will be used to adjust for multiple (two) confidence 
intervals (each arm is compared to the historical control). Since the clinical development strategy 
is to establish the shortest efficacious treatment duration, the 6-week regimen arm is tested first
and only if this is found to be non-inferior, the test will be performed for the 8-week regimen.
The confidence level is two-sided 95% for both confidence intervals.
Additional sensitivity analysis may be performed by applying different imputation rules for 
missing data. Missing data patterns will be analyzed and described in detail.
To aid in the evaluation of efficacy of the 3-DAA regimens, Bayesian posterior probabilities on 
the true SVR will be calculated using uninformative prior.
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment 
arm.
The potential association between treatment outcome and baseline factors such as stratification 
factors, geno/subtype, and baseline HCV RNA levels will be explored by subgroup analysis.
11.3.1.
Criteria for Endpoints
Efficacy Parameters
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.
Patient-reported Outcomes
The clinical importance of mean changes from baseline in PRO scores will be interpreted using 
the following guidelines:
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
EQ-5D-5L VAS mean change ≥±8.2 points

FSS mean change ≥ ±0.7 points
Values demonstrated to reflect clinically important changes in mean scores for CLDQ-HCV 
summary and domain scores, and SF-36v2 component and domain scores in subjects with 
chronic HCV infection will be provided in the SAP if available to aid in interpreting the clinical 
significance of mean PRO scores changes over time.
Proposed threshold values indicating clinically important improvement or worsening in a 
subject’s score for each PRO score are listed in Table 8.
Table 8:
Proposed Threshold Values Indicating Clinically Important Improvement or Worsening in 
Individual Subject’s PRO Scores
PRO Endpoints
Clinically Important 
Worsening in Outcome
Clinically Important 
Improvement in Outcome
CLDQ-HCV 
domain scores (1-7 scale)
summary score
≥0.5 point decrease
≥10 point decrease
≥0.5 point increase
≥10 point increase
EQ-5D VAS score
≥10 point decrease
≥10 point increase
FSS Total score
≥1 point increase
≥1 point decrease
SF-36v2
PCS
≥5 point decrease
≥5 point increase
MCS
≥5 point decrease
≥5 point increase
8 domain scores
≥10 point decrease
≥10 point increase
11.3.2.
Resistance Determination Analyses
The results of viral sequencing will be evaluated by the sponsor virologist. Pre-treatment 
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 pre-treatment NS3/4A, NS5A and NS5B polymorphisms 
on treatment outcome will be explored. These changes in viral sequence will not be regarded as 
AEs or SAEs.
Additional exploratory characterization of the viral genotype and phenotype may be performed 
and will be reported accordingly.
11.3.3.
Patient-reported Outcomes Analyses
Patient-reported outcomes scores will be analyzed descriptively by treatment arm as mean scores 
over time, and evaluated based on the proportion of subjects experiencing a clinically important 
improvement or worsening in PRO scores from baseline during study drug treatment and at 
follow-up visits at Weeks 4, 12, and 24. Time and duration of clinically important improvement 
or worsening in PRO scores will be analyzed and reported.
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11.4.
Pharmacokinetic Analyses 
PopPK Analysis for all Subjects
The PK samples taken from all subjects in the study (see Time and Events Schedule), as well as 
the sparse and rich PK samples collected in the PK substudies (see Time and Events Schedule: 
PK Assessments in PK Substudies) will be used for popPK model development and/or popPK 
model update. PopPK analysis of plasma concentration-time data of AL-335 and its metabolites, 
ODV, and SMV from all subjects (including those of PK substudies) will be performed using 
nonlinear mixed-effects modeling. Population PK 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. 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.
Descriptive statistics, including arithmetic mean, 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 its metabolites, ODV, and SMV.
Non-compartmental PK Analysis for Rich PK Sampling in the PK Substudy
For the intensive PK samples of the rich PK substudy, non-compartmental PK analysis of
AL-335 and its metabolites, ODV, and SMV will be performed using actual sampling time and 
plasma concentrations obtained from rich serial PK blood sampling at Week 4 for approximately 
20 subjects (arms A and B combined) (see Section 9.3). Descriptive statistics will be provided 
for the PK parameters derived, including graphical analyses of the data.
Analyses of protein binding and/or metabolite profiling may be conducted at the sponsor’s 
discretion and reported separately from this study.
11.5.
Pharmacokinetic/Pharmacodynamic Analyses 
Relationships of AL-335 (and its metabolites), ODV, and SMV population-derived exposure 
parameters (AUC24h and C0h) with SVR12 and with safety endpoints will be explored. These 
relationships will be presented in a graphical display.
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11.6.
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.
Where locally permitted and upon consent of the subject (in addition to the consent for the main 
part of the study) an additional optional blood sample will be collected at baseline for 
exploratory host DNA research related to AL-335 (and metabolites), ODV, and SMV, and 
limited to genes involved in the metabolism of the study drugs as well as drug transporter genes.
The statistical approach for analyzing the exploratory host DNA research may depend on the 
objective of the analyses (treatment response, side effects, metabolism) and possibly relevant 
genes at the time of analysis.
11.7.
Occupational/Employment Status Analysis
Occupational/employment status will be descriptively summarized by treatment arm over time.
11.8.
Medical Resource Utilization
MRU data will be descriptively summarized by treatment arm over time.
11.9.
Safety Analyses
Safety will be evaluated by means of AEs, clinical laboratory tests, vital signs, ECGs, 
echocardiography and physical examinations. The safety analysis will be done for each study 
phase separately (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 phase or that are a consequence of a pre-existing 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 one occurrence of the given event will be 
summarized by treatment arm. In addition, comparisons between treatment arms 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 a 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.
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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 arm.
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 baseline 
values (the initial ECG will be used as baseline).
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.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, RR interval,
QT interval, QTcF (primary correction method)11 and QT interval corrected for heart rate 
according to Bazett2 QT correction.
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 milliseconds, 
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of subjects 
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds.
All important 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% 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/heart rate, and blood pressure (systolic and diastolic) (supine) 
values and changes from baseline will be summarized at each scheduled time point. The 
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percentage of subjects with values beyond clinically important limits will be summarized (see
Attachment 2).
Physical Examination
Physical examination findings will be listed
11.10. Interim Analysis 
An interim analysis is planned at the SVR4 time point, ie, when all subjects have reached the 
SVR4 (W4 FU visit) time point or discontinued earlier. Additional interim analyses may be 
conducted if needed to support clinical development.
Since this is an open-label study, there is no need to unblind the treatment. An interim analysis 
SAP will be prepared before the interim analyses.
11.11. Data Review Committee
A DRC will be established to monitor data on a regular basis to ensure the continuing safety, 
efficacy and well-being of the subjects enrolled in this study. The DRC will review the HCV 
RNA data and evaluate the incidence of treatment failure due to virologic reasons (relapse as 
well as on treatment virological failure) on a regular basis to monitor the efficacy of the regimen 
in this target population and to ensure that the risks to the subject is balanced by the anticipated 
benefits. Upon review of the HCV RNA data, the DRC will make study conduct 
recommendations, which may include, but is not limited to, continuing the study without 
modifications and/or implementation of treatment extension.
Emerging safety data from this study will be reviewed at predetermined intervals. As a part of 
these safety evaluations, the DRC will also review AEs considered as anticipated for this patient 
population (see Attachment 8).
After the review of the accumulating efficacy and safety data from this study and consideration 
of data from other completed and ongoing studies, including the Phase 2a study AL-335-604, the 
DRC will make recommendations regarding the continuation of the study.
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).
In case of substantial changes to the study conduct, other than the treatment extension described 
in this protocol (see Section 3.1), an amendment to the protocol will be issued and submitted for 
approval by the competent authorities.
The DRC will consist of at least one medical expert in the relevant therapeutic area, one 
cardiologist (for the review and interpretation of any cardiac safety data) and at least one 
statistician. The DRC responsibilities, authorities, and operating procedures (including 
predefined futility criteria treatment arms) 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.
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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 non-investigational) 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 non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) 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).
Serious Adverse Event
An SAE based on ICH and EU 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,
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
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. 
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.
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).
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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 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 and/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).
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the SAE page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed ICF is obtained until the subject’s last study visit. Serious AEs must be reported 
using 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 a SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments. Anticipated events will be recorded and reported as described 
in Attachment 8.
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.
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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.
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 a SAE should be made by 
facsimile (fax).
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 a SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
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course of a subject's participation in a study must be reported as a 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: PK Assessments in PK 
Substudies).
The cause of death of a subject in a, whether or not the event is expected or associated with the 
study drug, is considered a SAE.
12.3.3.
Pregnancy 
Pregnancies in female subjects and female partners of male subjects will be reported from the 
time a signed and dated ICF is obtained until the end of the study.
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 by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate pregnancy notification form.
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.
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 on 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 
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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 on 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
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.15
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 for a 
list of excipients.17,18
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 drug will be dispensed in child-resistant packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
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14.4.
Preparation, Handling, and Storage 
All study drug must be stored at room temperature.
Refer to the pharmacy manual/study site investigational product 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 
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:

IBs for AL-335, ODV, and SMV, and their addenda,

Pharmacy manual/study site investigational product manual,

Echocardiography manual,

ECG manual,

IWRS manual,

Laboratory manual,

Medication diaries,

On-demand access to study-specific training directly on the electronic PRO (ePRO) device,

Touch-screen computer for entry of ePRO data,
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
ePRO Site User Manual,

Electronic Data Capture (eDC) Manual,

Sample ICF,

Contact information page.
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.
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 ICFs (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),
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
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), 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,

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).
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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, including permission to obtain 
information about his or her survival status, and agrees to allow his or her study physician to 
recontact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed, and subsequent disease-related treatments, or to obtain information about his or her 
survival status.
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 will be given to the subject.
At selected study sites participating in the PK substudies, the ICF will contain a separate section 
explaining the PK substudy and separate consent can be given for this substudy.
Where local regulations require, a separate ICF may be used for the required DNA (IL28B
genotype) component of the study.
Subjects will be asked for consent to provide an optional sample for host DNA research (where 
locally permitted). After informed consent for the study is appropriately obtained, the subject 
will be asked to consent, in addition to consenting for the main obligatory part of the study, 
indicating agreement to participate in the optional research component. Refusal to participate in 
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the optional research will not affect ineligibility for the study. A copy of this signed ICF will be 
given to the subject.
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 DNA, 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.
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 HCV infection, to understand differential drug responders, and to develop 
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tests/assays related to AL-335, ODV, and SMV and HCV infection. The research may begin at 
any time during the study or the post-study 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 10.3).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-specific Design Considerations.
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 non-acceptance, 
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 
IRB (and IEC 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 (see Contact Information page(s) provided separately). 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 randomized 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 documentation 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. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study 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,

History of smoking,

Blood pressure and pulse/heart rate,

Height and weight,

Details of physical examination,

MRU data.
The PRO assessments will be completed by subjects on touch-screen computers provided at the 
study site. The results will be recorded directly into the ePRO database and will be considered 
source data.
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.
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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.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture will be used for this study. The study data will be transcribed by study-
site personnel from the source documents onto an eCRF, and transmitted in a secure manner to 
the sponsor within the timeframe agreed upon between the sponsor and the study site. The 
electronic file will be considered to be the eCRF.
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 documentation. Data must be entered
into eCRFs in English. Study site personnel must complete the eCRF as soon as possible after a 
subject visit, and the forms should be available for review at the next scheduled monitoring visit.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool.
If corrections to a eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different 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, direct 
transmission of clinical laboratory data from a central laboratory, and direct transmission of PRO 
data to the ePRO vendor database and then into the sponsor's database. 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 eCRFs 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 eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
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documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of 
a 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 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRFs with the hospital or clinic records 
(source documents). 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 documentation (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 documentation 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
The study is considered 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 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 research data, generated 
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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 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, laboratory data from the 
selected laboratory and PRO data from the ePRO vendor database, 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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Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. 
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Gower E, Estes C, Blach et al. Global epidemiology and genotype distribution of the hepatitis C virus 
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Investigator’s Brochure: AL-335, Version 2. Alios BioPharma, Inc (September 2015).
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Investigator's Brochure: TMC435 (simeprevir), Edition 9, Addendum 1. Janssen Research & Development 
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Investigator's Brochure: TMC435 (simeprevir), Edition 9. Janssen Research & Development 
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Kohli A, Sims Z, Nelson A, et al. Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: final 
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Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir with/without ribavirin for treating 
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patients (COSMOS: a randomized study). Lancet 2014; 384(9556): 1756-1765.
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Lee MK, Yang HI, Yuan Y, L’Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus 
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Levey A, Stevens L, Schmid C, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 
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Martin M et al. Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review of 
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Olysio [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP; 2014. 
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Pasternak R, et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. 
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Sovaldi [EU Summary of Product Characteristics]. Cambridge: Gilead Sciences International Ltd; July 2015. 
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31.
Viekirax (ombitasvir/paritaprevir/ritonavir) [EU Summary of Product Characteristics], Abbvie Ltd; 2015.
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_Product_Information/human/003839/WC500183997.pdf. Accessed 17 March 2016.
32.
Technivie (ombitasvir/paritaprevir/ritonavir) US Product Information, Abbvie Ltd; June 2016. 
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World Health Organization. Hepatitis C. Available at: 
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35.
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.
36.
Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with 
ribavirin. N Engl J Med. 2014; 370: 1604-1614.
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CredibleMeds® Combined list of drugs that prolong QT and/or cause Torsades de Pointes (TDP). Arizona 
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38.
Gane EJ, Hyland RH, Y. Ying E et al. Safety and efficacy of short-duration treatment with GS-9857 combined 
with sofosbuvir/GS-5816 in treatment-naïve and DAA-experienced genotype 1 patients with and without 
cirrhosis. Journal of Hepatology 2015; 62, S264.
39.
Gane EJ, Hyland RH, Y. Ying E et al. Sofosbuvir/GS-5816 +GS-9857 for 6 or 8 Weeks in Genotype 1 or 3 
HCV-infected Patients. Hepatology 2015; 61 (Suppl 1): 226A.
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40.
Poordad F, Lawitz E, Gutierrez JA et al. C-SWIFT: Grazoprevir/elbasvir + sofosbuvir in cirrhotic and 
noncirrhotic, treatment-naïve patients with hepatitis C virus genotype 1 infection, for durations of 4, 6 or 8 
weeks and genotype 3 infection for durations of 8 or 12 weeks. Journal of Hepatology, 2015;62 (Suppl 2): 
S192–S193.
41.
Barold SS, Ilercil A, Leonelli F, Herweg B. First-degree atrioventricular block. J Interv Card Electrophysiol.
2006; 17:139–152.
42.
Investigator’s Brochure: AL-335, Version 2, Addendum 1. Alios BioPharma, Inc (April 2016).
43.
Investigator’s Brochure: AL-335, Version 2, Addendum 2. Alios BioPharma, Inc (August 2016).
44.
Investigator’s Brochure: ACH-0143102 Version 6 Addendum 4.a Janssen Research and Development 
(August 2016).
45.
Lawitz E, Flamm S, Yang JC et al. Retreatment of patients who failed 8 or 12 weeks of 
ledipasvir/sofosbuvir-based regimens with ledipasvir/sofosbuvir for 24 weeks. 50th Annual Meeting of the 
European Association for the Study of the Liver, Vienna, 22-26 April, 2015.
                                                
