Conditions: Chronic Hepatitis C
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 161
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of AL-335 in combination with odalasvir (ODV) with or without simeprevir (SMV) in participants with genotype (GT)1 or GT2 or GT3 chronic hepatitis C (CHC) infection.

Detailed description:

Arms:
arm 1: Treatment-naïve non-cirrhotic Hepatitis C virus (HCV)-infected participants will receive AL-335 and Odalasvir (ODV) with Simeprevir (SMV) for 8 weeks. arm 2: Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV for 8 weeks. arm 3: Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV with SMV for 6 weeks. arm 4: Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV up to 8 or 12 weeks. arm 5: Treatment-naïve non-cirrhotic HCV-infected participants will receive AL-335 and ODV with SMV up to 8 or 12 weeks. arm 6: Treatment naïve or treatment experienced HCV-infected participants with compensated cirrhosis will receive AL-335 and ODV with SMV for 8 weeks. arm 7: Treatment naïve or treatment experienced HCV-infected participants with compensated cirrhosis will receive AL-335 and ODV with SMV for 12 weeks. arm 8: Based on safety, pharmacokinetic (PK), and viral load data, the treatment duration (4 to 12 weeks) and dose levels (AL-335: 400-1,200 milligram \[mg\], ODV: 25-50 mg with/without SMV: 75-150 mg) may be changed for ongoing and future cohorts (up to 15) after obtaining agreement from the Sponsor and the Principal Investigator.

Interventions: intervention 1: AL-335 intervention 2: Odalasvir (ODV) intervention 3: Simeprevir (SMV)
Intervention descriptions: intervention 1: AL-335 tablets will be administered in a dose range of 400 to 1200 mg once daily (QD). intervention 2: ODV capsules will be administered in a dose range of 25 to 50 mg. intervention 3: SMV tablets will be administered in a dose range of 75 to 150 mg QD or every other day (QOD).

Protocol document:
Prot_000.pdf: 
 
 
Alios BioPharma, Inc 
260 E. Grand Ave 
South San Francisco, CA 94080 
 
Protocol Number: AL-335-604 
 
A Phase 2a, Open-Label Study to Evaluate the Safety, Pharmacokinetics and Efficacy of the 
Combination of AL-335 and Odalasvir, with or without Simeprevir, in Treatment-Naïve  
Subjects with Genotype 1, 2 or 3 Chronic Hepatitis C infection with or without compensated 
Child Pugh A Cirrhosis 
 
Drug Names: AL-335, ACH-3102 (odalasvir), simeprevir 
IND Number: This is a Non-IND Study 
EudraCT Number: 2016‐002845‐46 
 
 
Date: 03 May 2017 
Version 10.0 
 
 
The information contained in this document is confidential. 
Written authorization from Alios BioPharma Inc is required for its disclosure. 
 
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AL-335 
Protocol No. AL-335-604 
Version 10.0, 03 May 2017 
 
Contact Information 
For up-to-date contact information, see Study Binder: Emergency Contact Sheet. 
All serious pretreatment and treatment-emergent adverse events, including pregnancies 
and suspected pregnancies,1 occurring from the time of consent up to 6 months after study drug 
administration is completed, regardless of relationship to study drug, must be reported via fax to 
the Sponsor’s designee within 24 hours of knowledge of the event. 
Please 
all Serious Adverse Event Forms to:
fax 
 
CRO Pharmacovigilance  
SAE Fax Number: 
 
SAE e-mail address: 
 
Telephone contact: 
 
 
 
Sponsor’s Medical Monitor 
 MD 
Sponsor’s Medical Monitor 
Telephone contact: 
Mobile: 
 
Desk: 
 
SAE Fax Number: 
 
Alios BioPharma 
SAE e-mail address: 
 
Please also FAX to the recipient identified in the study reference binder. 
 
Any fatal or life-threatening event, adverse event which triggers study treatment stopping 
criteria (Section 4.7.1), pregnancy or suspected pregnancy must also be reported within 
24 hours by telephone. 
 
 
1 See Sections 7.1.1 and 7.1.3 for the definitions of pretreatment adverse event and serious adverse event. 
Pregnancy itself does not constitute an adverse event. 
 
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AL-335 
Protocol No. AL-335-604 
Version 10.0, 03 May 2017 
 