a Odalasvir Investigator’s Brochure Edition 6, Addendum 4 replaces all prior addenda; ie, Addendum 1, 2 and 3 are 
obsolete.
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ATTACHMENTS
Attachment 1:
WHO Scale for Determining the Severity of Adverse Events 
February 2003
ABBREVIATIONS (used in the table):
ULN = Upper Limit of Normal
Rx = Therapy
FEV1 = forced expiratory volume in 1 second
LLN = Lower Limit of Normal
IV = Intravenous
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.
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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 
(non-fasting 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 
albumin)
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 
arrhythmia or 
tetany
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Item
Grade 1
Grade 2
Grade 3
Grade 4
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
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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 
<80-70% 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% (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
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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 25-50%
normal activity 
decreased >50% 
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
a Revised by the sponsor
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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 mmHg
90 mmHg
Grade 1 or mild
-
>90 mmHg to <100 mmHg
>140 mmHg to <160 mmHg
Grade 2 or moderate
-
100 mmHg to <110 mmHg
160 mmHg to <180 mmHg
Grade 3 or severe
-
110 mmHg
180 mmHg
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.
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Attachment 3:
CLDQ-HCV Questionnaire
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Attachment 4:
5-level EuroQol 5-Dimension Questionnaire (EQ-5D-5L)
Health Questionnaire
English version for the USA
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
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Under each heading, please check the ONE box that best describes your health TODAY
MOBILITY
I have no problems walking

I have slight problems walking 

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 

USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
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
We would like to know how good or bad your health is 
TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box 
below. 
YOUR HEALTH TODAY =
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health       
you can imagine
The worst health 
you can imagine
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Attachment 5:
Fatigue Severity Scale (FSS)
Below are a series of statements regarding your fatigue. By fatigue we mean a sense of tiredness, 
lack of energy or total body give-out. Please read each statement and choose a number from 1 to 
7, where 1 indicates you completely disagree with the statement and 7 indicates you completely 
agree. Please answer these questions as they apply to the past TWO WEEKS.
Completely 
disagree
Completely 
agree
1. My motivation is lower when I am fatigued.
1
2
3
4
5
6
7
2. Exercise brings on my fatigue.
1
2
3
4
5
6
7
3. I am easily fatigued.
1
2
3
4
5
6
7
4. Fatigue interferes with my phyisal 
functioning.
1
2
3
4
5
6
7
5. Fatigue causes frequent problems for me.
1
2
3
4
5
6
7
6. My fatigue prevents sustained physical 
functioning.
1
2
3
4
5
6
7
7. Fatigue interferes with carrying out certain 
duties and responsibilities.
1
2
3
4
5
6
7
8. My fatigue is very disabling.
1
2
3
4
5
6
7
9. Fatigue interferes with my work, family or 
social life.
1
2
3
4
5
6
7
© 1985 Lauren B. Krupp. Reproduced with permission from the author.
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Attachment 6:
SF-36v2 Questionnaire
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Attachment 7:
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-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.
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Attachment 8:
Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease-related) or background regimen. For 
the purposes of this study the following events will be considered anticipated events:

Progression of underlying chronic hepatitis C:
a.
Cirrhosis and its complications:
o
Portal hypertension
o
Esophageal varices

Elderly population (age >65years)
o
Motor vehicle accident
o
Hip fracture
o
Carcinomas (other than hepatic related carcinomas including hepatocellular carcinomas)
Reporting of Anticipated Events
These events will be captured in the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse 
Events. These anticipated events are exempt from expedited reporting as individual single cases to Health 
Authorities, Investigators, and Independent Ethics Committee/Institutional Review Board. However, if 
based on an aggregate review it is determined that an anticipated event is possibly related to study drug, 
the sponsor will report these events in an expedited manner.
Data Review Committee
A Data Review Committee (DRC) will be established in this study to perform reviews of pre-specified 
anticipated events at an aggregate level. The DRC is a committee within the sponsor’s organization that is 
independent of the sponsor’s study team. The DRC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to
trigger an aggregate analysis of anticipated events, will be included in the SAP.
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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.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
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):
M. Biermer, MD
Institution:
Janssen Research & Development 
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.
LAST PAGE
NCT02765490


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rekha Sinha
10Apr2017, 17:33:14 PM, UTC
Document Approval by Delegation
NCT02765490

SAP_001.pdf: 
1
Statistical Analysis Plan for SVR4, SVR12 (Primary Analysis), and SVR24 (Final 
Analysis)
A Phase 2b, Multicenter, Randomized, Open-label Study to Investigate the Efficacy, 
Safety and Pharmacokinetics of Different Treatment Regimens of AL-335, Odalasvir, and 
Simeprevir in Treatment-naïve and Treatment-experienced Subjects With Chronic 
Hepatitis C Virus Genotype 1, 2, 4, 5 and 6 Infection Without Cirrhosis.
Protocol 64294178HPC2001; Phase 2b
AL-335, Odalasvir, TMC435 (simeprevir)
Issue/Report Date:  28 JUNE 2017
Document No.: EDMS-ERI-136059386
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.
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TABLE OF CONTENTS
ABBREVIATIONS..................................................................................................................... 4
1.
Introduction................................................................................................................... 6
1.1.
Trial Objectives............................................................................................. 6
1.2.
Trial Design .................................................................................................. 7
1.3.
Statistical Hypotheses for Trial Objectives................................................... 8
1.4.
Sample Size Justification ............................................................................. 8
1.5.
Randomization and Blinding ........................................................................ 9
2.
General Analysis Definitions......................................................................................... 9
2.1.
Visit Windows and Phase Definition............................................................. 9
2.2.
Pooling Algorithm for Analysis Centers...................................................... 12
2.3.
Analysis Sets.............................................................................................. 12
2.4.
Definition of Subgroups.............................................................................. 12
3.
Subject Information..................................................................................................... 14
3.1.
Demographics and Baseline Characteristics ............................................. 14
3.2.
Disposition Information............................................................................... 15
3.3.
Extent of Exposure..................................................................................... 16
3.4.
Treatment Adherence................................................................................. 16
3.5.
Protocol Deviations .................................................................................... 16
3.6.
Prior and Concomitant Medications ........................................................... 16
3.7.
Medical History........................................................................................... 17
3.8.
Treatment Extension .................................................................................. 17
4.
Efficacy ....................................................................................................................... 17
4.1.
Analysis Specifications............................................................................... 17
4.2.
Primary Efficacy Endpoint .......................................................................... 18
4.3.
Secondary Efficacy Endpoints ................................................................... 19
5.
Virology....................................................................................................................... 24
5.1.
Virology Assessments................................................................................ 24
5.2.
Virology Definitions..................................................................................... 25
5.3.
Virology Time Points and Samples ............................................................ 26
5.4.
Virology Analyses....................................................................................... 26
6.
Safety.......................................................................................................................... 27
6.1.
Adverse Events .......................................................................................... 27
6.2.
Clinical Laboratory Tests............................................................................ 31
6.3.
Vital Signs and Physical Examination Findings ......................................... 33
6.4.
Electrocardiogram Parameters .................................................................. 34
6.5.
Echocardiographic(ECHO) Parameters..................................................... 37
6.6.
Graphical Patient Profiles........................................................................... 38
7.
Patient-Reported Outcomes (PRO)............................................................................ 38
7.1.
CLDQ-HCV................................................................................................. 39
7.2.
EQ-5D-5L ................................................................................................... 40
7.3.
FSS............................................................................................................. 41
7.4.
SF-36v2...................................................................................................... 42
7.5.
Proposed Thresholds Indicating Clinically Important Changes from 
Baseline in PRO......................................................................................... 44
8.
Pharmacokinetics/Pharmacodynamics ...................................................................... 44
8.1.
Pharmacokinetics....................................................................................... 44
8.2.
Pharmacokinetic/ Pharmacodynamic Analyses ......................................... 45
9.
Health Economics....................................................................................................... 47
10.
References ................................................................................................................. 47
Appendix 1: Phase Allocation/Combining AEs........................................................................ 48
Appendix 2a: Search Terms for Events of Special/Clinical Interest........................................ 49
Appendix 2b: Rash – SMQ19.1............................................................................................... 50
Appendix 3: CARDIAC EVENTS - SMQ19.1 .......................................................................... 51
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Appendix 4: EQ-5D VALUATION INDEX - US........................................................................ 63
Appendix 5: PREDEFINED MAJOR PROTOCOL DEVIATIONS ........................................... 63
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ABBREVIATIONS
ADaM
Analysis Data Model
AE
Adverse Event
BMI
Body Mass Index
CFB
Change from Baseline
CI
Confidence Interval
CTP
Clinical Trial Protocol
DAA
Direct-Acting Antivirals
DBP
Diastolic Blood Pressure
DRC
Data Review Committee
ECG
Electrocardiogram
ECHO
Echocardiogram / Echocardiography
ECI
Events of Clinical Interest
eCRF
Electronic Case Report Form
EOT
End Of Treatment
ESI
Events of Special Interest
FU
Follow-up
HCV
Hepatitis C Virus
HLT
High Level Term
HLGT
High Level Grouping Term
IA
Interim Analysis
ICH
International Conference on Harmonisation
IFN
Interferon
ITT
Intent-To-Treat
KM
Kaplan Meier
LLOQ
Lower Limit of Quantification
LOD
Limit of Detection
LV
Left Ventricular
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
NAP
Not Applicable
ODV
Odalasvir
Peg
Pegylated
PRO
Patient Reported Outcomes
PT
Preferred Term
QD
Quaque Die, Once Daily
QTc
Corrected QT Interval
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RAS
Resistance Associated Substitution
RNA
Ribonucleic Acid
RVR
Rapid Virologic Response
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SE
Standard Error
SI
Standard International
SMV
Simeprevir
SMQ
Standardised MedDRA Queries
SOC
System Organ Class
SVR
Sustained Virologic Response
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TE
Treatment-emergent
VBT
Viral Breakthrough
VR
Virologic Response
vRVR
Very Rapid Virologic Response
WHO
World Health Organization 
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1.
INTRODUCTION
This 64294178HPC2001 Statistical Analysis Plan (SAP) covers the SVR4 interim 
analysis, the SVR12 Primary Analysis, and the SVR24 Final Analysis. It contains 
definitions of analysis sets, derived variables and statistical methods for the analysis.
Separate documents for mock shells and a Table of Contents are 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
The primary objective of this trial is to evaluate the efficacy, i.e., sustained virologic 
response 12 weeks after the end of treatment (SVR12), of a combination treatment with 
AL-335, Odalasvir (ODV), and Simeprevir (SMV) for 6 and 8 weeks in chronic HCV 
genotype 1, 2, 4, 5 or 6 infected subjects without cirrhosis.
Secondary Objectives 

To evaluate the safety and tolerability of a 6- and 8-week treatment regimen 
containing AL-335, ODV, and SMV in subjects without cirrhosis,

To evaluate SVR4 and SVR24 of a 6- and 8-week treatment regimen containing 
AL-335, ODV, and SMV in subjects without cirrhosis,

To evaluate on-treatment viral kinetics in a 6- and 8-week treatment regimen 
containing AL-335, ODV, and SMV in subjects without cirrhosis,

To evaluate the incidence of on-treatment failure during a 6- and 8-week 
treatment regimen containing AL-335, ODV, and SMV in subjects without 
cirrhosis,

To evaluate the incidence of viral relapse after an 6- and 8-week treatment 
regimen containing AL-335, ODV, and SMV in subjects without cirrhosis,

To assess changes from baseline in HCV NS3/4A, NS5A, and NS5B sequence in 
subjects not achieving SVR,

To evaluate the effect of the presence or absence of baseline HCV NS3/4A 
polymorphisms (including Q80K), NS5A polymorphisms and/or NS5B 
polymorphisms on treatment outcome (SVR12, on-treatment failure, viral relapse, 
and emergence of resistance), 

To evaluate concordance between SVR4, SVR12, and SVR24,

To evaluate the pharmacokinetics (PK) of AL-335 (and its 2 metabolites ALS-
022399 and ALS-022227; AL-335 and its metabolites ALS-022399 and ALS-
022227 are further referred to as AL-335 [and metabolites]), ODV, and SMV, in 
plasma,

To evaluate the relationship between the population-derived exposure parameters 
of AL-335 (and metabolites), ODV, and SMV (ie, area under the plasma 
concentration-time curve from time 0 until 24 hours post dosing [AUC24h] and 
predose plasma concentrations [C0h]) with SVR12 and safety,
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
To explore the impact of HCV and its treatment with AL-335+ODV+SMV on the 
Fatigue Severity Scale (FSS) total score and the 5-level EuroQol 5-Dimension 
(EQ-5D-5L) Visual Analog Scale (VAS) score.
Exploratory Objectives

To explore the effect of prior HCV treatment history, baseline host and disease 
related characteristics including but not limited to HCV geno/subtype, baseline 
HCV ribonucleic acid (RNA) level, genetic factors (eg, interleukin-28B [IL28B] 
genotype), race, sex and age on treatment outcome,

To explore the impact of HCV and its treatment with AL-335+ODV+SMV on 
symptoms, functioning and health-related quality of life (HRQoL), using patient-
reported outcomes (PROs), ie, EQ-5D-5L domain scores, Short Form 36 version 2 
(SF-36v2) Physical Component Summary and Mental Component Summary 
scores, and Chronic Liver Disease Quality of Life Questionnaire – HCV (CLDQ-
HCV) summary and domain scores,

To explore the impact of HCV treatment with AL-335+ODV+SMV on 
occupational/employment status,

To describe the impact of HCV treatment on medical resource utilization (MRU).
1.2.
Trial Design
This is a Phase 2b, multicenter, randomized, open-label study.  It consists of a 6 week 
screening period, followed by one of 2 treatment arms (either 6 or 8 weeks), and a 24 
week follow up period.  Approximately 300 subjects were planned to be randomized. 
The actual number of subjects randomized is 365, as described in the Protocol 
Amendment 4. Randomization was to one of the 2 treatment groups shown below in a 1:1
ratio:

Arm A (N=183): AL-335 800 mg qd + ODV 25 mg qd + SMV 75 mg qd for 6 
weeks

Arm B (N=182): AL-335 800 mg qd + ODV 25 mg qd + SMV 75 mg qd for 8 
weeks
The randomization is stratified by HCV treatment history (treatment naive vs treatment 
experienced) and HCV genotype/subtype (1a or 2 versus 1b, 4, 5, or 6).  Subjects with an 
undefined genotype 1 subtype at screening are assigned to the 1b, 4, 5 or 6 stratification 
group.
If treatment extension is recommended by the DRC, the treatment duration of the arms 
may be extended up to a maximum of 12 weeks. Treatment extension was not 
recommended by the DRC however.
Further Trial Design details are available in the Protocol.
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1.2.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is sustained virologic response 12 weeks after the end of 
treatment. Subjects are considered to have achieved SVR12 if the following condition has 
been met: HCV RNA < lower limit of quantification (LLOQ), detected or not detected 12 
weeks after the end of treatment (EOT). The LLOQ for the HCV RNA COBAS®
AmpliPrep/COBAS® TaqMan® Test v2.0, used in this study, is 15 IU/mL.
1.3.
Statistical Hypotheses for Trial Objectives
The SVR12 rate is non-inferior in at least one treatment arm to the performance 
benchmark of 98% (based on historical interferon [IFN]-free, direct-acting antivirals 
(DAA) regimens) with a non-inferiority margin of 10%.
Statistical testing will be conducted using null hypothesis H0: C-T≥M vs. Ha: C-T<M at a 
significance level of 0.05, 2-sided, where C is the historical control rate of 98%, M is the 
non-inferiority margin 10%, and T is the expected SVR rate in the treatment arm.
This is equivalent to the lower bound of a 95% 2-sided CI exceeding 88%.
A fixed sequence approach will be used to adjust for the multiplicity of the comparison of 
the SVR12 rate in the two treatment arms against the historical control. The SVR12 rate 
in the 6 week treatment arm will be tested first against the historical control at a 
significance level of 0.05, 2-sided. If non-inferiority is established then the SVR12 rate in 
the 8 week treatment arm will be tested against the historical control at a significance 
level of 0.05. 2-sided.
The fixed sequence approach will be applied only for the ITT population. Additional
analyses will also be conducted in the per protocol and non-VF excluded populations 
without applying the fixed sequence approach.
1.4.
Sample Size Justification
The description of the sizing based on 300 subjects is described below.
The sample size consideration is based on non-inferiority testing against performance 
benchmark 98% based on historical data (ASTRAL 1-3 studies) in an IFN-free, 2-DAA 
(SOF/velpatasvir [VEL]) regimen for 12 weeks of treatment. Statistical hypothesis will 
be tested per arm using the CI approach with the lower bound of CI excluding a 
predefined threshold for non-inferiority of SVR12. The SVR performance benchmark is 
chosen to be 98% based on ASTRAL 1-3 studies, in which, across genotypes 1-6, SVR 
was observed to be 98% with 95% CI: 97% to 98.8%. In a subgroup of cirrhosis (F4), the 
SVR was 96% with 95% CI: 92.8% to 98.4%). Non-inferiority margin 10% was 
determined by referencing the most recent data from the ASTRAL-2 study, where 10% 
non-inferiority margin was used to compare 2-DAA (SOF/VEL) to active control 
SOF+RBV for non-inferiority. Additionally, recent data from a 3-DAA regimen plus 
RBV (Abt-450/r + ombitasvir + dasabuvir + RBV) in comparison to the historical control
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in a DAA with PegIFN/RBV used 10.5% non-inferiority margin for the non-inferiority 
testing. Therefore, a 10% non-inferiority margin was chosen for this Phase 2b study for 
the non-inferiority testing against historical control. Using a 2-sided 95% CI and 
assuming an expected SVR rate of 98% for each arm, a sample size of 150 subjects per 
arm will provide at least 90% power to reject the inferiority hypothesis by showing that 
the lower limit of the 2-sided 95% CI on the observed SVR will exceed 88% (the upper 
boundary of the 95% CI for the control rate minus 10%).
Note that the 65 additional subjects enrolled does not meaningfully affect the power 
considerations reported above to demonstrate non-inferiority of SVR12. Additionally, 
182 subjects enrolled per arm (365 in total) will provide the probability to observe an 
adverse event (AE) with an incidence of 0.1%, 0.5%, 0.8%, and 1% of 16.6% (30.6%), 
59.8% (84.0%), 76.8% (94.7%), and 83.9% (97.4%), respectively.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly 
assigned to 1 of the 2 treatment arms in a 1:1 ratio based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the 
sponsor. The interactive voice response system (IVRS) or interactive web response 
system (IWRS) will assign a unique treatment code, which will dictate the treatment 
assignment and matching study drug kit for the subject. The requestor must use his or her 
own user identification and personal identification number when contacting the 
IVRS/IWRS, and will then give the relevant subject details to uniquely identify the 
subject. Randomized subjects in arms A and B will be stratified by HCV treatment 
history (treatment-naïve versus treatment-experienced) and HCV geno/subtype 
(genotypes 1a or 2 versus genotypes 1b, 4, 5 or 6).
Blinding is non-applicable as this is an open label study.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows and Phase Definition
Phases will be constructed as follows: 
Weeks
-6
D1
D2
D3
W1
W2
W3
W4
W6
W8
W10
W12
W18
W30
W32
6 Wks
Scr.
AL-335 + ODV + SMV
Follow up
8 Wks
Scr.
AL-335 + ODV + SMV
Follow up
Trial phase
Start date
End date
Screening
(phase 0)
Minimum of Date of signing 
the informed consent and 
1 day before first study drug intake
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Trial phase
Start date
End date
Date of the first screening 
visit
Treatment
(phase 1)
Date of first study drug intake
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 Intake:  In the above computations, missing data for first study 
drug intake may be imputed as the date of baseline visit in (a) interim analyses and (b) 
preliminary (non-final) analyses.
Date of Last Study Drug Intake:  In the above computations, missing data for last study 
drug intake may be imputed for (a) interim analyses and (b) subjects discontinuing as 
follows:
1) Interim analyses:  Date of Last Study Drug Intake = Min (Data cutoff date, Date 
of baseline visit + 6 or 8 weeks depending on arm).
2) Discontinued Subjects:  Date of Last Study Drug Intake = 
a.
Date of the early treatment withdrawal visit, if non-missing otherwise
b. Date of 1st available Follow-up visit – 28, if non-missing otherwise
c.
Date of last contact.
The number of days in the phase (Reldy) is defined as:
Visits on or after the reference day:  Reldy = visit date – refdy+1   
Visits before the reference day:       Reldy = visit date – refdy       
Reference date (Refdy) above is defined as:
Screening & Treatment Phases:  Refdy = Date of first study drug intake (if non-
missing), otherwise date of baseline visit.
Follow-up Phase:  Refdy = Start Date of follow-up phase.
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 (reldy).  In the below, ‘Target day’ is the 
planned reldy for the analysis time point.  Actual observed relday’s in the ‘Time Interval’ 
shown are assigned to the analysis time point.
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Trial 
phase
Target dayb
Analysis time point
(numeric version)
Analysis time point
Time interval 
(reldy)a
ARM 1
Screening
-∞
-1
Screening
<0
Treatment 
phase
1
0
Baselinea
<=1
2
0.2
Day 2
[2,2]
3
0.3
Day 3
[3,5]
8
1
Week 1
[6,12]
15
2
Week 2
[13,19]
22
3
Week 3
[20,26]
29
4
Week 4
[27,36]
43
6
Week 6
[37, + ∞]
last visit while on 
study therapy or 
within 3 days after 
the day of last dose
999
EOT
Follow-up 
phase
25
12
Follow-Up Week 4
[1,39]
53
16
Follow-Up Week 8
[40,67]
81
20
Follow-Up Week 12
[68,102]
123
24
Follow-Up Week 18
[103,144]
165
32
Follow-Up Week 24
[145, + ∞]
ARM 2 
Screening
-∞
-1
Screening
<0
Treatment 
phase
1
0
Baselinea
<=1
2
0.2
Day 2
[2,2]
3
0.3
Day 3
[3,5]
8
1
Week 1
[6,12]
15
2
Week 2
[13,19]
22
3
Week 3
[20,26]
29
4
Week 4
[27,36]
43
6
Week 6
[37, 50]
57
8
Week 8
[51, + ∞]
last visit while on 
study therapy or 
within 3 days after 
the day of last dose
999
EOT
Follow-up 
phase
25
12
Follow-Up Week 4
[1,39]
53
16
Follow-Up Week 8
[40,67]
81
20
Follow-Up Week 12
[68,102]
123
24
Follow-Up Week 18
[103,144]
165
32
Follow-Up Week 24
[145, + ∞]
a  If the reldy of the baseline value closest to the target day is less than 0, only the record closest to the 
target day will be retained in the Analysis Data Model (ADaM) dataset, otherwise only the record(s) with 
reldy 1 will be kept.
b Target day in follow up phase equals target day in the protocol minus 3 days due to definition of start of 
follow-up phase.
Note: In case of treatment extension recommended by the DRC, a supplementary table to 
the above will be added.
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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.
2.2.
Pooling Algorithm for Analysis Centers 
No pooling of analysis sub-centers will be performed in this study.
2.3.
Analysis Sets
Intent-to-treat (ITT) population: All randomized subjects who took at least 1 dose of 
investigational medication.
Non-VF excluded population: all ITT subjects excluding the subjects who did not achieve 
SVR12 due to reasons other than virologic failure, including subjects with missing data at 
the SVR12 time point and subjects who discontinued all treatment prematurely (e.g. AE 
or withdrawal of consent).
The per-protocol (PP) population is the set of all subjects in the ITT population with the 
exclusion of any subjects deemed to have a major protocol deviation that may affect the 
assessment of efficacy. The major protocol deviations that may affect the assessment of 
efficacy will be identified prior to database lock. Specific details are provided in 
Appendix 
5.
All analyses will be done on the ITT population. Selected efficacy analyses including on 
the primary efficacy endpoint will be done also on the Non-VF excluded population and 
the per protocol population. These are to be specified prior to Database Lock. Additional 
analyses on the per protocol population may be produced in case of >10% of subjects 
with a major protocol deviation that may affect the assessment of efficacy. Demographic 
and baseline characteristics specifically should be done on the ITT, per protocol and non-
VF excluded populations.
Prior to each database lock, an Excel spreadsheet listing all major protocol deviations will 
be produced. This will undergo medical review according to the major PD criteria list in 
Appendix 5, and a new column will be added indicating if each major PD will lead to that 
subject being excluded from the per protocol population.
2.4.
Definition of Subgroups
The following subgroups will be investigated for efficacy, combinations of more than one  
subgroup may also be done.  In case subgroup categories are smaller than 10 subjects 
within a treatment arm, subgroup categories might be combined. 