Table of Contents 
 
CONTACT INFORMATION ............................................................................................... 2 
TABLE OF CONTENTS ...................................................................................................... 3 
IN-TEXT FIGURES .............................................................................................................. 7 
IN–TEXT TABLES ............................................................................................................... 7 
ABBREVIATIONS ................................................................................................................ 9 
LIST OF STUDY DRUGS AND METABOLITES .......................................................... 11 
DEFINITIONS ..................................................................................................................... 11 
SYNOPSIS ............................................................................................................................ 12 
1.0 
BACKGROUND AND RATIONALE ................................................................... 24 
1.1 
Background Information on Hepatitis C Virus .......................................................... 24 
1.2 
AL-335 Background .................................................................................................. 24 
1.2.1 
Clinical Experience for AL-335 With or Without ODV and SMV ............ 25 
1.3 
ODV Background ...................................................................................................... 32 
1.3.1 
Summary of Cardiac Safety in Animal Studies .......................................... 32 
1.3.2 
Previous Clinical Experience for ODV ...................................................... 33 
1.4 
SMV Background ...................................................................................................... 35 
1.4.1 
Previous Clinical Experience for SMV ...................................................... 36 
1.5 
Rationale for the Study and Study Design ................................................................. 38 
1.6 
Rationale for Permitting Women of Child Bearing Potential .................................... 38 
1.7 
Risk-Benefit Assessment ........................................................................................... 39 
2.0 
STUDY DESIGN ...................................................................................................... 40 
2.1 
Summary .................................................................................................................... 40 
2.2 
Study Schema............................................................................................................. 43 
3.0 
STUDY OBJECTIVES AND ENDPOINTS .......................................................... 45 
3.1 
Study Objectives ........................................................................................................ 45 
3.1.1 
Primary Objectives ..................................................................................... 45 
3.1.2 
Secondary Objectives ................................................................................. 45 
3.2 
Study Endpoints ......................................................................................................... 45 
3.2.1 
Primary Endpoint ........................................................................................ 45 
3.2.2 
Secondary Endpoints .................................................................................. 45 
4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................ 46 
4.1 
Study Population ........................................................................................................ 46 
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4.2 
Inclusion Criteria ....................................................................................................... 46 
4.3 
Exclusion Criteria ...................................................................................................... 49 
4.4 
Subject Screening and Enrollment ............................................................................. 51 
4.4.1 
Screening Examination ............................................................................... 51 
4.5 
Subject Completion .................................................................................................... 52 
4.6 
Subject Discontinuation ............................................................................................. 52 
4.6.1 
Subject Treatment Discontinuation Criteria ............................................... 52 
4.6.2 
Procedures for Subjects Who Discontinue Treatment ................................ 53 
4.6.3 
Withdrawal from the Study......................................................................... 53 
4.6.4 
Documentation of Discontinuation of Subjects .......................................... 54 
4.7 
Study Discontinuation ................................................................................................ 54 
4.7.1 
Study Treatment Stopping Criteria ............................................................. 54 
4.8 
Futility Criteria........................................................................................................... 55 
4.8.1 
Predefined Criteria to Determine the Futility of an Individual Treatment 
Regimen ...................................................................................................... 55 
5.0 
DOSING REGIMEN ............................................................................................... 56 
5.1 
Rationale for Dosage Selection .................................................................................. 56 
5.1.1 
AL-335 ........................................................................................................ 56 
5.1.2 
Simeprevir ................................................................................................... 56 
5.1.3 
Odalasvir ..................................................................................................... 57 
5.1.4 
Dosing Regimens for Patients With Mild (Child Pugh A) Cirrhosis ......... 57 
5.2 
Description of Study Drug and Background Therapy ............................................... 57 
5.2.1 
AL-335 ........................................................................................................ 57 
5.2.2 
Simeprevir ................................................................................................... 57 
5.2.3 
Odalasvir ..................................................................................................... 58 
5.3 
Dose Preparation and Administration ........................................................................ 58 
5.4 
Treatment Delay or Interruption ................................................................................ 58 
5.5 
Missed Doses ............................................................................................................. 58 
5.6 
Overdoses ................................................................................................................... 58 
5.7 
Dose Modifications .................................................................................................... 58 
5.8 
Ordering Study Drug.................................................................................................. 59 
5.9 
Drug Accountability................................................................................................... 59 
5.10 
Disposition of Used, Partially Used, and Unused Study Medication Containers ...... 59 
5.11 
Concomitant Medications .......................................................................................... 59 
5.12 
Prohibited Medications .............................................................................................. 60 
5.13 
Special precautions .................................................................................................... 61 
5.14 
Special Dietary Requirements.................................................................................... 62 
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6.0 
STUDY PROCEDURES ......................................................................................... 62 
6.1 
Schedule of Events ..................................................................................................... 62 
6.2 
On-study Evaluations and Procedures ....................................................................... 71 
6.2.1 
Pharmacokinetic Blood Sampling .............................................................. 71 
6.2.2 
Laboratory Evaluations ............................................................................... 72 
6.2.3 
HCV RNA Evaluations ............................................................................... 72 
6.2.4 
HCV Resistance Evaluation........................................................................ 72 
6.2.5 
12-Lead Electrocardiograms ....................................................................... 73 
6.2.6 
Echocardiograms ........................................................................................ 73 
6.2.7 
Vital Signs................................................................................................... 74 
6.2.8 
Physical Examinations ................................................................................ 74 
6.2.9 
Contraception .............................................................................................. 74 
7.0 
SAFETY MONITORING AND REPORTING .................................................... 74 
7.1 
Definitions.................................................................................................................. 74 
7.1.1 
Pretreatment Events .................................................................................... 74 
7.1.2 
Adverse Events ........................................................................................... 74 
7.1.3 
Serious Adverse Events .............................................................................. 75 
7.2 
Documenting and Reporting of AEs (including SAEs) ............................................. 75 
7.2.1 
Documenting and Reporting Pretreatment Events...................................... 75 
7.2.2 
Documenting and Reporting AEs ............................................................... 76 
7.2.3 
Assigning Attribution of AEs ..................................................................... 77 
7.2.4 
Classifying Action Taken With Study Drug ............................................... 77 
7.2.5 
Classifying AE Outcome ............................................................................ 77 
7.2.6 
Documenting and Reporting Serious Pretreatment Events and SAEs ........ 78 
7.2.7 
Documenting and Reporting of Pregnancy ................................................. 78 
7.3 
Follow-up of AEs and SAEs ...................................................................................... 78 
7.4 
Sponsor’s Review of AEs and SAEs ......................................................................... 79 
7.5 
Special Safety Considerations .................................................................................... 79 
7.5.1 
Creatine Kinase ........................................................................................... 79 
7.5.2 
Cardiotoxicity ............................................................................................. 80 
7.5.3 
Prolonged QTc (i.e., >500 msec or change from baseline of >60 msec) ... 82 
7.5.4 
Renal Safety Monitoring ............................................................................. 82 
7.6 
Rash (including photosensitivity conditions)............................................................. 82 
7.7 
Acute Allergic Reaction ............................................................................................. 86 
7.8 
Liver Function Tests .................................................................................................. 87 
7.9 
ALT, AST, and Bilirubin Elevations ......................................................................... 88 
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8.0 
STUDY VARIABLES AND MEASUREMENTS ................................................. 91 
8.1 
Safety Variables/Measurements ................................................................................. 91 
8.1.1 
Adverse Events ........................................................................................... 91 
8.1.2 
Clinical Laboratory Measurements ............................................................. 91 
8.1.3 
Prior and Concomitant Medications ........................................................... 92 
8.2 
Efficacy Variables/Measurements ............................................................................. 92 
8.2.1 
Virologic Response ..................................................................................... 92 
8.2.2 
On-Treatment Failure ................................................................................. 92 
8.2.3 
Relapse ........................................................................................................ 93 
8.3 
Viral Resistance ......................................................................................................... 93 
8.4 
PK Measurements ...................................................................................................... 93 
9.0 
STATISTICAL CONSIDERATIONS ................................................................... 93 
9.1 
General Considerations .............................................................................................. 93 
9.2 
Study Endpoints ......................................................................................................... 93 
9.2.1 
Primary Endpoint ........................................................................................ 93 
9.2.2 
Secondary Endpoints .................................................................................. 94 
9.3 
Determination of Sample Size ................................................................................... 94 
10.0 
STATISTICAL METHODS ................................................................................... 94 
10.1 
Study Population ........................................................................................................ 94 
10.1.1 
Subject Disposition ..................................................................................... 94 
10.1.2 
Replacement of Subjects ............................................................................. 95 
10.1.3 
Procedures for Handling Missing, Unused, or Spurious Data .................... 95 
10.2 
Analysis Populations .................................................................................................. 95 
10.2.1 
Safety and Efficacy Populations ................................................................. 95 
10.2.2 
Pharmacokinetic Population ....................................................................... 95 
10.2.3 
Per Protocol Population .............................................................................. 95 
10.3 
Demographics and Baseline Characteristics .............................................................. 95 
10.4 
Safety Analysis .......................................................................................................... 95 
10.4.1 
Adverse Events ........................................................................................... 95 
10.4.2 
Vital Signs, ECG, Physical Examination, and Laboratory Assessments.... 95 
10.4.3 
Concomitant Medications ........................................................................... 96 
10.5 
Pharmacokinetic Analysis .......................................................................................... 96 
10.6 
Pharmacodynamic Analysis ....................................................................................... 96 
10.7 
Efficacy Analysis ....................................................................................................... 96 
10.8 
Pooled Safety/Efficacy............................................................................................... 97 
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11.0 
ADMINISTRATIVE CONSIDERATIONS .......................................................... 97 
11.1 
Study Compliance ...................................................................................................... 97 
11.2 
Informed Consent and Protected Subject Health Information Authorization ............ 97 
11.3 
Subject Screening Log ............................................................................................... 98 
11.4 
Case Report Forms ..................................................................................................... 98 
11.5 
Study Monitoring Requirements ................................................................................ 98 
11.6 
Retention of Records.................................................................................................. 99 
11.7 
Long-Term Retention of Samples for Additional Future Research ........................... 99 
11.8 
Confidentiality and Publication Policy ...................................................................... 99 
11.9 
Conduct of Study and Protection of Human Subjects ............................................. 100 
12.0 
REFERENCES ....................................................................................................... 100 
13.0 
APPENDICES ........................................................................................................ 102 
 
In-text Figures 
Figure 2-1 
Study Schema ............................................................................................ 44 
 
In–text Tables 
Table 1-1. 
Completed, Initiated and Planned Cohorts^ (Cohorts 1-15), Including 
Available VK Data – As of 17 February 2017 .......................................... 28 
Table 1-2. 
Preliminary Mean (SD)* PK Parameters of AL-335 and its Metabolites 
(ALS-022399 and ALS-022227), ODV, and SMV at Week 2 up to 
Cohort 6 (AL-335-604 PK Substudies) .................................................... 31 
Table 2-1. 
Completed, Initiated, and Planned Cohorts^ with Available VK Data ..... 42 
Table 5-1. 
Concomitant Medication to be Administered With Caution .................... 60 
Table 5-2. 
Prohibited Medications ............................................................................. 61 
Table 6-1. 
Schedule of Events for 8 or 12*-Week Treatment Groups ....................... 63 
Table 6-2. 
Schedule of Events for a 6-Week Treatment Group ................................. 65 
Table 6-3. 
Schedule of Events for a 4-Week Treatment Group ................................. 67 
Table 6-4. 
Schedule of Events for Post-dosing (Safety and Virology) Follow-up 
Visits (All Treatment Cohorts).................................................................. 69 
Table 7-1. 
Guidelines for Subjects Developing Rash Grade 1 to Grade 4 ................. 83 
Table 7-2. 
Guidelines for Subjects Developing Allergic Reactions ........................... 86 
Table 7-3. 
Treatment-Emergent Grade 1 to Grade 4 ALT or AST Elevation and 
Grade 1 to Grade 4 Total Bilirubin Elevation ........................................... 89 
Table 7-4. 
Guidelines for Subjects Developing ALT and/or AST Elevations ........... 90 
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Protocol No. AL-335-604 
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Table 7-5. 
Guidelines for Subjects Developing Bilirubin Elevations ........................ 91 
 