Prior HCV treatment (Naive, Experienced)

Baseline HCV RNA (<6,000,000 IU/mL; 6,000,000 IU/mL)
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
IL28B genotype (CC, CT, TT); and also (CC, non-CC)

HCV geno/subtype (1a [Overall, with Q80K at baseline, without Q80K at 
baseline], 1b, 1other, 2, 4, 5, 6); and also by stratification factor 
(genotypes 1a or 2 versus genotypes 1b, 1other, 4, 5 or 6)

Gender (male, female)

Race (Caucasian, Black or African American, Asian, Other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Age category [≤45; >45-≤65; >65] 

BMI [<25; 25-<30; ≥30]

Fibrosis stage (F0/1; F2; F3) (investigator determination)

Fibrosis stage (non-F3; F3) (criteria determination)

HCV RNA at early time points: Day 3, Day 7, Week 2, Week 4:
(<15IU/mL not detected, <15IU/mL detected, <15 IU/mL not detected or
detected) (Week 2 and Week 4 not to be done for the efficacy endpoints of 
HCV RNA at Week 2 and at Week 4)

Presence of NS3/4A, NS5A and/or NS5B baseline polymorphisms (yes, 
no) (refer to virology section)
In addition, the above subgroups for efficacy (except for HCV geno/subtype) should be 
further evaluated split by HCV geno/subtype (1a,1b, 1other, 2, 4, 5, 6). Also evaluate 
these efficacy subgroups for each subtype within an HCV genotype. Categories with a 
small number of subjects might be combined. Care should be taken in interpreting any 
subgroups with a small number of subjects.
Subgroups for PRO will include:
SVR12 (yes, no)
BMI [<25; 25-<30; ≥30]
Gender (male, female)
Age category [≤45; >45-≤65; >65]
Prior HCV treatment history (Naive, Experienced)

HCV geno/subtype (genotypes 1a or 2 versus genotypes 1b, 1other, 4, 5 or 6)
The following subgroups will be investigated for safety:

Prior HCV treatment (Naive, Experienced)

Age category [≤45; >45-≤65; >65]

Gender (male, female)

Race (Caucasian, Black or African American, Asian, Other)

BMI [<25; 25-<30; ≥30]
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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
-
Age at screening (years)
-
Age at screening (years, categories: ≤45; >45 - ≤65; >65)
-
Race (American Indian or Alaska Native, Asian, Black or African American, 
Caucasian, Native Hawaiian or Other Pacific Islander, Other, Unknown, Not 
Reported)
-
Ethnicity (Hispanic or Latino, 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 (<6,000,000IU/mL; 6,000,000 IU/mL)
-
HCV geno/subtype: 1a, 1b, 1other, 2, 4, 5, 6. For 1other, 2, 4, 5, 6 show also a 
breakdown of each subtype.
-
IL28B genotype (CC, CT, TT); and also (CC, non-CC)
-
For subjects with Fibroscan Results, Fibrosis Result (kPa) summary statistics
-
For all subjects, Metavir Fibrosis stage (F0/F1, F2, F3) (investigator determination)
-
For all subjects, Metavir Fibrosis stage (non-F3, F3) (criteria determination)
-
Prior HCV treatment (Treatment-naive, Treatment-experienced)
-
Mode of HCV infection (Blood Transfusion, Intravenously Injectable Drug Use, 
Occupational Exposure, Mother To Child Transmission, Heterosexual Contact, MSM, 
Hemophilia-Associated Injections, Other)
-
Duration of HCV infection (years) (= (baseline date – date of HCV infection + 
1)/365.25, rounded to 1 decimal).
-
Time since diagnosis (years) ( = (baseline date – date of diagnosis + 1)/365.25, 
rounded to 1 decimal)
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3.1.1.
Liver Fibrosis Staging Parameters
Documentation of Absence of Cirrhosis:
All subjects will be tested (based on Fibroscan, Biopsy, or both) to determine the liver 
fibrosis stage and to document an absence of cirrhosis as part of eligibility criteria.  
Presence or absence of cirrhosis (Yes, No) will be computed as positive if either the 
Fibroscan or Biopsy results are positive for cirrhosis.  Liver fibrosis staging by either 
Fibroscan and biopsy are determined by the investigator and recorded in the CRF. As an
additional criteria based determination, subjects with liver fibrosis stage F3 will be
selected as those with a Fibroscan result of >9.5 to ≤12.5 kPa, and also those with an F3 
determination where only the biopsy was performed.  
Any subjects in the study with cirrhosis will be considered a major protocol deviation.
Liver Staging Parameters
All subjects will have a Fibroscan if feasible.  Subjects for whom Fibroscan is not 
feasible will have a liver biopsy. Liver staging data will be summarized.
3.1.2.
Definition of Prior HCV Treatment
Subjects with chronic HCV infection in this study will be either Treatment-naïve or 
Treatment-experienced, defined as follows:
Treatment-naives:  Subjects who have never received treatment with any 
approved or investigational drug (including DAA’s, IFN-based treatments,
and vaccines) for chronic HCV infection.
Treatment-experienced:   Subjects who have received at least one previous 
course of IFN (Peg or non-Peg) with or without RBV but have never 
received treatment including an approved or investigational HCV DAA.
3.2.
Disposition Information
Tabulations will be provided for the following disposition information:
-
Number of subjects screened, randomized, randomized
and not treated, 
randomized 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 end of treatment page of the
electronic case report form [eCRF])
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-
Number of subjects prematurely discontinuing the trial and the reason for 
discontinuation. Reasons for discontinuation are obtained from the end of trial
page of the eCRF. 
3.3.
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 
arm. Treatment duration for subjects who did not complete treatment will also be 
summarized descriptively by treatment arm.
3.4.
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.
In addition, the percentage of drug that was used based on pill count will also be 
summarized: 100 x (amount dispensed – amount returned)/amount dispensed.
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 arm. Concomitant medication are 
allocated to phases based on their start date. If the concomitant medication starts in a 
specific phase, then the concomitant medication is allocated to that phase. A concomitant 
medication can be allocated to more than one phase. Concomitant medications will be 
tabulated by treatment arm and phase.
Incomplete dates (i.e. 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.
3.8.
Treatment Extension
If treatment extension is recommended by the DRC, the treatment duration of the arms 
may be extended up to a maximum of 12 weeks (see Section 1.2). In this event a table 
will be foreseen to show the number of subjects per arm with a treatment extension.
4.
EFFICACY
4.1.
Analysis Specifications
4.1.1.
Level of Significance
See Section 1.3
4.1.2.
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.
4.1.3.
SVR4 time point efficacy analysis
For the interim analysis when all subjects have reached the SVR4 time point or 
discontinued earlier, for subjects not yet reaching the time point of SVRx (where x=8, 12, 
18, or 24), SVRx will not be evaluated. Further, for secondary efficacy endpoint 
definitions (Section 4.3) which include a statement on achieving/not achieving SVR12,
this statement should be disregarded for such subjects not yet reaching the time point of 
SVR12 in the SVR4 analysis (a similar approach was taken for the DRC SAP).
In the SVR4 analysis, subjects should not be recorded as being a failure under ‘Missing at 
time point of SVR12’. However, the viral relapse evaluation should still be done, and will 
be relative to the Week 12 Follow-up time point. So, for example, a subject not yet 
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reaching the time point of SVR12 could have achieved SVR4 but also have a viral 
relapse which occurred after the SVR4 time point. Late viral relapse is not evaluable for 
subjects not yet reaching the time point of SVR12.
Additionally, it should be noted that viral breakthrough is a stopping rule for this study.
4.2.
Primary Efficacy Endpoint
The primary efficacy endpoint is sustained virologic response 12 weeks after the end of 
actual treatment, as defined below.
4.2.1.
Definition
SVR12 is defined as follows:

1= success:
o
at the timepoint of SVR

HCV RNA Not Detected or

HCV RNA <LLOQ Detected 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

≥ 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 Detected 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.
Timepoint of SVR:
o
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.)
o
or, if not available, the first available measurement at least 12 weeks after 
the actual EOT (i.e. the first available measurement after the SVR12 
analysis window)
o
or, if not available (i.e. no measurement at least 12 weeks after the actual 
EOT), the subject is considered a failure. Note: For the SVR4 analysis, if 
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the time point of SVRx (x=8, 12, 18 or 24) has not been reached then 
those SVR time points will not be evaluated.
4.2.2.
Primary Efficacy Analysis Method
Statistical testing will be conducted using null hypothesis H0: C-T≥M vs. Ha: C-T<M at a 
significance level of 0.05, 2-sided, where C is the historical control rate of 98%, M is the 
non-inferiority margin 10%, and T is the expected SVR rate in the treatment arm.
This is equivalent to the lower bound of a 95% 2-sided CI exceeding 88%. An exact 95% 
2-sided Clopper-Pearson CI will be calculated.
A fixed sequence approach will be used to adjust for the multiplicity of the comparison of 
the SVR12 rate in the two treatment arms against the historical control. The SVR12 rate 
in the 6 week treatment arm will be tested first against the historical control at a 
significance level of 0.05, 2-sided. If non-inferiority is established then the SVR12 rate in 
the 8 week treatment arm will be tested against the historical control at a significance 
level of 0.05, 2-sided.
The fixed sequence approach will be applied only for the ITT population. Additional
analyses will also be conducted in the per protocol and non-VF excluded populations 
without applying the fixed sequence approach.
4.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
-
Evaluated during the treatment phase includes:

The proportion of subjects with On-Treatment Virologic Response at all available 
treatment timepoints (HCV RNA Not Detected, HCV RNA Not Detected or HCV 
RNA <LLOQ Detected);

The proportion of subjects with viral breakthrough;

The proportion of subjects with on-treatment failure
-
Evaluated during the follow up phase includes:

The proportion of subjects with SVR4;

The proportion of subjects with SVR8;

The proportion of subjects with SVR18;

The proportion of subjects with SVR24;

The proportion of subjects with post-treatment failure;

The proportion of subjects with viral relapse;

The proportion of subjects with late viral relapse (relapse at a later time point than 
SVR12);

Time from EOT to viral relapse
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4.3.1.
Definitions
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:

“HCV RNA Not Detected”

“HCV RNA Not Detected or HCV RNA <LLOQ 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 non-missing 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 non-missing Week 4 measurement while on therapy (or within 3 days of the date 
of last dose))
On-Treatment failure is defined as subjects who did not achieve SVR12 with confirmed 
HCV RNA ≥LLOQ at EOT or for which the last available on-treatment measurement is 
HCV RNA ≥LLOQ and for which no follow-up measurements are available, or subjects 
with viral breakthrough (see below).
Viral breakthrough is defined as subjects with a confirmed increase while on study 
therapy of > 1 log10 IU/mL in HCV RNA level from the nadir (= lowest value 
measured in between baseline and current value) when the lowest value reached is 
>=LLOQ, or a confirmed HCV RNA level of > 100 IU/mL while on study therapy in 
subjects who previously achieved HCV RNA Not Detected or HCV RNA <LLOQ 
Detected. A subject with viral breakthrough does not subsequently achieve SVR12.
Viral breakthrough is a type of on-treatment failure.
In this study, viral breakthrough is a treatment stopping rule, meaning all study drugs 
should be discontinued.
The proportion of subjects with a viral breakthrough is defined as follows:
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
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)
Confirmed means that the criterion should be fulfilled at 2 or more consecutive time 
points or at the last observed 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: Post-treatment failure, includes subjects with:
o
Viral relapse after completed treatment
o
Viral relapse after premature discontinuation of treatment
o
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
Evaluated in the follow-up phase:
SVR4, SVR8, SVR18 and SVR24 are defined similarly as SVR12 but with 4, 8, 18 and 24 
weeks instead of 12 weeks. Note: For the SVR4 analysis, if the time point of SVRx (x=8, 
12, 18, or 24) has not been reached then those SVR time points will not be evaluated.
In addition, for SVR24, the timepoint of SVR is defined as follows:
o
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.)
o
or, if not available, the first available measurement at least 24 weeks after 
the actual EOT (i.e. the first available measurement after the SVR24 
analysis window)
o
or, if not available, the last measurement available in the SVR18 analysis 
window, on condition that the time point of SVR24 has been reached
o
or, if not available, the last measurement available in the SVR12 analysis 
window, on condition that the time point of SVR24 has been reached
o
or, if not available, the subject is considered to have not achieved SVR24. 
Note: For the SVR4 and SVR12 analyses if the time point of SVR24 has 
not been reached then SVR24 will not be evaluated.
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For SVR18, the timepoint of SVR is defined as follows:
o
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.)
o
or, if not available, the first available measurement at least 18 weeks after 
the actual EOT (i.e. the first available measurement after the SVR18 
analysis window)
o
or, if not available, the last measurement available in the SVR12 analysis 
window, on condition that the time point of SVR18 has been reached
o
or, if not available, the subject is considered to have not achieved SVR18. 
Note: For the SVR4 and SVR12 analyses if the time point of SVR18 has 
not been reached then SVR18 will not be evaluated.
Viral relapse is defined as follows:
1 =  viral relapse
a) Subject is not achieving SVR12 (see definition in 4.2.1) 
    and
b) Subject is not an on-treatment failure (see above) 
    and
c)
Post treatment HCV RNA measurement fulfill one 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 post-treatment measurement available and not a 
viral relapse
2 = no post-treatment 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
a) Subject is achieving SVR12 (see definition in 4.2.1) 
    and
b)
Post treatment HCV RNA measurement beyond the SVR12 time point 
fulfill one the following conditions:
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o
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.
Time to virologic response is defined as the number of days since the first day of 
medication intake until the first day that the threshold was achieved. The following 
thresholds are considered:
- HCV RNA Not Detected
- HCV RNA <LLOQ (Detected or Not Detected)
4.3.2.
Analysis Methods
All analyses will be done on the ITT population. Selected efficacy analyses will be done 
also on the Non-VF excluded population. These are to be specified prior to Database 
Lock.
The difference in SVR12 rates between the 6 week and 8 week treatment arms (6 weeks –
8 weeks) will be calculated, together with a 2-sided 95% CI for the difference, calculated
using a normal approximation with continuity correction.
SVR4, SVR8, SVR18 and SVR24 rates will additionally be calculated.
Descriptive statistics (n, mean (se), median, interquartile ranges and ranges) per time 
point for the continuous parameters (actual values and change from baseline in log10 HCV 
RNA).
Tabulations (numbers and proportions and 95% CI) per treatment group and time point 
for the categorical parameters will be provided.
Cross-tabulations of HCV RNA for SVR4 by SVR12, and for SVR12 by SVR24 will be 
provided.
Subgroup analyses as defined in section 2.4 and combination of these factors will be 
performed for the following efficacy endpoints: SVR12, SVR4, HCV RNA at Week 2, 
HCV RNA at Week 4, HCV  RNA at EOT, viral breakthrough, viral relapse, and a 95% 
CI will be constructed around the different subgroups. Viral relapse will also be presented 
by treatment completion.
In addition, the reason for success/failure will be explored by type of failure and 
completion of study treatment.
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A ‘time to viral relapse’ analysis will be conducted if at least 5 subjects in total have an 
event.  Kaplan-Meier estimates per arm will be calculated. In addition, Kaplan-Meier 
curves per arm will be constructed.
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 9.8.6 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.
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 post-baseline in 
subjects not achieving SVR, focusing on the time of virologic failure and the end of 
study.
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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 below.
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)
4
ED43 (GU814265)
5
SA13 (AF064490)
6
EUHK2 (Y12083)
-
Treatment-emergent substitutions are defined as amino acids detected post-
baseline ≥15% and not detected (i.e. <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% 
post-baseline.
-
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 
post-baseline 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.
-
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 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, i.e. 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: ITT population excluding the subjects who did not 
achieve SVR12 due to reasons other than VF, including subjects with missing data at 
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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).
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 will be tabulated to
evaluate the impact on response.
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 post-baseline 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 including the reason of 
failure, relevant baseline disease and demographic characteristics, all amino acid changes 
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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 otherwise specified, all safety analysis will use ITT.
6.1.
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). All reported AEs will 
be included in the analysis.
6.1.1.
Definitions
For the purpose of the analysis, AEs are allocated to the study phase. The phase 
allocation of AEs consists of a combination of two steps: 

AEs are allocated to phases

Overlapping/consecutive AEs are combined
This is detailed in Appendix 1.  
Treatment-Emergent AE(TEAE)
Treatment-emergent AEs are AEs that start on or after the first dose or that are a 
consequence of a pre-existing condition that has worsened since baseline.
AE duration calculation
Duration is calculated as End date – Start date + 1.
Prevalence
The 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.
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Anticipated AEs
An anticipated event is an adverse event (serious or non-serious) that commonly occurs 
as a consequence of the underlying disease or condition under investigation (disease-
related) or background regimen. For the purposes of this study the following groups of 
events will be considered anticipated events:

Progression of underlying chronic hepatitis C:
a.
Cirrhosis and its complications:
o
Portal hypertension
o
Esophageal varices

Elderly population (age >65years)
o
Motor vehicle accident
o
Hip fracture
o
Carcinomas (other than hepatic related carcinomas including hepatocellular 
carcinomas)
6.1.2.
Analysis Methods
All AE analyses will be performed over the treatment and follow-up phases using 
incidence tabulations (n and %).  (i.e., Separate analyses will not be prepared for 
treatment and follow-up phases, rather all AE’s occurring during either the treatment or 
follow-up phase will be tabulated together, without regard as to which phase they were 
in). 
Only treatment-emergent AEs will be analyzed.
6.1.2.1.
General AE Profile
To get an overall understand of safety profile, a brief summary table using frequency and 
percentage will be provided. It will include below information:
•
Any AEs
•
AEs by WHO toxicity
•
Treatment related AEs
•
AEs with fatal outcome
•
Serious AEs (SAEs)
•
AEs leading to permanent stop of study medication
•
Relation to HCV infection
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The incidence and the incidence rate of treatment-emergent AEs by system organ class 
(SOC) and preferred term (PT) will be calculated. The incidence rate for treatment-
emergent AEs in at least 5% of subjects will be tabulated separately.
The incidence and incidence rate of AEs with WHO toxicity grade 3 or 4, SAEs, 
treatment related AEs, AE with fatal outcome and AEs leading to permanent stop of 
study medication will also be tabulated by SOC and PT. 
The incidence and comparable prevalence rate per 2-week time interval for any AEs will 
be tabulated and plotted to evaluate the safety profile over time (treatment and follow-up 
phase).
Treatment-emergent AEs will be considered for below subgroup analysis by SOC and 
PT:

Age (≤ 45,  > 45 - ≤ 65  and  > 65 yrs)

Sex

Race

BMI (< 25 kg/m2, >= 25 - < 30 kg/m2 and >= 30 kg/m2)
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.
Anticipated AEs (serious vs non-serious) will be presented using incidence. Summary of 
demographics, concomitant medication class and time to onset for the patients who had 
anticipated AEs will be provided as well.
Listings will be provided for all subjects with any AEs, subjects with serious AEs 
(SAEs), subjects who had AEs leading to death, subjects had AEs leading to permanent 
stop of any drug among AL-335, ODV and SMV, and subjects who had grade 3 or 4 
AEs. Also AE listing will be provided for the events which meet study stopping rules. 
Anticipated AEs will be listed as well. Listings should be provided for each phase 
including screening.
6.1.2.2.
Events of Special/Clinical Interest
Events of special interest (ESI) and events of clinical interest (ECI) are clinical or 
nonclinical findings that may suggest potential safety issues or toxicities in humans. 
Events as ESIs and ECIs that require special collection and/or reporting are specified by 
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an interdisciplinary team led by the clinical team via MedDRA term or Standardised 
MedDRA Queries (SMQ) term grouping exercise.
The events of interest are listed in below table. Please refer the search terms related to 
MedDRA and MedDRA SMQ in Appendix 2A and 2B which will be finalized prior to 
database lock.
Events of Interest
Defined by
Events of special interest
Cardiac Events
SMQ
Increased Bilirubin
MedDRA PTs
Events of clinical interest
Rash (all type)
MedDRA HLTs, PTs, SMQ
Photosensitivity conditions
MedDRA PTs
Pruritus
MedDRA HLT
A brief summary table will be provided for the number of subjects with events of 
interests in treatment and follow-up phases. Subgroup evaluation will also be performed 
for the brief summary results.
The incidence rates of the events of interest by WHO toxicity grades, treatment 
relationship, with fatal outcome, as a 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.
Time to the first occurrence of the events of interest will be summarized and described 
using Kaplan Meier (KM) Curve also.
The incidence and prevalence per 2-week time interval will be summarized and plotted 
over the treatment and follow-up phase.
Subgroup analysis will be conducted for each event of interest by PT. Subgroup 
evaluation includes:

Age (≤ 45,  > 45 - ≤ 65  and  > 65)

Sex

Race

BMI (< 25 kg/m2, >= 25 - < 30 kg/m2 and >= 30 kg/m2)
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Additionally, for cardiac events, below graphs will be considered:

Spaghetti plots of selected laboratory parameters (creatine kinase and BNP) by 
treatment group over time for the patients who had cardiac events

Bar graphs of the worst toxicity grade of cardiac events over time by treatment 
group
Listings will be provided for the subjects with events of special/clinical Interest. The 
separate listings for subjects with event of interest of cardiac event and rash from SMQ 
will be provided.  
6.2.
Clinical Laboratory Tests
Clinical Lab data are collected at the Screening, Baseline, Week 1, Week 2, Week 4, 
EOT, FU Week 4, Week 12, and Week 24. Blood samples for serum chemistry and 
hematology and urine sample for urinalysis are collected.
Baseline is the Day 1 measurement, if available.  If not available the Screening value will 
be used.
All analyses will be done on standardized international (SI)-converted values. 
6.2.1.
Definitions
World Health Organization (WHO) Toxicity Grade
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, i.e. 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 the grades, no distinction will be made between test results of samples obtained under 
fasting and under non-fasting conditions: in case limits under fasting and non-fasting 
conditions differ, the limits of the conditions (fasting/non-fasting) of scheduled visits as 
planned in the clinical trial protocol will always be used, also for samples obtained under 
a different condition (e.g. samples of withdrawal visits).  
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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. 
DAIDS coding for CK
Creatine Kinase (CK) was not planned to be coded in the protocol. However, for analysis 
purpose it will be coded using DAIDS (version 2.0) as below:
Grade 1: 3 to < 6 x ULN 
Grade 2: 6 to < 10 x ULN
Grade 3: 10 to < 20 x ULN
Grade 4: ≥ 20 x ULN
6.2.2.
Analysis Methods
All analyses will be performed on the treatment and follow-up phases.
All lab parameters with numeric values will be analyzed using descriptive statistics on 
actual values and changes from baseline over time.
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
Below plots and graphs will be produced to describe the overall and individual 
evaluations for selected laboratory parameters by timepoints: 

Plots of mean(SE) by treatment group over time (selected laboratory parameters*)

Spaghetti plots of the selected laboratory parameters by treatment group based on 
actual values for the patients who had abnormality on treatment or follow-up 
phase
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
Bar graphs of the treatment emergent abnormality by toxicity grade over time for 
selected laboratory parameters
Selected lab parameters* include ALT, AST, total bilirubin, indirect bilirubin, direct 
bilirubin, lipase, amylase, ALP, gamma-glutamyl transferase (GGT), creatine kinase, B-
type natriuretic peptide (BNP) and estimated glomerular filtration rate (e-GFR).
Listings will be provided for all laboratory parameters, and the subjects who had grade 3 
or greater laboratory results separately.  The lab results for subjects who had cardiac 
events will be provided as well.
Pregnancy test results will be listed as well.
6.3.
Vital Signs and Physical Examination Findings
Vital signs are assessed at following timepoints: Screening, Baseline, Weeks 2, 4, 6, 8 
(for Arm B), EOT, FU Week 4, and Week 24.  
Baseline is the day 1 measurement, if available.  If not available the Screening value will 
be used.
The following vital signs parameters will be analyzed:

Pulse/heart rate (bpm): supine

Systolic blood pressure, SBP (mmHg): supine

Diastolic blood pressure, DBP (mmHg): supine
6.3.1.
Definitions
Pulse, DBP and SBP are classified in the following abnormality codes:
Pulse (bpm)
DBP (mmHg)
SBP (mmHg)
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 post-baseline 
scheduled and unscheduled measurements
-
The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered 
equally important, i.e. if a subject has as well an abnormally low as an abnormally 
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high or graded value post-baseline, both abnormalities are shown in the tables. 
(This means that the sum of the percentages can be more than 100%)
Treatment-emergent
An abnormality (abnormality based on the definition above) 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.
Abnormality of vital signs will be described by frequency and percentage using below 
methods: 

Tabulation of the worst treatment-emergent abnormality of vital signs

Tabulation of normality/abnormality of vital signs over time

Cross-tabulations for the worst abnormality versus baseline 
Plots of mean (SE) by treatment group over time will be provided for all vital signs 
parameters. A listing of abnormalities of vital signs (all parameters) will be provided as 
well. 
Physical examination data will only be listed.
6.4.
Electrocardiogram Parameters
The triplicate electrocardiogram (ECG) are available for the following time points:  
Screening, Baseline, D2, D3, Weeks 1-4, 6, 8 (for Arm B), and FU Week 4.  Baseline is 
the Day 1 measurement, if available.  If not available the Screening value will be used.
The mean of the triplicate ECGs will be analyzed. The ECG parameters include:

Heart rate

PR interval

QRS interval

RR interval
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
QT interval corrected for heart rate according to Bazett’s QT formula (QTcB) (if 
available) 

QT interval corrected for heart rate according to Fridericia’s QT formula (QTcF) 
(if available)
6.4.1.
Definitions
For absolute HR, PR and QRS, the following abnormality categories are defined:
HR
PR
QRS
abnormally low
≤50 bpm
< 120 ms
NAP
abnormally high
≥120 bpm
> 200 ms
≥ 120 ms
Per protocol, 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 below:
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 ms 
Grade 2: ≥ 250 ms OR Type I 2nd degree AV block 
Grade 3: Type II 2nd degree AV block OR Ventricular pause ≥ 3000 ms
Grade 4: Complete AV block
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: 

QTc ≤ 450 ms (normal)

450 ms < QTc ≤ 480 ms (borderline)

480 ms < QTc ≤ 500 ms (prolonged)
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
QTc > 500 ms (pathologically prolonged)
For increases from baseline in QTc (ms) the following categories are defined: 

< 30 ms (normal)

[30; 60] ms (borderline) 

> 60 ms (abnormally high)
Only increases in QTc ≥ 30 ms 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 post-baseline scheduled and 
unscheduled measurements
-
The abnormalities ‘abnormally low’ and ‘abnormally high’ are considered equally 
important, i.e. 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%)
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’ post baseline (or vice versa) 
is also treatment-emergent.
6.4.2.
Analysis Methods
All analyses will be performed on the treatment and follow-up phases.
ECG parameters will be analyzed using descriptive statistics on actual values and change 
from baseline over time.
Overall ECG interpretations, such as Normal and Abnormal, which are collected in 
eCRF, will be summarized by timepoint. Also 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 the 
baseline value

Cross-Tabulation of the worst QTc increase versus the abnormality on the actual 
value
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Plots of actual mean(SE), mean of change from baseline(SE) by treatment group over 
time will be produced. Spaghetti plots of ECG parameters based on actual values and 
change from baseline will be produced for patients who had treatment-emergent
abnormalities. Spaghetti plots of PR for the patients who had prolonged PR interval or 
AV block (grade>=1) will be produced too.
A listing of ECG abnormalities (all parameters) will be provided. It will contain both 
actual and change from baseline values.  
6.5.
Echocardiographic(ECHO) Parameters
ECHO data is available for the Screening, Week 4, and FU Week 4.  The screening value 
will be used as the baseline.
ECHO parameters include: 

Left ventricular (LV) ejection fraction (EF) single plane (%) 

LV fractional shortening (%)                                       

LV posterior wall (LVPW) diastolic thickness (cm)                                      

Systolic volume (mL)           