 
 
 
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Protocol No. AL-335-604 
Version 10.0, 03 May 2017 
 
Abbreviations 
Term 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-τ 
Area under the plasma concentration-time curve during the dosing interval τ 
BMI 
Body mass index 
BP 
Blood pressure 
CHC 
Chronic hepatitis C 
CK 
Creatine kinase 
Cmax 
Maximum measured drug concentration 
CRF 
Case Report Form 
CYP 
Cytochrome P450 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECX 
X% maximal effective concentration 
EF 
Ejection fraction 
EOT 
End of treatment 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GT 
Genotype 
HAV 
Hepatitis A virus immunoglobulin 
IgM 
Immunoglobulin M 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
IC50 
50% inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International Normalization Ratio 
IRB 
Institutional Review Board 
kPa 
Kilo Pascal 
LFC 
liquid-filled capsule 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
No-observed-adverse-effect level 
NS 
Nonstructural protein 
ODV 
Odalasvir 
OTC 
Over the counter 
PegIFN 
Pegylated interferon 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
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Protocol No. AL-335-604 
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Term 
Definition 
qd 
Once daily 
qod 
Every other day 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMV 
Simeprevir 
SOC 
System Organ Class 
SUSAR 
Serious and Unexpected Adverse Reaction 
SVR 
Sustained virologic response 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to reach the maximum plasma concentration 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 
 
 
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AL-335 
Protocol No. AL-335-604 
Version 10.0, 03 May 2017 
 
List of Study Drugs and Metabolites 
Compound 
Number 
Alternative 
Compound ID 
Comment 
AL-335 
ALS-022335 
Investigational drug; Sp isomer; phosphoramidate prodrug of the uridine 
nucleoside analog ALS-022227 
ALS-022227 
– 
parent uridine nucleoside analog, major metabolite of AL-335 in systemic 
circulation  
ALS-022235 
– 
5’-triphosphate of ALS-022227 (NTP), active intracellular entity 
ALS-022399 
– 
major metabolite of AL-335 in systemic circulation 
Odalasvir 
ACH-0143102; ODV 
Investigational drug; HCV nonstructural protein 5A (NS5A) inhibitor 
Simeprevir 
SMV 
an oral HCV protease inhibitor for the treatment of hepatitis C 
NTP: nucleoside triphosphate. 
 
Definitions 
End of study: 
Week 24 Virology Follow-up Visit either after last planned dose date or, if virologic 
failure occurred prior to this date, after time of failure for the last subject treated 
End of treatment (EOT) 
Completion of dosing or premature discontinuation of treatment, whichever is earlier 
On-treatment Virologic 
Response 
HCV RNA results satisfying a specified threshold. 
The following thresholds will be considered at any timepoint: 
<LLOQ undetectable 
<LLOQ detectable 
<LLOQ undetectable/detectable 
Sustained 
Virologic 
Response (SVR) 
The subject has HCV RNA <LLOQ detectable or undetectable 4, 8, 12, 18 or 24 weeks 
after the actual end of study drug treatment. 
Failure (no SVR12) 
Subjects who did not achieve SVR12, including: 
• 
on-treatment failure (see below) 
• 
post-treatment failure, includes subjects with: 
o 
viral relapse (see below); 
o 
missing HCV RNA at timepoint of SVR12. 
On-treatment Failure 
Subjects who did not achieve SVR12 and with confirmed HCV RNA ≥LLOQ at the 
actual end of study drug treatment. Includes subjects: 
• 
With viral breakthrough, defined as a confirmed increase of >1 log10 in HCV RNA 
from nadir, or confirmed HCV RNA of >100 IU/mL in subjects whose HCV RNA 
had previously been <LLOQ while on treatment. 
• 
With Inadequate virologic response defined as <1 log10 decline from baseline in 
HCV RNA after 4 weeks of treatment 
• 
Who do not experience viral breakthrough or inadequate virologic response and have 
confirmed HCV RNA ≥LLOQ at the actual end of study drug treatment (e.g., 
completed study drug treatment, discontinued due to adverse events, withdrawal of 
consent). 
Viral Relapse 
Subjects who did not achieve SVR12, with HCV RNA <LLOQ at the actual end of study 
drug treatment and confirmed HCV RNA ≥LLOQ during follow up. 
HCV: hepatitis C virus; LLOQ: lower limit of quantitation; RNA: ribonucleic acid. 
 
 
 
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Synopsis 
A Phase 2a, Open-Label Study to Evaluate the Safety, Pharmacokinetics and Efficacy of 
the Combination of AL-335 and Odalasvir, with or without Simeprevir, in 
Treatment-Naïve Subjects with Genotype 1, 2 or 3  
Chronic Hepatitis C infection with or without compensated Child Pugh A Cirrhosis 
Protocol No. : 
AL-335-604 
Phase:  
2a 
Study Drugs: 
AL-335, Odalasvir (ODV), Simeprevir (SMV) 
IND Number: 
This is a non-IND study 
EudraCT No.: 
2016–002845–46 
Background 
Therapy: 
None 
Comparator:  
None 
Indication: 
Chronic hepatitis C (CHC) 
Study Design:  
This open-label study will assess the safety, pharmacokinetics and efficacy of 
an orally administered combination of AL-335 and ODV with or without 
SMV in treatment-naïve and treatment experienced subjects with CHC 
infection. Up to 320 subjects with CHC genotype (GT) 1, 2, or 3 infection 
will be enrolled to receive up to 1200 mg once daily (qd) of AL-335 in 
combination with ODV up to 50 mg qd or qod, with or without up to 150 mg 
qd SMV.  
Based on emerging safety, pharmacokinetic (PK), and efficacy data, the 
following study parameters may be changed for ongoing and future cohorts 
after obtaining agreement from the Sponsor and the Principal Investigator:  
• Treatment duration: 4-12 weeks 
• Dose levels: 
o 
AL-335: 400-1200 mg qd 
o 
ODV: 25-50 mg (dosed either qd or every other day [qod]) 
o 
SMV: 75-150 mg qd (if evaluated in a cohort) 
• Genotype: GT1 and/or GT2 and/or GT3; Cohorts may also be 
limited to specific subtypes (e.g., GT1a only) or may include all 
subtypes. 
• Cohort size: 10-20 subjects. In ongoing cohorts in which a dosing 
regimen is modified (e.g., treatment duration is extended) due to 
apparently insufficient efficacy/safety, the cohort size may be 
increased such that 20 subjects at the final dosing regimen are 
enrolled in that cohort.  
• Population: Treatment-naïve non-cirrhotic HCV-infected subjects 
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and treatment naïve or treatment experienced  HCV-infected 
subjects with compensated cirrhosis (decompensated cirrhosis 
prohibited) 
• Viral load: A viral load threshold may be included in determining 
eligibility for a cohort if higher viral loads are projected to have 
unacceptable efficacy. This threshold may be derived from 
emerging data (e.g., prior cohorts), medical literature, etc.  
• Number of cohorts: Up to a total of 16 cohorts (maximum 
N=320 subjects) with the above defined constraints may be enrolled. 
The planned study design is depicted in Figure 1.  
Figure 1– Study Design 
The initial 8-week treatment cohort (Cohort 1) will consist of at least 50% 
HCV GT1a. After 4 weeks of treatment in the 8 week treatment cohort, 
safety, viral load and available PK data from at least 16 of 20 subjects will be 
reviewed by the Sponsor in consultation with the Principal Investigator prior 
to initiation of enrollment of additional cohorts. If necessary, the review may 
be extended to include the full PK data set from the Week 2 intensive PK 
assessment.  
After the initial cohort (Cohort 1), subsequent cohorts may be enrolled 
concurrently or in a staggered fashion. Effective as of approval of protocol 
version 7, prior to evaluating a given treatment regimen in subjects with 
cirrhosis or for a shorter duration, efficacy, safety, and available PK data for 
that treatment regimen in subjects without cirrhosis and/or for a longer 
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duration will be reviewed. Specifically, data from at least 10 subjects at the 
SVR4 time point will be reviewed and, if acceptable (see Section 4.8), 
subsequent cohorts evaluating shorter durations and/or subjects with cirrhosis 
will be initiated. The timing of initiating enrollment in these subsequent 
cohorts will be coordinated such that SVR12 data from at least 10 subjects in 
the earlier cohort will be available before the end of treatment visit occurs for 
the first subject in the subsequent cohort. This timing is designed to enable 
extension of the treatment duration in the subsequent cohort if the earlier 
cohort is determined to have insufficient efficacy. 
Based on data available as of 17 February 2017, the following cohorts have 
been completed, initiated or are planned (Synopsis Table 1). Available viral 
kinetic (VK) data are also included in the table. Cohorts 6 through 12 are 
currently open for enrollment or planned at the time of this protocol 
finalization. The cohort regimens will only change if emerging data requires 
they be altered for safety purposes. Some planned cohorts may not be 
enrolled if emerging data are not supportive or suggest the cohort is not 
necessary to achieve the study’s objectives. 
Synopsis Table 1. 
Completed, Initiated, and Planned Cohorts^ with 
Available VK Data 
 