Diastolic volume (mL)  
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.
ECHO parameters will be analyzed using descriptive statistics on actual values, change 
from baseline and percentage change from baseline over time. 
Number and percentage of subjects with abnormality based on normal ranges will be 
summarized over time for each ECHO parameter.  
The maximum change from baseline in LVEF will be tabulated. It includes the number 
and percent of subjects with LVEF decline of > 10% from baseline or <=10% from 
baseline, decline of >= 10% and resulting in an LVEF < 50%, decrease in LVEF >10% 
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from baseline with reversible decrease in LVEF or with no resolution, the summary of 
the time of onset and duration when LVEF decrease >10%, and LVEF increase > 10% 
etc.
Number and percentage of subjects will be summarized by visit for subjects who have a 
decrease in LVEF of:

>5% but <=10% 

>10%
Below graphs will be produced:

Plots of actual mean (SE), mean of change from baseline (SE) will be produced 
by treatment group over time

Spaghetti plots based on actual values for each ECHO parameter by treatment 
group for the patients who had abnormal values during any post-dose time point 
(Week 4, and FU Week 4)  
A listing of ECHO with actual value, change from baseline, % change from baseline for 
all parameters will be provided as well.
6.6.
Graphical Patient Profiles
A set of graphical patient profiles will be produced for each subject.  Data presented will 
include baseline characteristics, medical history, disposition, study drug exposure, 
HCVRNA levels, and concomitant medications.
7.
PATIENT-REPORTED OUTCOMES (PRO)
This section contains statistical methods for the analysis of the PRO data. Further 
analysis may be conducted and reported separately to support psychometric validation of 
PRO instruments.
The following patient-reported outcomes (PRO) assessments will be evaluated:

CLDQ-HCV (Chronic Liver Disease Quality of Life)

EQ-5D-5L (Health Status and Quality of Life)

FSS (Fatigue Severity Scale)

SF-36v2 (Short Form-36 version 2)
The number (and percentage) of subjects completing each PRO instrument at each time 
points will be tabulated.
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7.1.
CLDQ-HCV
7.1.1.
Definitions
The CLDQ-HCV is a validated disease-specific instrument to assess health-related 
quality of life (HRQoL) in patients with chronic hepatitis C. The instrument covers 
HRQoL concepts including fatigue, activity, emotional function, abdominal symptoms, 
systemic symptoms and worry. The CLDQ-HCV is comprised of 29 items. The answers 
to each of the items are from 1-7 on a Likert scale, with higher values representing better 
HRQoL.
CLDQ-HCV includes four HRQoL domains and a summary score2, 3. The domain scores 
and summary score are calculated as the average of the non-missing items:

activity and energy (AE): average of items 1, 3, 4, 5, 7, 18

emotional (EM): average of items 6, 8, 9, 11, 16, 23, 24, 27, 28

worry (WO): average of items 14, 15, 17, 19, 20, 21, 22, 29

systemic (SY): average of items 2, 10, 12, 13, 25, 26

CLDQ-HCV summary score: average of the 4 domain scores
A score will be derived if at least 50% of the items or domain scores are available 
respectively.
7.1.2.
Analysis Methods
Descriptive statistics for the actual and change from baseline values at each time point 
will be displayed for each derived parameter. In addition, mean changes from baseline 
will be explored per subgroup as defined in section 2.4. The clinically important 
threshold of 0.5 will be used to interpret the mean change from baseline in the domain 
and summary scores.
The number (and percentage) of subjects with clinically important improvement/ 
worsening will be presented for each score. Clinically important thresholds are defined in 
section 7.5. The time (in weeks) to first clinically important improvement from baseline 
in CLDQ-HCV summary and domain scores during the treatment and follow-up phase 
will be graphically presented by means of Kaplan-Meier curves. If applicable, the 
median, 1st and 3rd quartiles of the time to first clinically important improvement from 
baseline will also be presented using point and interval estimates.
A cumulative distribution function will be drawn at different time points (baseline and 
changes from baseline at Week 4, EOT and the follow-up assessments).
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7.2.
EQ-5D-5L
7.2.1.
Definitions
The EQ-5D-5L evaluates a subject’s self-rated health state on 5 dimensions. 
Additionally, a visual analogue scale (VAS) records the subject’s self-rated health on a 
vertical, VAS.
The EQ-5D will be analyzed as follows:

EQ-5D descriptive system: 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression); each with 5 response levels:
-
Level 1: indicating no problem
-
Level 2: indicating slight problems
-
Level 3: indicating  moderate problems
-
Level 4: indicating severe problems
-
Level 5: indicating extreme problem

EQ-5D VAS: a continuous score ranging from 0 to 100 (best imaginable health 
state=100 and worst imaginable health state=0)

EQ-5D Valuation index (VI): The information of the 5 dimensions of the descriptive 
system summarized into one index (a weighted scoring of the 5 dimension scores 
with a possible range from 0 to 1)
a.
Assign the level code 1 to 5 to each level of the 5 dimensions
b. Create a health state for each patient-time point combination. A health 
state is a combination of 5 level codes; one level code for each dimension. 
The dimensions are ordered as described above.
E.g. health state 12311 indicates ‘no problems in walking about, slight problems 
washing or dressing myself, moderate problems doing usual activities, no pain or 
discomfort, not anxious or depressed’.
c.
Assign an index value (valuation index) to each observed health state 
using the US crosswalk value set as defined in appendix 4. Based on the 
origin of the subjects, another method can be used.
Missing data
1) If – for a subject and time point – one (or more) dimensions of the descriptive 
system are missing then
-
The EQ-5D VAS will be tabulated if non-missing
-
The valuation index will not be tabulated
-
The non-missing dimensions of EQ-5D descriptive system will be 
summarized
2) If – for a subject and time point – the EQ-5D VAS is missing then the EQ-5D 
descriptive system and valuation index will be tabulated if complete.
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7.2.2.
Analysis Methods
For the EQ-5D descriptive system, the number (and percentage) of subjects per 
dimension and problem level by time point will be tabulated. A shift table of the 
responses versus baseline will also be provided per dimension and time point.
For the EQ-5D VAS and for the Valuation index, descriptive statistics for the actual and 
change from baseline values at each time point will be displayed. In addition, mean 
changes from baseline will be explored per subgroup as defined in section 2.4. The 
clinically important threshold of 8 will be used to interpret the mean change from 
baseline in the VAS. 
To assess the effect of treatment on EQ-5D VAS, within-treatment comparisons will be 
performed in a cross-sectional manner per time points using Wilcoxon signed-rank test 
(paired test with subject’s own baseline). To assess the impact of treatment duration on 
VAS, a between-group comparison of the changes from baseline will be performed at 
EOT, FU Week 4, FU Week 12 and FU Week 24 using Van Elteren test stratified by 
Prior HCV treatment history (Naive, Experienced) and HCV geno/subtype (genotypes 1a 
or 2 versus genotypes 1b, 4, 5 or 6). The tests will be conducted at a significance level of 
0.05, 2-sided.
The number (and percentage) of subjects with clinically important improvement/ 
worsening will be presented for EQ-5D VAS. The time (in weeks) to first clinically 
important improvement from baseline in EQ-5D VAS during the treatment and follow-up 
phase will be graphically presented by means of Kaplan-Meier curves. If applicable, the 
median, 1st and 3rd quartiles of the time to first clinically important improvement from 
baseline will also be presented using point and interval estimates.
A cumulative distribution function of the EQ-5D VAS will be drawn at different time 
points (baseline and changes from baseline at Week 4, EOT and the follow-up 
assessments).
7.3.
FSS
7.3.1.
Definitions
The Fatigue Severity Scale (FSS) is an instrument with 9 items. Item responses are 
measured on a 7-point Likert scale ranging from strongly disagree (1 point) to strongly 
agree (7 points). Higher response values indicate higher level of fatigue. 
The 9 items are combined into one total score. If the number of missing items is less than 
4, the total score is the average of the non-missing items; else the total score is missing.
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7.3.2.
Analysis Methods
Descriptive statistics for the actual and change from baseline values at each time point 
will be displayed. In addition, mean changes from baseline in the FSS will be explored 
per subgroup as defined in section 2.4. The clinically important threshold of 0.5 will be 
used to interpret the mean change from baseline in the total FSS score. 
To assess the effect of treatment on FSS, within-treatment comparisons will be performed 
in a cross-sectional manner per time points using Wilcoxon signed-rank test (paired test 
with subject’s own baseline). To assess the impact of treatment duration on FSS, a 
between-group comparison of the changes from baseline will also be performed at EOT, 
FU Week 4, FU Week 12 and FU Week 24 using Van Elteren test stratified by Prior 
HCV treatment history (Naive, Experienced) and HCV geno/subtype (genotypes 1a or 2 
versus genotypes 1b, 4, 5 or 6). The tests will be conducted at a significance level of 0.05, 
2-sided.
The number (and percentage) of subjects with clinically important improvement/ 
worsening will be presented for FSS. The time (in weeks) to first clinically important 
improvement from baseline in FSS during the treatment and follow-up phase will be 
graphically presented by means of Kaplan-Meier curves. If applicable, the median, 1st
and 3rd quartiles of the time to first clinically important improvement from baseline will 
also be presented using point and interval estimates.
A cumulative distribution function will be drawn at different time points (baseline and 
changes from baseline at Week 4, Week 8, EOT and the follow-up assessments).
7.4.
SF-36v2
7.4.1.
Definitions
SF-36v2 is a generic 36-item instrument measuring HRQoL, where participants self-
report on items in a domain scale that have between 2-6 response choices per item using 
Likert-type responses (eg, none of the time, some of the time, etc.). SF-36v2 can be 
interpreted using T-scores from 8 domain scales and 2 summary scores – Physical 
Component Summary (PCS) and Mental Component Summary (MCS).
Responses to all items will be used to derive the 8 health domain scales except item #2. 
No recoding will be done for item #2; the original response will be tabulated. Each of the 
8 domain scales will be derived by first taking the sum of the responses per domain1:

Physical Functioning (PF): 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j

Role-Physical (RP): 4a, 4b, 4c, 4d

Bodily Pain (BP): 7, 8

General Health (GH): 1, 11a, 11b, 11c, 11d

Vitality (VT): 9a, 9e, 9g, 9i
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
Social Functioning (SF): 6, 10

Role-Emotional (RE): 5a, 5b, 5c

Mental Health (MH): 9b, 9c, 9d, 9f, 9h
The total domain scores of domain scales will be transformed into a range from 0 to 100; 
0=worst HRQoL, 100=best HRQoL. The scores (0-100 scores) will then be standardized 
using means and standard deviations from the 2009 U.S. general population, and 
converted to norm-based scores using a T-score transformation (mean = 50, SD = 10) 1. 
Two aggregate component scores will be derived as linear combination of the 
standardized (2009 U.S. norm) scores using weights from principal component analysis. 
Each aggregate component score will be transformed to the corresponding PCS T-score 
and MCS T-score (mean = 50, SD = 10) 1.
The domain scale scores and component summary scores will be calculated using the 
QualityMetric Health Outcomes™Scoring Software, version 4.5.1 or a later version. In 
case of missingness the Full Missing Score Estimation (MSE) method or Item Response 
Theory (IRT) will be used, if applicable, for imputation of missing values1. SF-36v2 item 
#2, the health domain scale T-scores, PCS T-scores and MCS T-scores will be analyzed.
7.4.2.
Analysis Methods
Descriptive statistics for the actual and change from baseline at each time point will be 
displayed. In addition, mean changes from baseline in health domain scale and summary 
measures will be explored per subgroup as defined in section 2.4. Clinically important 
threshold (5 for subscales and 5 for summary measures) will be used to interpret the 
mean change from baseline. Frequency tabulation (n, %) of the response categories of 
item #2 of the SF-36v2 instrument will be tabulated per time point for each treatment 
group.
The number (and percentage) of subjects with clinically important improvement/ 
worsening will be presented. The time (in weeks) to first clinically important 
improvement from baseline in PCS and MCS during the treatment and follow-up phase 
will be graphically presented by means of Kaplan-Meier curves. If applicable, the 
median, 1st and 3rd quartiles of the time to first clinically important improvement from 
baseline will also be presented using point and interval estimates.
A cumulative distribution function will be drawn at different time points (baseline and 
changes from baseline at Week 4, Week 8, EOT and the follow-up assessments).
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7.5.
Proposed Thresholds Indicating Clinically Important Changes 
from Baseline in PRO
PRO Instrument
Mean Changea
from baseline
Individual Subject’s 
Changea from baseline
CLDQ-HCV 
4 domain scores
summary score
≥0.5 point
≥0.5 point
≥0.5 point
≥0.5 point
EQ-5D VAS score
≥8 points
≥8 points
FSS Total score
≥0.5 point
≥1 point
SF-36v2
PCS
≥5 points
≥5 points
MCS
≥5 points
≥5 points
8 domain scores
≥5 points
≥5 points
a This change refers to either an increase or a decrease >= threshold
8.
PHARMACOKINETICS/PHARMACODYNAMICS
8.1.
Pharmacokinetics
Blood samples for PK assessments of AL-335 (and its 2 metabolites ALS-399 and ALS-
227), ODV, and SMV will be collected from all subjects at the Week 4 visit, the Week 6 
visit (arm B) and at the EOT visit at any time during the visit.
Based on the individual plasma concentration-time data from all subjects, exposure 
parameters of AL-335 (and its two metabolites), ODV, and SMV will be derived using 
population PK (popPK) modelling. The following exposure parameters for AL-335 (and 
metabolites), ODV, and SMV will be derived using nonlinear mixed-effects modelling: 
AUC24h, C0h, and Cmax (if popPK model allows the estimation of Cmax).
These exposure parameters will be derived at the Week 4 visit and at the EOT visit (week 
6 arm A), and at the Week 4 visit, Week 6 visit and at the EOT visit (week 8 arm B). The 
mean value over these visits for each exposure parameter of AL-335, ALS-399, ALS-
227, ODV and SMV will be used in tabulations and plots described in section 9.1.1. 
8.1.1.
Analysis methods
Descriptive statistics, including arithmetic mean, SD, coefficient of variation, median, 
minimum, maximum, and geometric mean will be presented for each exposure parameter 
(AUC24h, C0h, and Cmax if model allows) of AL-335 (and metabolites), ODV, and SMV 
for each treatment group and also pooled over treatment groups.
Box and whisker plots for each exposure parameter (AUC24h, C0h, and Cmax) of AL-335 
(and metabolites), ODV, and SMV will be presented by treatment group and also pooled 
over treatment groups.
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8.2.
Pharmacokinetic/ Pharmacodynamic Analyses
Each exposure parameter (AUC24h, C0h, and Cmaxif model allows) of AL-335 (and 
metabolites), ODV, and SMV will be categorized into quartiles for each treatment group. 
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure 
parameters (AUC24h, C0h, and Cmax) with efficacy will be explored as follows.
The number and percentage of subjects with the following by quartiles of the exposure 
parameters of AL-335 (and metabolites), ODV, and SMV will be tabulated for each 
treatment group:

SVR12

RVR

SVR4

SVR24

On-treatment failure (also broken down by type of failure: Viral breakthrough; 
Confirmed HCV RNA ≥ LLOQ at EOT; Other)

Not detected at EOT

Viral relapse
Box and whisker plots for each exposure parameter (AUC24h, C0h, and Cmax) of AL-335 
(and metabolites), ODV, and SMV for each treatment group will be presented by each 
efficacy response.
For each treatment group the following scatterplots will be produced:

ODV AUC24h versus SMV AUC24h.