^N=10-20 per cohort; in any ongoing cohorts in which a dosing regimen is modified (e.g., 
treatment duration is extended) due to apparently insufficient efficacy/safety, the cohort 
size may be increased such that 20 subjects at the final dosing regimen are enrolled in that 
cohort  
 
This protocol permits enrollment of up to 16 cohorts. The maximum 
permissible enrollment in this study is up to 320 subjects. 
Safety and tolerability will be evaluated on an ongoing basis through 
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assessment of adverse events (AEs), blood and urine sample analyses, 
collection of electrocardiograms (ECG), echocardiograms, vital signs and 
physical examinations. PK data will be routinely reviewed as it becomes 
available.  
All enrolled subjects will be monitored from Day 1 through end of follow up 
for on treatment failure or relapse as defined by the criteria outlined in 
Sections 8.2.2–8.2.4, respectively. Where necessary, the Sponsor will offer 
appropriate retreatment within a separate protocol or, if the subject is unable 
or unwilling to participate in that trial, the Sponsor will provide 
reimbursement for locally available HCV treatment for any subjects that 
experience on treatment failure or relapse, subject to local regulations. See 
Section 2.0, Study Design, for additional information.  
PK samples will be obtained at a single time point prior to dosing at all 
routine study visits while subjects are receiving study medication as well as at 
Weeks 3 and 6, 2-4 hours postdose, and at Weeks 4 and 8, 6-8 hours 
postdose. In addition, for a subgroup of up to 250 subjects, additional PK 
samples will be obtained at Week 2 for all treatment groups.  
See Section 6.0 for details of Study Procedures. 
Objectives: 
The primary objective of this study is as follows: 
• To evaluate the safety and tolerability of AL-335 in combination with 
ODV with or without SMV in subjects with GT1 or GT2 or GT3 CHC 
infection 
The secondary objectives of this study are as follows: 
• To evaluate the efficacy of treatment with AL-335 in combination 
with ODV±SMV in subjects with GT1 or GT2 or GT3 CHC infection  
• To evaluate the pharmacokinetics of AL-335 (and metabolites), 
ODV±SMV in plasma 
• To evaluate the viral kinetics of HCV RNA in subjects with GT1 or 
GT2 or GT3 CHC infection treated with AL-335 in combination with 
ODV±SMV 
• To evaluate the effect of baseline host and disease-related 
characteristics on treatment outcome  
• To evaluate the impact of the presence of a nonstructural protein 
(NS) 3 polymorphism (e.g., Q80K; SMV-containing arms only) 
and/or NS5A and NS5B polymorphisms at baseline on treatment 
outcome  
• To evaluate the viral resistance profile after ≤12 weeks administration 
of AL-335 in combination with ODV±SMV. 
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Primary 
Endpoint: 
• Safety data, including but not limited to tabulation of AEs, physical 
exam, vital signs, 12-lead ECGs, echocardiograms, and clinical 
laboratory results (including chemistry, hematology, and urine)  
Secondary 
Endpoints: 
• The proportion of subjects who have a sustained virologic response 
(SVR; i.e., HCV RNA concentration below the lower limit of 
quantitation [<LLOQ; <15 IU/mL]) at 4, 8, 12, 18 and 24 weeks after 
the last actual dose of treatment 
• PK parameters for AL-335 (and metabolites), ODV and SMV in 
plasma 
• The proportion of subjects who experience virologic relapse during 
the follow-up period.  
• The proportion of subjects who have on treatment failure while 
receiving study medication 
• Viral kinetics, as determined at different timepoints during treatment 
by the proportion of subjects who achieve 
- HCV RNA <LLOQ undetectable 
- HCV RNA <LLOQ 
• Time to achieve undetectable HCV RNA and <LLOQ HCV RNA 
• The amino acid sequence of the NS5A, NS5B and NS3/4A proteins at 
baseline and post-baseline in subjects who fail treatment  
• Effect of various baseline and host disease-related characteristics on 
treatment outcome 
Duration of 
Treatment and  
Study Period: 
Up to 43 weeks (from screening through study completion) for each enrolled 
subject as follows: 
• Screening: Up to 50 days 
• Study Period: Up to 12 weeks 
• Follow-up: Up to 24 weeks after completion of study medications 
Number of Sites 
and Location: 
Up to 50 sites globally 
Sample Size: 
Up to 320 treatment-naïve and treatment experienced subjects with CHC 
infection will be enrolled in up to 16 cohorts. Since this is an exploratory 
study, no formal sample size calculation has been performed. A total sample 
size of 10-20 subjects/cohort is considered sufficient to explore the safety, 
pharmacokinetics, and efficacy of the possible study regimens in various 
HCV-infected subpopulations (e.g., GT1, compensated cirrhosis, etc). 
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Inclusion 
Criteria: 
Main Inclusion Criteria for All Subjects: 
1. Subject has provided written consent. 
2. In the Investigator’s opinion, the subject is able to understand and 
comply 
with 
protocol 
requirements, 
instructions, 
and 
protocol-stated restrictions and is likely to complete the study as 
planned. 
3. Male or female, 18–70 years of age. 
4. Body mass index (BMI) 18–35 kg/m2, inclusive.  
5. A woman of childbearing potential must have a negative serum 
(β-human chorionic gonadotropin) pregnancy test at screening.  
6. Female subjects must either: 
• not be of childbearing potential defined as:  
i. 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 (per reference laboratory), OR 
ii. Surgically sterile (e.g., underwent total hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation/bilateral 
tubal clips without reversal operation), or otherwise 
incapable of becoming pregnant, 
• OR 
i. 
be of childbearing potential AND 
ii. 
not heterosexually active (e.g., abstinent or homosexual) 
from 
screening 
until 
6 
months 
after 
study 
drug 
administration (or longer, if dictated by local regulations), 
OR 
iii. 
if heterosexually active  
o have a vasectomized partner (confirmed sterile per verbal 
account of the subject), OR 
o using an acceptable method of birth control from screening 
and agree to continue to use the same method of 
contraception throughout the study and for 6 months after 
study drug administration (or longer, if dictated by local 
regulations). Acceptable methods of birth control include: 
oral hormone-based contraceptives, an IUD, being either 
hormonal (i.e., IUS) or non-hormonal, other non-oral 
hormone-based contraception methods (e.g., injectable, 
implants, transdermal system, vaginal ring), or a double-
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barrier method (eg, male condom + either a diaphragm or 
cervical cap with or without spermicide).   Condom use by 
male partners with reproductive potential is required in all 
circumstances except when female subjects are using 
acceptable birth control methods which are long term in 
nature and do not require high degrees of compliance (e.g. 
IUDs, depot-form injectables, implants).     
o See also the NOTES regarding contraception considerations 
that apply to men and women at the bottom of Inclusion #7 
7. Male subjects must either: 
• 
be surgically sterile (had a vasectomy), or otherwise incapable 
of fathering a child, OR 
• 
not be heterosexually active (e.g., abstinent or homosexual) 
from enrollment (Day 1) in the study until at least 6 months 
after study drug administration, OR 
• 
if heterosexually active: 
o 
have a partner who is postmenopausal (2 years 
amenorrhea), surgically sterile (e.g., has had a total 
hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation/bilateral tubal clips without reversal operation), 
or otherwise incapable of becoming pregnant OR 
o 
be practicing an acceptable method of birth control from 
enrollment in the study (Day 1) and agree to continue to 
use the same method of contraception throughout the 
study and for at least 6 months after study drug 
administration (or longer, if dictated by local 
regulations). An acceptable method of birth control for 
male subjects is a double-barrier method (e.g., male 
condom+either diaphragm or cervical cap with or 
without spermicide).  
 