ODV AUC24h versus ALS-227 AUC24h

SMV AUC24h versus ALS-227 AUC24h
Different colors will be used to distinguish between subjects achieving SVR12 and those 
not achieving SVR12.
For each of AL-335 (and metabolites), ODV, and SMV, a scatterplot of change in HCV 
RNA from baseline to Day 7 versus AUC24h and a scatterplot of the actual HCV RNA 
value at Week 4 versus AUC24h will be presented.
Relationships of AL-335 (and metabolites), ODV, and SMV population-derived exposure 
parameters (AUC24h, and Cmax) with safety will be explored as follows.
The number and percentage of subjects with the following by quartiles of the exposure 
parameters of AL-335 (and metabolites), ODV, and SMV will be tabulated for each 
treatment group:

Any AE

Any AE worst grade 1 or 2

Any AE worst grade 3 or 4

Any AE at least possibly related to AL-335+ODV+SMV (any drug)

Any AE with fatal outcome

Any SAE

Any SAE at least possibly related to AL-335+ODV+SMV (any drug)

AE leading to permanent stop of All Study Medication

AE leading to temporary interruption of All Study Medication
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AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
46
The number and percentage of subjects with the following by quartiles of the exposure 
parameters of AL-335 will be tabulated for each treatment group:

Any AE at least possibly related to AL-335

Any SAE at least possibly related to AL-335

AE leading to permanent stop of AL-335

AE leading to temporary interruption of AL-335
The number and percentage of subjects with the following by quartiles of the exposure 
parameters of ODV will be tabulated for each treatment group:

Any AE at least possibly related to ODV

Any SAE at least possibly related to ODV

AE leading to permanent stop of ODV

AE leading to temporary interruption of ODV
The number and percentage of subjects with the following by quartiles of the exposure 
parameters of SMV will be tabulated for each treatment group:

Any AE at least possibly related to SMV

Any SAE at least possibly related to SMV

AE leading to permanent stop of SMV

AE leading to temporary interruption of SMV
Only treatment emergent adverse events will be tabulated.
The number and percentage of subjects with the following adverse events of interest by 
quartiles of the exposure parameters of AL-335 (and metabolites), ODV, and SMV will 
be tabulated for each treatment group. 

Cardiac events

Increased Bilirubin

Rash (all types)
Box and whisker plots for each exposure parameter of AL-335 (and metabolites), ODV, 
and SMV for each treatment group will be presented by for subjects with and without 
each type of event of interest given above.
The number and percentage of subjects with treatment-emergent PR abnormally high (PR 
> 200 ms) and the number and percentage of subjects in each PR interval category during 
the treatment phase will be tabulated by exposure quartile of AL-335 (and metabolites), 
ODV, and SMV for each parameter and treatment group. The worst PR value during the 
treatment phase will be used to determine abnormality and PR interval category (<120 
ms, >=120 - <=200 ms, >200 - <=240 ms, >240 - <=300 ms, >300 ms).
Box and whisker plots for each exposure parameter of AL-335 (and metabolites), ODV, 
and SMV for each treatment group will be presented by for subjects with and without 
treatment emergent PR abnormally high.
The maximum change from baseline in selected laboratory parameters (ALT, AST, CK, 
total bilirubin, direct bilirubin, indirect bilirubin, and BNP) during the treatment phase 
will be plotted versus AUC24h for each of AL-335 (and metabolites), ODV, and SMV.
NCT02765490


AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
47
9.
HEALTH ECONOMICS
Medical resource utilization will be summarized descriptively.
Occupational/employment status will also be descriptively summarized by treatment arm.
10.
REFERENCES
1.
Maruish, M. E. (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated
2.
Younossi, Z. M., Boparai, N., McCormick, M. (2000) A disease-specific health-related 
quality of life instrument for chronic hepatitis C: CLDQ-HCV. Hepatology. 32, 838.
3.
Younossi, Z. M., Stepanova, M., Henry L. (2016). Performance and validation of chronic 
liver disease questionnaire-hepatitis C version (CLDQ-HCV) in clinical trials of patients 
with chronic hepatitis C. Elsevier, 19, 544–551.
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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 (i.e. day and/or month and/or year missing)
Partial start or stop dates:  
1. The partial start date (i.e. 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 (i.e. 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 (i.e. the cut-off 
date).
STEP 2: combining adverse events
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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:
1) In case a non-active phase (e.g. 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 non-active phase (e.g. 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
non-active phase is followed by a
non-active 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.
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 
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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
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
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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
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
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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
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
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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
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Narrow
Extrasystoles
Narrow
Tachyarrhythmia
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
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AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
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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
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
NCT02765490


AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
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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
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
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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
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
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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
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Broad
Left ventricular dilatation
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
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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
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
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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
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
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AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
62
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
Broad
Syncope
Broad
Ventricular arrhythmia
Broad
Ventricular fibrillation
Broad
Ventricular flutter
Broad
Ventricular tachyarrhythmia
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AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
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APPENDIX 4: EQ-5D VALUATION INDEX - US
Please refer the following link:
http://www.euroqol.org/news-list/article/interim-scoring-for-the-eq-5d-5l-eq-5d-5l-
crosswalk-index-value-calculator.html
APPENDIX 5: PREDEFINED MAJOR PROTOCOL DEVIATIONS
The predefined major protocol deviations of this study are described in the Protocol 
Deviation Criteria document. The deviations that may affect the assessment of efficacy 
are a subset of the predefined major protocol deviations and are indicated with ‘Yes’ in 
the Exclude from Per Protocol Analysis’ column. For some major PDs as indicated a 
case-by-case evaluation will be performed as to whether the assessment of efficacy will 
be affected.
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
INCLUSION CRITERIA (Subjects must meet the below inclusion criteria)
1
Man or a woman between 18 and 70 
years of age, extremes included.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 1 not
met 
.
Checks/listings
Case-by-case 
evaluation
Major
Note: For Singapore, age limit starts at 21 
years due to local regulations
2
BMI of 18.0 to 35.0 kg/m2, extremes 
included.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 2 not 
met
Checks/listings
Case-by-case 
evaluation
Major
3
Documented chronic HCV infection: 
diagnosis of HCV infection >6 
months before the first screening 
assessment.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 3 not 
met
Source Docs
No
Major
4
HCV genotype 1, 2, 4, 5 or 6 
infection, determined at screening.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 4.1 not 
met
Checks/listings
Yes
Major
If the subject has Genotype 3 then it should be 
recorded in exclusion
5
HCV RNA plasma levels >10 000 
IU/mL at screening.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 6 not 
met 
Checks/listings
Yes
Major
Note: Retesting of laboratory values that lead 
to exclusion will be allowed once during the 
screening phase to assess eligibility
6
Either be HCV treatment-naïve, or 
treatment-experienced. 
Tx 
experienced defined as having 
received HCV therapy consisting of 
IFN (pegylated or non-pegylated) 
with or without RBV.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 7.1 not
met
Checks/listings
Source Docs
Yes
Major
As these situations may need clinical assessment, 
the monitors are requested to provide details of the 
case to Quintiles Medical Monitor/SRP to confirm 
the criterion is met.
7
Female subjects of childbearing 
potential must have a negative 
serum 
(β-human 
chorionic 
gonadotropin) pregnancy test at 
screening.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 8 not 
met
Checks/listings
No
Major
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
8
Female subjects must 
-either be not of childbearing potential 
or
must be postmenopausal for at least 12 
months (i.e., 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
- be surgically sterile (have had a 
hysterectomy, bilateral oophorectomy, 
or bilateral tubal ligation/bilateral tubal 
clips without reversal operation), or 
otherwise be incapable of pregnancy.
Or
- be of childbearing potential and not 
heterosexually active (e.g., abstinence) 
from screening until 12 weeks after the 
EOT (or longer, if dictated by local 
regulations) 
Or
have a vasectomized partner 
(confirmed sterile per verbal account of 
the subject),Or
if heterosexually active, be 
participating an acceptable method of 
birth control from screening 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). 
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 9.2 not 
met
Checks/Listings
No
Major
Oral hormone-based contraceptives are not allowed 
from 14 days before baseline until 4 weeks after the 
EOT
Note: The FSH level
will be tested in female subjects who are 
postmenopausal for less than 2 years
9
The subject must be willing and 
able to comply with the protocol 
requirements, 
including 
the 
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 10 not 
met
Checks/Listings
Case-by-case 
evaluation
Major
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
Prohibitions
and 
Restrictions 
described 
in 
Section 4.3
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
10
Subject 
must 
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.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 11 not 
met
Source Docs
Yes
Major
11
Subject must voluntarily sign an 
ICF as such indicating that he or 
she understands the purpose of 
and procedures required for the 
study and is willing to participate in 
the study.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 12 not 
met
.
Checks/listings
No
Major
If an ICF is updated to include new data and 
was not read and signed   by the patient, the 
deviation to be evaluated before classifying as 
major or not.  
This applies to main ICF and/or DNA ICF 
and/or consent form for PK sub study in 
Omega 1
12
The 
subject 
should 
have 
documented 
“Absence 
of 
Cirrhosis”.
“Absence of Cirrhosis” is defined by 
the following results:

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
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 13.1 not 
met
Checks/listings
Yes
Major
Note: Liver biopsy should only be considered 
as an alternative in subjects where Fibroscan 
is not feasible
13
Female subject 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.
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 14 not 
met
Source Docs
No
Major
14
Female subjects must have a negative 
highly sensitive urine pregnancy test at 
Day 1. 
Entered but did 
not 
satisfy 
criteria
.
Inclusion criterion 15 not 
met
Checks/listings
No
Major
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
15
Male subject must be surgically sterile 
(had a vasectomy), or otherwise 
incapable of fathering a child.
Or
Male subject must be not 
heterosexually active (eg, abstinence) 
from enrollment (Day 1) until at least 
12 weeks after the EOT
Or 
Male subject if heterosexually active 
has a partner who is postmenopausal 
(at least 12 months or until 2 years or 
more of  amenorrhea), surgically sterile 
(has had a hysterectomy, bilateral 
oophorectomy, or bilateral tubal 
ligation/bilateral tubal clips without 
reversal operation), or otherwise 
incapable of becoming pregnant 
Or
Male subject if heterosexually active 
with a woman of childbearing 
potential, be practicing an acceptable 
method of birth control, as defined in 
protocol Inclusion Criterion 16, from 
enrolment in the study (Day 1) 
throughout the study and for at least 12 
weeks after the EOT (or longer, if 
dictated by local regulations). 
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 16 not 
met
Checks/Listings
No
Major
16
Male subjects must agree not to donate 
sperm during the study until 12 weeks 
after the EOT (or longer, if dictated by 
local regulations)
Entered but did 
not 
satisfy 
criteria
Inclusion criterion 17 not 
met
. 
Source Docs
No
Major
EXCLUSION CRITERIA
17
Subject 
has 
co-infection 
with 
multiple HCV genotypes,
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 1 met
Checks/Listings
(External 
Data 
Transfer)
Yes
Major
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
18
Subject has co-infection with HIV
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 2 met
Checks/listings
Yes
Major
Absence of any  inclusion/exclusion lab data is 
considered a major deviation
19
Presence of cirrhosis 
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 3.1 met
Checks/Listings
Yes
Major
20
Subject has prior exposure to an 
HCV DAA, either in combination 
with PegIFN or IFN-free,
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 4 met
Source 
Documents
Yes
Major
Note: This is applicable only for HCV 
treatment-experienced subjects
21
Subject has evidence of liver 
disease 
of 
non-HCV 
etiology 
(exclusion criterion 5).
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 5 met
Source 
Documents
Medical 
review 
listing
No
Major
22
Subject has evidence of liver 
disease 
of 
non-HCV 
etiology 
(exclusion criterion 5.1).
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 5.1 met
Source 
Documents
Medical 
review 
listing
No
Major
Note: Canada-specific criterion
23
Subject has evidence of hepatic 
decompensation (history or current 
clinical 
evidence 
of 
ascites, 
bleeding 
varices 
or 
hepatic 
encephalopathy).
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 6 met
Source 
Documents
Medical 
review 
listing
Yes
Major
24
Subject 
has 
taken/used 
any 
disallowed therapies as noted in 
Section 8.
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 7 met
Source 
Documents/
Check-listing/
Medical 
Review 
Listing
Case-by-case 
evaluation
Major
25
Subject has a history of malignancy 
within 5 years before screening 
(refer to CTP for exceptions).
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 8 met
.
Source 
Documents
Medical 
review 
listing
No
Major
26
Subject 
has 
known 
allergies, 
hypersensitivity, or intolerance to 
AL-335, ODV,
or SMV or their 
excipients   .
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 9 met
Source 
Documents
No
Major
27
Subject has presence of significant 
co-morbidities, 
conditions 
or 
clinically significant findings during 
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 10 met
.
Source 
Documents
No
Major
NCT02765490


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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
screening for which, in the opinion 
of the investigator, participation 
would not be in the best interest of 
the subject.
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
28
Subject was a recipient of an organ 
transplant 
(check 
CTP 
for 
exception).
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 11 met
Source 
Documents
No
Major
29
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% or any other echocardiogram 
finding suggestive of clinically
relevant cardiomyopathy;
abnormal 
electrocardiogram 
(ECG) 
findings 
such 
as: 
significantly
abnormal PR [PR interval >200 
milliseconds], QRS intervals or
corrected QT interval [QTc] >450 
milliseconds for male subjects and
>470 
milliseconds 
for 
female 
subjects 
 evidence of any heart block;
 evidence of right bundle branch 
block or left bundle branch block;
history or family history of 
prolonged QT syndrome (torsade 
depointes) 
or 
sudden 
cardiac 
death.
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 12 met
Source 
Documents 
Check-listing
No
Major
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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
30
Any of the following laboratory 
abnormalities at screening:
 Platelet count <75 x 10³/μL or 
<75 x 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 x 
10³/μL or <1.00 x 109/L;
 Alanine aminotransferase (ALT) 
and/or aspartate aminotransferase 
(AST) >10 x upper limit of normal 
(ULN);
 Total serum bilirubin >1.5 x ULN;
 Albumin <3.5 g/dL or <35 g/L;
Estimated glomerular filtration 
rate (eGFR) of <50 mL/min/1.73 m² 
.
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 13 met
Source Docs
+
Check Listing
No
Major
Note: Retesting of laboratory values that lead 
to exclusion will be allowed once during the 
screening phase to assess eligibility
31
Subject 
has 
other 
abnormal 
screening laboratory results that 
are considered clinically significant 
by the investigator.
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 14 met
Source Docs
No
Major
32
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.
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 15 met
Source Docs
No
Major
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.
NCT02765490


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73
Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
33
Pregnant, planning on becoming 
pregnant (during treatment and up 
to 12 weeks after the EOT), or 
breast-feeding female subject, or 
male subject whose female partner 
is 
pregnant 
or 
planning 
on 
becoming pregnant.
Entered but did
not 
satisfy 
criteria
Exclusion criterion 16 met
Source Docs
No
Major
34
Subject 
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.
Entered but did 
not 
satisfy 
criteria
Exclusion criterion 17 met
Source Docs
Medical Listings
Yes
Major
35
Subject has findings suggestive of 
hepatocellular carcinoma.
Entered but did 
not 
satisfy 
criteria
Exclusion 
criterion 
18.1 
met
Source Docs
Checks/Listings
Yes
Major
36
Subjects with HCV genotype 3 
infection. 
Entered but did 
not 
satisfy 
criteria
Exclusion Criterion 19 met
Checks/Listings
Yes
Major
WITHDRAWAL CRITERIA (Treatment withdrawal )
37
The investigator believes that for 
safety reasons (eg, AE) it is in the 
best interest of the subject to 
discontinue study treatment.
Developed  
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from study treatment even 
after investigator confirmed 
that the subject should 
discontinue study treatment 
for safety reasons <specify 
reason>
Source 
Document/Medical 
review Listing
No
Major
38
The subject becomes pregnant.
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from 
study 
treatment 
although the subject is 
pregnant.
Or
Check/Listing
No
Major
39
The subject has a grade 3 rash
Developed 
treatment 
withdrawal 
Subject was not withdrawn 
from the SMV treatment 
although a 
Check/Listing
No
Major
ODV and AL-335 treatments can continue with 
discretion of the investigator
NCT02765490


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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
criteria but not 
withdrawn
Grade 3 rash occurred 
NCT02765490


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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
40
The subject has a grade 4 rash
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from study treatment 
although a grade 4 rash 
occurred 
Check/Listing
No
Major
41
The subject has a grade 3 or 4 
allergic reaction
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from study treatment 
although a <specify “grade 3” 
or “grade 4” allergic reaction 
occurred >
Medical review
Listing/check -
Listing
No
Major
As 
these 
situations 
may 
need 
clinical 
assessment, the monitors are requested to 
provide details of the case to study physician 
(s) to confirm the deviation before filing a Major 
Deviation form.
42
The subject has a confirmed grade 
4 ALT and/or AST value that is >2 
times the baseline value;
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from 
study 
treatment 
although Grade 4 AST or 
ALT value greater than 2 
times baseline value was 
confirmed
Medical Listing/Lab 
alerts/
No
Major
Confirmatory measurement to be done within 
72 hours after receipt of the results.
43
The subject has a confirmed grade 
4 
bilirubin 
value 
which 
is 
considered a sign of worsening liver 
disease, or for which there is no 
identifiable explanation
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from study treatment, 
although subject had a 
confirmed grade 4 bilirubin 
value considered a sign of 
worsening liver disease or for 
which there is no other 
identifiable explanation.
Medical
Listing/Listing
No
Major
Confirmatory measurement within 72 hours 
after receipt of the results. 
44
For concurrent grade 4 ALT and/or 
AST 
elevations 
>2 
times 
the 
baseline value and grade 4 bilirubin 
values, subjects should have a 
confirmatory measurement within 
72 hours after receipt of the results. 
In case of confirmed grade 4 
elevations, the study drugs should 
be discontinued.
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from study treatment, 
although For concurrent 
grade 4 ALT and/or AST 
elevations >2 times the 
baseline value and grade 4 
bilirubin values, subjects 
should have a confirmatory 
measurement within 72 hours 
after receipt of the results. In 
case of confirmed grade 4 
elevations, the study drugs 
should be discontinued
Medical 
Listing/Listing
No
Major
NCT02765490


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Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
45
The subject has severe worsening 
of hepatic disease
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from the study treatment 
although the subject 
experienced a severe 
worsening of hepatic disease.
Source
document/Medical
Listing
No
Major
As these situations may need clinical assessment, 
the monitors are requested to provide details of the 
case to Study physician (s) to confirm before filing 
a Major Deviation form.
46
The subject has a confirmed grade 
4 pancreatic amylase or lipase 
elevations, with confirmed presence 
of 
signs 
consistent 
with 
pancreatitis.
Developed  
treatment 
withdrawal 
criteria but not 
withdrawn
The study treatment wasn’t 
interrupted 
although 
subject has a confirmed 
grade 
4 
pancreatic 
amylase 
or 
lipase 
elevations, or the presence 
of signs consistent with 
pancreatitis.
Source
document/Medical
Listing
No
Major
47
The subject has clinical signs 
suggestive of muscle injury
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from
the study treatment although 
the subject has clinical signs 
suggestive of muscle injury
Source
document/Medical
Listing
No
Major
48
If CK is ≥20 × ULN, , AL-335 should 
be discontinued. Continuation of 
ODV and SMV should
be discussed with the sponsor on a 
case-by-case basis
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from the study treatment 
although the CK is ≥ 20 X 
ULN
Source 
document/Medical 
Listing
No
Major
49
For asymptomatic subjects with no 
clinical 
evidence 
of 
congestive 
heart failure:
Subject has  a decrease  in LVEF ≥10% 
from baseline and resulting in an LVEF 
of <50%, 
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from
the study treatment although 
the subject has a decrease in 
LVEF ≥ 10% from baseline 
and resulting in an LVEF of 
<50%, 
Source Documents
No
Major
NCT02765490


AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
77
Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
50
Subject is symptomatic and has an 
absolute decrease in LVEF ≥5% 
from baseline
Developed  
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from
the study treatment although 
the subject has  Symptoms 
and  absolute decrease in 
LVEF ≥5% from baseline
Source Documents
No
Major
51
Subject has a PR interval of >300 ms  
Developed  
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from 
ODV 
treatment 
although the subject had a 
PR interval of >300 ms.
Source Documents
No
Major
52
Subject has a second degree or 
higher AV block.
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from
ODV treatment although 
the subject had a second 
degree or higher  AV 
block.
Checks/Listings
No
Major
ODV to be stopped; AL-335 and SMV can continue 
at investigator discretion
53
Subject has QTc value of >500 
milliseconds 
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from
The 
ODV 
treatment 
although the subject had 
QTc 
value 
of 
>500 
milliseconds
Checks/Listings
No
Major
54
Subject has a confirmed eGFR <30 
mL/min, 
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Study treatment was not 
interrupted 
although 
subject had a confirmed 
eGFR <30 mL/min
Checks/Listings 
No
Major
55
The subject has a grade 4 AE at 
least possibly related to one of the 
study drugs
Developed 
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from
Study treatment although the 
subject has grade 4 AE at 
least possibly related to one 
of the study drugs.
Listings
No
Major
NCT02765490


AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
78
Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
56
Subject meets treatment stopping 
rule for viral breakthrough, but 
continued study treatment. 
Developed  
treatment 
withdrawal 
criteria but not 
withdrawn
Subject was not withdrawn 
from
the 
study 
treatment 
although subject meets
treatment stopping rule for 
viral
breakthrough at <specify
visit>.
Medical 
Review 
Listings/lab alerts
No
Potentially Major
.If continues treatment
for > 14 days after
confirmation to stop all study
Medications.
DOSAGE & ADMINISTRATION
57
The dose of SMV and/or AL-335 
and/or ODV was not according to 
protocol.
Received wrong 
treatment or 
incorrect dose
Please update to “Subject 
received wrong dose of 
<specify 
study 
medication> 
(includes 
overdose 
or 
suboptimal dose).
Checks/Listings
Yes
potentially Major 
Dose adjustments are not allowed.
.
Consult SRP for case evaluation
58
AL-335, and/or ODV, and/or SMV 
intake was temporarily interrupted 
(either individual or two or all three 
study drugs ) for more than 3 
consecutive days
Received 
wrong 
treatment 
or 
incorrect dose
<Specify 
AL-335, 
ODV, 
and/or 
SMV> 
were 
temporarily interrupted
for 
<specify 
duration> 
days.
Checks/Listings
Yes
Potentially Major 
Restart of medications to be done only after 
consultation with Sponsor.
59
Subject was dosed without being 
randomized.
Received 
wrong 
treatment 
or 
incorrect dose
Subject was dosed without
being randomized.
Checks/Listings
Yes
Major
CONCOMITANT MEDICATION
60
The 
subject 
takes/has 
taken 
disallowed medication as defined 
per protocol.
Subject 
used 
Disallowed 
medication.
Subject not compliant on 
the disallowed concomitant 
treatment
Medical 
review 
listing
Case-by-case 
evaluation
Potentially Major.
As 
these 
situations 
may 
need 
clinical 
assessment, the monitors are requested to 
provide details of the case to the PK Expert 
and Study physician(s) to confirm 
NCT02765490


AL-335, Odalasvir, Simeprevir: Statistical Analysis Plan 64294178HPC2001
79
Sequence 
No.
Description
Protocol 
Deviation 
Coded Term 
(DVDECOD)
Protocol Deviation 
Term (DVTERM)
*Check/Listing
*Medical listing
**Source docs
Exclude from PP 
(i.e. with a major 
PD that might 
impact efficacy)
Classification/Remarks
OTHER – STUDY PROCEDURES
61
A standard laboratory test (not 
specified as eligibility related labs) 
was not performed
during screening period, but the 
subject
was administered at least 1 dose of 
the
study medication.
Other
<Specify test, e.g. “Blood
sugar”> not performed at
screening, 
but 
subject 
entered
the trial.
Checks/Listings
No
Potentially Major
62
The subject missed two or more 
consecutive planned visits in the 
trial.
Other
Subject missed <specify 
visit> visit
Checks/Listings
Case-by-case 
evaluation
Potentially Major
Missing visits with no preceding or post visit 
data to carry forward leading to lack of data will 
be considered major.
Consultation with Study physician (s) is required to 
confirm
63
Subject continued to take study 
treatment 
after 
withdrawal 
of 
consent from the trial.
Other
Subject continued to take 
study 
treatment 
after 
withdrawal of consent from 
the trial.
Checks/Listings
No
Potentially Major
64
Subject had a screening period 
beyond 6 weeks and no safety re-
screening was done.
Other
The 
randomization 
was 
done out of time window 
<specify timing>.
Checks/Listings
No
Potentially Major
Screening may be extended beyond 6 weeks on a 
case-by-case basis after discussion with the sponsor. 
65
Site reported protocol deviation not 
specified elsewhere.
Other
Site reported protocol
Deviation 
not 
specified 
elsewhere: <specify>.
Checks/Listings
No
Potentially Major
66
Pharmacokinetic blood sample was 
not collected
Other
Pharmacokinetic 
blood 
sample was not collected
Checks/Listings
No
Potentially Major
67
Subject 
completed 
paper 
questionnaire instead of ePRO
Other
Subject completed paper 
questionnaire instead of 
ePRO
Checks/Listings
No
Potentially Major
NCT02765490