NOTE 1: Male subjects with a female partner who uses hormonal 
contraceptives (oral, injectable, implants) or a 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 2: 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. 
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NOTE 3: A male and female condom should not be used together 
due to risk of breakage or damage caused by latex friction. 
NOTE 4: Contraceptive use by men and 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 
8. Subjects must agree to refrain from sperm/egg donation from start 
of dosing through 6 months after the completion of study drug 
administration. 
9. GT1a or 1b or GT2 or 3 CHC, depending on cohort, with positive 
HCV antibody and a positive HCV RNA at screening including 
documentation of CHC infection for at least 6 months. Genotype 
testing must occur at a screening visit. NOTE: GT1 patients are 
eligible for inclusion even if they cannot be successfully subtyped 
unless a specific subtype is required for a cohort. 
10. Screening HCV RNA viral load ≥50,000 IU/mL, except for 
subjects with compensated cirrhosis (Child-Pugh Class A) who 
may have HCV RNA viral load ≥104 IU/mL. 
11. Treatment naïve (i.e., no prior exposure to any approved or 
investigational drug(s) including direct-acting antivirals, and 
interferon-based treatment regimens) or, in subjects with cirrhosis, 
treatment experienced (defined as subjects who experienced 
virologic relapse after receiving a full course of pegylated 
interferon+ribavirin (peg/riba) treatment).  Prior use of any direct 
acting antiviral in combination with peg/riba is not permitted. 
12. Fibroscan, collected within 6 months of baseline visit, with liver 
stiffness score ≤12.5 kPa to be eligible (except for subjects with 
cirrhosis, see below). 
• Subjects with compensated cirrhosis must meet the Child-Pugh 
Class A definition (see Appendix G) and at least one of the 
following criteria: 
i. Liver biopsy result indicating the presence of cirrhosis (e.g., 
Metavir F4; Ishak >5) or 
ii. Fibroscan evaluation with a liver stiffness score >12.5 kPa 
13. Subject is otherwise in good health as deemed by the investigator, 
based on the findings of a medical evaluation including medical 
history, physical examination, laboratory tests and ECG. 
14. Willing to avoid prolonged sun exposure and use of tanning 
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devices while taking SMV and through 4 weeks of follow up. 
Subjects should also be advised to use a broad-spectrum sunscreen 
and lip balm of at least sun protection factor >30 to help protect 
against potential sunburn. 
Exclusion 
Criteria:  
Subjects will be ineligible for this study if they meet any of the following 
criteria: 
1. Pregnant, planning on becoming pregnant (during treatment 
and up to 6 months 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 
6 months after the EOT) 
2. Other than CHC with or without compensated cirrhosis, 
clinically 
significant 
cardiovascular, 
respiratory, 
renal, 
gastrointestinal, hematologic, neurologic, thyroid or any other 
medical illness or psychiatric disorder, as determined by the 
Investigator and/or Sponsor’s Medical Monitor. 
3. History or other clinical evidence of significant or unstable 
cardiac disease (e.g., angina, congestive heart failure, 
myocardial infarction, diastolic dysfunction, significant 
arrhythmia, 
coronary 
heart 
disease, 
and/or 
clinically 
significant ECG abnormalities), moderate to severe valvular 
disease or uncontrolled hypertension at screening. 
4. Screening echocardiogram ejection fraction <55% or any 
other echocardiographic finding suggestive of clinically 
relevant cardiomyopathy. 
5. Creatinine clearance of <60 mL/min (Cockcroft-Gault). 
6. Positive test for HAV IgM, HBsAg, or HIV Ab.  
7. Abnormal screening laboratory results that are considered 
clinically significant by the investigator. 
8. History of clinical hepatic decompensation, e.g., variceal 
bleeding, spontaneous bacterial peritonitis, ascites, hepatic 
encephalopathy or active jaundice within the last year. 
9. Any condition that, in the opinion of the investigator, would 
compromise the study’s objectives or the well-being of the 
subject or prevent the subject from meeting the study 
requirements. 
10. Participation in an investigational drug trial or having 
received an investigational vaccine within 30 days or 
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5 half-lives (whichever is longer) prior to study medication. 
11. Clinically significant abnormal screening ECG findings (e.g., 
PR >200 msec, QRS interval >120 msec or corrected QT 
interval (QTc) >450 msec for male subjects and >470 msec 
for female subjects), based on an average of triplicate ECGs. 
Any evidence of heart block or bundle branch block is also 
exclusionary. 
12. History or family history of abnormal ECG intervals, for 
example prolonged QT syndrome (torsade de pointes) or 
sudden cardiac death. 
13. The subject has a positive prestudy drug screen, including 
methadone unless the drug is prescribed by the subject’s 
physician. The list of drugs that should be screened for 
includes 
amphetamines, 
barbiturates, 
cocaine, 
opiates, 
phencyclidine (PCP), and benzodiazepines. Drug use without 
a physician prescription may be permitted on a case by case 
basis after review by the Sponsor in consultation with the 
investigator. 
14. Laboratory abnormalities including: 
• 
Hematocrit <0.34 
• 
White blood cell counts <3,500/mm3 (<1,000/mm3 for 
subjects with compensated cirrhosis) 
• 
Absolute neutrophil count <1,000/mm3 (<750/mm3 for 
subjects with compensated cirrhosis) 
• 
Platelets ≤120,000/mm3 (platelets <70,000/mm3 for 
subjects with compensated cirrhosis) 
• 
Glycosylated hemoglobin (HbA1C) >55 mmol/mol or 
7.2% 
• 
Prothrombin time ≥1.5 × ULN 
• 
Albumin ≤32 g/L, bilirubin ≥1.5 mg/dL at screening 
(subjects with documented Gilbert’s disease allowed) 
• 
Serum ALT concentration ≥5× ULN 
• 
CK >1.5× ULN 
A single repeat laboratory evaluation under appropriate 
conditions (e.g., fasted, no antecedent exercise) is allowed for 
eligibility determination. 
15. Any 
condition 
possibly 
affecting 
drug 
absorption 
(e.g., gastrectomy or other significant gastrointestinal tract 
surgery, such as gastroenterostomy, small bowel resection, or 
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active enterostomy). 
16. Clinically significant blood loss or elective blood donation of 
significant volume (i.e., >500 mL) within 60 days of first dose 
of study drug; >1 unit of plasma within 7 days of first dose of 
study drug. 
17. Evidence of clinically relevant active infection that would 
interfere with study conduct or its interpretation. 
18. History of regular alcohol intake >10 standard drinks per 
week of alcohol for females and >15 standard drinks per week 
for males (one unit is defined as 10 g alcohol) within 
3 months of the screening visit. 
19. The use of prohibited medications, including prescription, 
over-the-counter (OTC) medications, herbal medications, 
inducers or inhibitors of CYP450 enzymes or drug 
transporters (including P-gp) within 14 days prior to the first 
dose of study medication is excluded, unless previously 
approved by the Sponsor’s Medical Monitor. NOTE: Chronic 
medication use is permitted so long as they are medically 
necessary, deemed acceptable by the Principal Investigator 
and Medical Monitor, and not Prohibited Medications (see 
Section 5.12).  
20. Hypersensitivity to the active substances (including sulfa 
allergy) or to any of the excipients of AL-335, ODV or SMV. 
21. Evidence on recent (within 6 months) liver ultrasound of 
hepatic mass or lesion concerning for malignancy (subjects 
with cirrhosis only). 
Dosage Form 
and Strength: 
AL-335 
will 
be 
supplied 
as 
100-mg 
and 
400-mg 
tablets. 
ODV will be supplied as film-coated 25-mg and 50-mg tablets. 
SMV will be supplied as 75-mg, 100-mg and150-mg capsules. 
Dose Regimen: 
Study medications will be administered (see Section 6.0) under fed 
conditions. Subjects will be advised to take oral qd doses of AL-335 and 
SMV (if applicable), and qd or qod doses of ODV, with approximately 
250 mL of room temperature, non-carbonated water. The treatment duration, 
dosing frequency, doses, genotypes, cohort size, and CHC subpopulation in a 
given cohort may be modified based upon review of emerging safety, efficacy 
and/or PK data (see Study Design, above). Cohorts 2–15 may or may not 
include SMV.  
Mean projected plasma exposures of ALS-022399, ALS-022227, and ODV at 
the 
doses 
selected 
in 
study 
cohorts 
will 
not 
exceed 
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no-observed-adverse-effect level (NOAEL) exposures obtained from 
nonclinical toxicology studies. SMV doses will not exceed the approved dose. 
Predosing and 
Concomitant 
Medications: 
None 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
Background Information on Hepatitis C Virus 
There are approximately 170 million people or 3% of the world’s population infected with 
hepatitis C virus (HCV) (World Health Organization, WHO) with more than 365,000 deaths per 
year resulting from long-term complications (Perz et al. 2006). Chronic hepatitis C (CHC) is the 
most common chronic liver disease in the United States and Europe and is the leading cause for 
liver transplantation in these regions. CHC infection results in a significant risk of developing 
long-term complications such as cirrhosis and hepatocellular carcinoma, although estimates for 
the progression rates vary. The risk of hepatic decompensation in subjects with cirrhosis is 
approximately 5% per year (Poynard et al. 1997) and the 5-year survival rate after 
decompensation is around 50% (Planas et al. 2004). 
1.2 
AL-335 Background 
AL-335 is a uridine base nucleoside monophosphate prodrug (or nucleotide analog) being 
developed as an orally administered anti-HCV therapeutic. AL-335 retains potent antiviral 
activity against all genotypes, including most HCV replicons that show resistance to other 
direct-acting antiviral agents. AL-335 is efficiently converted to ALS-022235, the active NTP, in 
human hepatocytes.  
Neither AL-335 (IC50 >100 µM at 37°C) nor its metabolites (IC50 >100 µM) blocked the human 
ether-a-go-go gene (hERG) potassium channel current at physiologically relevant concentrations. 
In the in vivo safety pharmacology studies, AL-335 did not have any central nervous 
system-related effects or respiratory effects in rats nor cardiovascular changes in dogs up to the 
highest doses tested (1000 mg/kg/day). In 14-day and 91-day repeat-dose toxicity studies, 
AL-335 was well tolerated in rats and dogs with no changes in hematology, serum chemistry, or 
histopathology up to 1000 mg/kg/day, the highest dose tested (the no-observed-adverse-effect 
level [NOAEL]). In rats, exposure to AL-335 was very low due to rapid degradation by 
esterases; however, plasma exposures of the metabolites ALS-022399 and ALS-022227 
increased with dose. In dogs, plasma exposure to all 3 analytes increased with increase in dose 
with no significant accumulation upon repeated dosing. At the NOAEL of 1000 mg/kg/day 
following 91 days of repeated dosing, the plasma exposures (AUC0-24) in rats and dogs, 
respectively, were below the limit of quantitation (BQL) and 2690 ng•h/mL for AL-335, 
1570 and 15,700 ng•h/mL for ALS-022399, and 5980 and 51,900 ng•h/mL for ALS-022227.  
In rat and rabbit embryo-fetal developmental studies, preliminary data indicate that AL-335 did 
not cause any changes in intrauterine growth or survival or fetal morphology at any dosage level 
up to the highest doses of 1000 and 300 mg/kg/day, respectively. In addition, preliminary data 
also indicated that AL-335 did not have any adverse effects/disturbances in the reproductive 
process from pre-mating to conception and from conception to implantation in rats up to the 
highest dose of 1000 mg/kg/day. This included identification of deficits in estrous cycling, tubal 
transport, implantation, and development of the pre-implantation stages of the embryo in the 
female and functional reproductive effects (alterations in libido and epididymal sperm 
maturation) in the male.  
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AL-335 is metabolized by esterases. It has demonstrated a low inhibition potential to CYPP450 
enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (IC50 
>26 µM). The metabolites, ALS-022399 and ALS-022227, also had low inhibition potentials to 
the above enzymes with IC50 >48 µM for ALS-022399 and IC50 >40 µM for ALS-022227. 
AL-335 and metabolites are not expected to cause drug–drug interaction with other drugs that are 
metabolized by CYPP450 enzymes. AL-335 is a substrate of P-glycoprotein (P-gp) transporter, 
but does not have the potential to inhibit P-gp or OATP1B1/1B3. The metabolites, ALS-022399 
and ALS-022227, are neither substrates nor inhibitors of P-gp, OATP1B1/1B3, OAT1/3 and 
OCT2 transporters. 
1.2.1 
Clinical Experience for AL-335 With or Without ODV and SMV 
1.2.1.1 
AL-335 Monotherapy 
As of 8 September 2016, the safety and pharmacokinetics of AL-335 monotherapy versus 
placebo as single ascending doses (SAD) administered orally ranging from 100-1,200 mg has 
been evaluated in 48 healthy volunteers in Parts 1 and 2 of Study AL-335-601. Safety and 
pharmacokinetic (PK) differences after receiving a 400-mg tablet in the fed versus fasted state 
were assessed in Part 2 of this study. In both of these Parts of the study, all doses of AL-335 
were well tolerated with only 3 treatment-emergent adverse events (TEAEs) being reported. All 
TEAEs (palpitations [N=1 event] and toothache [N=2 events in 1 subject]) occurred in 
AL-335-treated subjects (100 and 200 mg doses, respectively), however, none of these events 
were considered serious, severe in intensity, nor likely related to AL-335. No TEAEs were 
reported in subjects receiving single doses of AL-335 greater than 200 mg. Additionally, no 
clinically significant findings were observed with respect to clinical laboratory, vital signs, 
physical examination, Holter, or electrocardiogram (ECG) recordings.  
In the multiple ascending doses part of AL-335-601 (Part 3), as of 8 September 2016, 64 subjects 
with CHC infection (including subjects with genotype (GT) 1, 2, 3, and 4 infection without 
cirrhosis and subjects with GT1 infection with compensated cirrhosis) have received 7 daily 
doses of up to 1200 mg of AL-335 or placebo. Among these subjects, no treatment-emergent 
SAEs have been reported and only 1 TEAE (acute tonsillitis, placebo group) led to study drug 
discontinuation. Among the TEAEs (N=26) reported in subjects dosed with AL-335, 14, 7, and 1 
have been mild, moderate, or severe in intensity, respectively. The severe AE (CK elevation; 
peak 10× upper limit of normal [ULN]) occurred on Dosing Day 3 in a subject who received 
800 mg AL-335. The subject, who is a professional athlete, had an elevated creatine kinase (CK) 
1.9× ULN) at baseline and admitted to having exercised prior to the event. The subject’s CK 
elevations were asymptomatic and declined despite continued dosing and did not require 
discontinuation of study drug. The most commonly reported (≥2 events) TEAEs in subjects 
receiving AL-335 were: headache (7 events), hyperbilirubinemia (2 events), elevated alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) (2 events each, all of which occurred 
after completion of dosing in these CHC-infected subjects), drowsiness (2 events), and common 
cold (2 events). None of these AEs in AL-335-treated subjects occurred in a significant 
imbalance relative to subjects dosed with placebo, nor were any of these considered clinically 
significant enough to require intervention (e.g., premature discontinuation of study drug). No 
clinically significant ECG, laboratory, vital sign, or physical exam findings suggestive of a safety 
concern have been identified. No important differences in the safety profile of AL-335 were 
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identified between subjects infected with CHC in the presence or absence of compensated 
cirrhosis. 
In this study, the mean maximal reduction of HCV RNA after 7 days of dosing with 400 mg of 
AL-335 was -2.7 log10 IU/mL. The mean maximal reduction of HCV RNA after 7 days of dosing 
with 800 mg of AL-335 in GT1, 2, and 3 groups was -4.0, -4.5 and -4.8 log10 IU/mL, 
respectively. The mean maximal reduction of HCV RNA after 7 days of dosing with 1,200 mg of 
AL-335 in GT1 subjects was -4.5 log10 IU/mL (preliminary data). In subjects with GT1 and 
compensated cirrhosis, the mean maximal reduction after 7 days of dosing with 800 mg AL-335 
was -3.5 log10 IU/mL. No viral breakthrough was observed. 
With respect to pharmacokinetics, in Study AL-335-601, AL-335 was rapidly (half-life <1 hour) 
converted to ALS-022399 and subsequently to ALS-022227. PK data from the single ascending 
dose phase also demonstrate that plasma exposures of AL-335 and its metabolites ALS-022399 
and ALS-022227 (parent nucleoside), increased linearly up to the 800 mg dose; increases were 
less than dose proportional between the 800 and 1,200 mg doses, especially for ALS-022227 
which reached a plateau at 1,200 mg. Upon administration of AL-335 with high fat food in Part 2 
of the study, delayed time to reach the maximum plasma concentration (Tmax) was noted for all 
3 analytes. A slight increase in AL-335 and ALS-022399 area under the plasma 
concentration-time curve (AUC) was observed with no significant changes in maximum drug 
concentration (Cmax). Food did not affect Cmax or AUC of ALS-022227. Inter subject variability 
in plasma exposure for 3 analytes were reduced when AL-335 was administered with food.  
In the multiple ascending dose part of Study AL-335-601, following repeated 800 mg AL-335 
administrations in subjects with differing genotypes, no difference was observed in the exposure 
for AL-335, ALS-022399 or ALS-022227. Consistent with SAD findings, a less than 
dose-proportional increase in AL-335, ALS-022399 and ALS-022227 exposure was observed 
between 800 mg qd and 1,200 mg qd. For subjects with CHC GT1 infection with compensated 
cirrhosis, an increase in Cmax and AUC0-last for AL-335 (~30% to 40%) and ALS-022399 (~20%) 
was seen compared to the CHC GT1-, 2- and 3-infected subjects without compensated cirrhosis. 
1.2.1.2 
AL-335 in Combination With ODV and SMV 
Study AL-335-602  
The safety and pharmacokinetics of multiple doses of varying combinations of AL-335, ODV, 
and SMV was assessed in 32 healthy volunteers in Study AL-335-602. Subjects were 
administered on a daily basis at least one of the following compounds: 800 mg AL-335, 150 mg 
SMV, and/or ODV, given as a 150 mg LD on the first day of treatment followed by a 50 mg 
maintenance dose on subsequent days. All subjects were dosed with study drugs for a total 
duration of 23 days. 
Among enrolled subjects, no treatment-emergent serious adverse events (SAEs) were reported. 
Only 1 TEAE (tooth abscess, assessed as unrelated to study drugs) resulted in treatment 
discontinuation. All reported TEAEs (N=20) were mild (N=14) or moderate (N=6) in severity. 
The most commonly reported TEAEs (i.e., ≥2 events) were fatigue (N=8 events) and soft stools 
(N=3 events), none of which were considered clinically concerning or required medical 
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intervention (e.g., concomitant medication). No clinically significant laboratory, ECG, vital sign, 
or physical exam findings suggestive of a safety concern have been identified. 
AL-335 had no impact on either SMV or ACH 3102 exposures. ODV increases SMV exposures 
by approximately 1.8-fold. SMV increases ODV exposure by 1.5-fold. Co-administration of all 
3 drugs resulted in significant increase in AL-335 exposures (7- to 8-fold) and metabolite 
ALS-022399 (2.6- to 2.8-fold) and slight increase in ALS-022227 (1- to 1.1-fold), as well as a 
1.6-fold increase in both SMV and ODV exposures.  
Study HPC1001: Drug drug interaction with oral contraceptives  
Effect of steady-state AL-335, ODV and 3 DAA combination (SMV+AL-335 +ODV) on single 
dose pharmacokinetics, safety and tolerability of oral contraceptives (drosperinone and ethinyl 
estradiol) was assessed in 24 healthy subjects.  Preliminary results indicate that there was no 
effect of AL-335, ODV or 3 DAA combination on the pharmacokinetics of drosperinone.  
Ethinyl estradiol pharmacokinetics were not impacted by AL-335 or ODV. There was a slight 
increase in ethinyl estradiol exposure (Cmax 29% and AUC 19%) with the 3 DAA combination. 
Therefore the 3DAA combination is not considered to affect the efficacy of oral contraceptives 
and no dose-adjustment is required.   
Study AL-335-604 
As of 6 February 2017, 123 CHC subjects have received at least one dose in Cohorts 1, 1b, 2 and 
3 (N=20/cohort) and in Cohorts 4 (n=13), 5 (n=19) and 6 (n=11) in Study AL-335-604. Actual 
dosing regimens in these cohorts and available viral kinetic (VK) data at posttreatment visits (as 
of 17 February 2017) are defined in Table 1-1.  
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Table 1-1. 
Completed, Initiated and Planned Cohorts^ (Cohorts 1-15), Including 
Available VK Data – As of 17 February 2017 
 
^ N=10-20 per cohort; In any ongoing cohorts in which a dosing regimen is modified (e.g., treatment duration is 
extended) due to apparently insufficient efficacy/safety, the cohort size may be increased such that 20 subjects at 
the final dosing regimen are enrolled in that cohort. TBD: to be determined  
 
In this study, two treatment-emergent SAEs were reported. One event, which occurred in 
Cohort 1b, was transition cell carcinoma of the urethra, which was identified during the trial 
when the subject reported a history of recurrent urinary tract infections and macroscopic 
hematuria, both of which began prior to enrollment in the study. This event was considered 
unrelated to study drug. A second event, Mobitz Type I 2nd degree AV block, occurred in a 
subject in Cohort 1 with a mean PR of 204 msec at baseline that then became progressively 
longer. After 5 weeks of daily dosing with 400 mg AL-335, 50 mg ODV, and 100 mg SMV, she 
developed Wenckebach phenomenon. The subject had no cardiac history, and was not taking any 
systemic concomitant medications. The Investigator indicated that she was asymptomatic during 
the course of this event. A cardiac evaluation, including clinical assessment by a cardiologist, 
CK assessments, and echocardiograms (at baseline, after 4 weeks’ dosing, at time of study drug 
discontinuation, and 4 weeks after discontinuing study drug) were all unremarkable. This PR 
prolongation/Wenckebach event was considered probably attributable to ODV (events similar to 
this have been reported in other studies of ODV), but was also considered possibly related to 
SMV and AL-335. Due to the progressive nature of the subject’s PR prolongation and the need 
for combination therapy to minimize emergence of viral resistance, all 3 study drugs were 
discontinued in this subject at Week 5. After discontinuing study drugs, the subject’s 
Wenckebach/progressive PR prolongation resolved with a return to her baseline PR interval. A 
second subject had a baseline elevated PR interval (~240 msec) which did not change 
significantly in the presence of dosing, however, in light of the SAE described above, as a 
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precaution, ODV was discontinued in this subject. These are the only 2 subjects that have 
prematurely discontinued study drug.  
As of 6 February 2017, a total of 336 TEAEs have been reported in Study AL-335-604, all of 
which were mild (N=306) or moderate (N=30) in severity. The most commonly reported 
(≥6 events) events were: contusion, cough, diarrhea, fatigue, headache, back pain, and upper 
respiratory tract infection. Among the subset of subjects with cirrhosis that have received at least 
one dose of study drugs (N=11), study treatment has been well tolerated with 48 TEAEs 
reported: all of which were mild (N=43) or moderate (N=5). There were no commonly reported 
events (≥6 events) at the time of this protocol amendment.  With the exception of the single 
observed case of progressive PR prolongation with resulting Wenckebach phenomenon 
described above, no clinically significant echocardiogram, ECG, laboratory, vital sign, or 
physical exam findings suggestive of a safety concern have been identified. Additionally, no 
important differences in the safety profile of AL-335 have been identified between subjects 
infected with CHC in the presence or absence of compensated cirrhosis. 
With respect to efficacy, a description of available SVR data in ongoing Study AL-335-604 is 
presented in Table 1-1.  
In Cohorts 1b and 4, both evaluating the combination of AL-335 and ODV without SMV 
(2DAA) for 8 weeks in non-cirrhotic treatment-naïve genotype 1 HCV-infected subjects, 
4 subjects, (N=2 in Cohort 1b, N=2 in Cohort 4) have experienced virologic relapse to date. In 
the 2 relapse subjects from Cohort 1b, sequencing has identified the emergence of mutations in 
the HCV NS5A gene known to confer resistance to ODV (M28T in combination with T64A in 
Subject 
 and Y93H in combination with T21A in Subject 
) but no emerging 
mutations in the HCV NS5B gene associated with AL-335 resistance were observed. Sequencing 
data are not yet available for the relapse subjects in Cohort 4. Based on the first 3 cases of 
virologic relapse in 2DAA-containing regimens, a decision was made to stop further enrollment 
in Cohort 4, in which 13 subjects had been enrolled. At the time this decision was made, 
8 subjects in Cohort 4 were still on treatment and, in an effort to minimize further cases of 
virologic relapse in these subjects receiving 2DAA, the treatment duration was extended from 
8 to 12 weeks. The subjects in Cohort 4 who had already completed treatment by the time this 
decision was made continue to be closely monitored. In Cohort 5, which is still ongoing, the 
duration of treatment was increased from 8 to 12 weeks in response to initial antiviral data 
suggesting that longer treatment might be more appropriate for this population.  
Preliminary data from the PK substudy up to Cohort 6 (as of 17 February 2017) are provided in 
Table 1-2. Increasing the dose of AL-335 from 400 mg (Cohort 1) to 800 mg in patients without 
cirrhosis (Cohorts 1b to 4) increased AL-335 and its metabolites (ALS-022399, monophosphate 
precursor, and ALS-022227, parent nucleoside) exposures in a less than dose-proportional 
manner. The exposures of the parent nucleoside metabolite ALS-022227 at the 800-mg dose in 
this study were similar to those previously observed at the 800-mg dose level in study AL-335-
601, , at which AL-335 demonstrated potent viral activity over a 7 day period.  There was no 
apparent difference in AL-335 and its metabolites’ exposures in patients with compensated 
cirrhosis (Cohort 6), although limited PK data are currently available. (n=5) . ODV exposure in 
Cohort 1 (mean Cmax and C24h were 636 and 384 ng/mL, respectively) was ~2- to 2.5-fold higher 
than observed in previous studies in which ODV was found to be highly efficacious 
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(Study ACH102-017: mean Cmax and Ctrough were 182 and 119 ng/mL, respectively, in Group 1 
and 215 and 133 ng/mL, respectively, in Group 2). ODV exposures decreased in proportion to 
the change in dosing administration (from qd in Cohort 1 to qod in Cohorts 1b, 2, and 3).  
Available PK data from Cohort 6 (N=6), indicated that the observed range of ODV exposures 
were similar in compensated cirrhotic patients (Cohort 6) compared to non-cirrhotic patients on 
the same dosing regimen (Cohorts 2 and 3). A less than dose-proportional decrease in SMV 
exposure levels was observed when decreasing the dose of SMV from 100 mg (Cohort 1) to 
75 mg (Cohorts 2 and 3). Exposures at the SMV 75-mg dose were generally consistent with 
those previously found to be efficacious (TMC435-C205). SMV exposures were similar in 
compensated cirrhotic patients (Cohort 6) compared to non-cirrhotic patients on the same dosing 
regimen (Cohorts 2 and 3). 
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Table 1-2. 
Preliminary Mean (SD)* PK Parameters of AL-335 and its Metabolites 
(ALS-022399 and ALS-022227), ODV, and SMV at Week 2 up to Cohort 6 
(AL-335-604 PK Substudies) 
Cohort 
Dosing Regimen 
Analytes 
Cmax  
(ng/mL) 
AUC0-24h 
(ng•h/mL) 
Tmax  
(h) 
1 
(N=11) 
AL-335 400 mg qd+ODV 50 mg qd 
+SMV 100 mg qd 
ALS-022335 
415 (318) 
1,043 (895) 
2 (0.5-4) 
ALS-022399 
104 (52) 
467 (224) 
3 (1-6) 
ALS-022227 
364 (129) 
2,916 (1,028) 
4 (2-4) 
SMV 
1,928 (1,205) 
25,025 (15,228) 
6 (4-12) 
ODV 
636 (261) 
11,809 (4,918) 
6 (4-12) 
1b 
(N=8) 
AL-335 800 mg qd+ODV 50 mg qod 
for 8 weeks 
ALS-022335 
533 (256) 
1,166 (552) 
3 (1-4) 
ALS-022399 
139 (53) 
606 (212) 
3 (2-4) 
ALS-022227 
355 (144) 
2,910 (824) 
4 (3-6) 
SMV 
NA 
NA 
NA 
ODV 
344 (177) 
5,407 (2,965) 
6 (4-12) 
2 
(N=3) 
AL-335 800 mg qd+ODV 50 mg qod 
+SMV 75 mg qd for 8 weeks 
ALS-022335 
734 (863) 
2,062 (2,851) 
2 (1-4) 
ALS-022399 
184 (147) 
1,088 (963) 
3 (2-4) 
ALS-022227 
644 (227) 
5,417 (1,922) 
4 (3-6) 
SMV 
1,031 (815) 
14,415 (12,274) 
6 (6-6) 
ODV 
259 (184) 
4,416 (2,945) 
9 (9-9) 
3 
(N=6) 
AL-335 800 mg qd+ODV 50 mg qod 
+SMV 75 mg qd for 6 weeks 
ALS-022335 
631 (370) 
1,499 (920) 
1 (1-2) 
ALS-022399 
180 (73) 
864 (375) 
3 (2-3) 
ALS-022227 
641 (113) 
5,026 (1,436) 
3 (2-4) 
SMV 
1,566 (1,160) 
22,681 (20,159) 
6 (4-9) 
ODV 
425 (104) 
7,087 (2,132) 
6 (6-9) 
4 
(N=1) 
AL-335 800 mg qd+ODV 50 mg qod 
for 8 or 12 weeks 
ALS-022335 
674 
1753 
3 
ALS-022399 
176 
932 
4 
ALS-022227 
554 
5155 
6 
SMV 
NA 
NA 
NA 
ODV 
148 
1939 
6 
5 
(N=0) 
AL-335 800 mg qd+ODV 50 mg qod 
+SMV 75 mg qd for 8 or 12 weeks 
ALS-022335 
ND 
ND 
ND 
ALS-022399 
ND 
ND 
ND 
ALS-022227 
ND 
ND 
ND 
SMV 
ND 
ND 
ND 
ODV 
ND 
ND 
ND 
6 
(N=5) 
AL-335 800 mg qd+ODV 50 mg qod 
+SMV 75 mg qd for 8 weeks in 
patients with compensated cirrhosis 
ALS-022335 
561 (283) 
1131 (652) 
1 (1-1) 
ALS-022399 
159 (63) 
655 (213) 
2 (1-3) 
ALS-022227 
633 (355) 
4756 (1867) 
3 (2-6) 
SMV 
1853 (959)  
27677 (16008) 
6 (4-6) 
ODV 
248 (206) 
4215 (3018) 
6 (3-9) 
*Tmax: median (range) 
NA = not applicable; ND = no data 
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Additional information regarding AL-335 is available in the AL-335 Investigator’s Brochure and 
Addendum.  
1.3 
ODV Background 
ODV is a nonstructural protein 5A (NS5A) inhibitor being developed as an orally administered 
anti-HCV therapeutic. ODV has demonstrated potent antiviral activity against all genotypes, 
including HCV replicons that show resistance to other HCV NS5A inhibitors. 
ODV has demonstrated a low inhibition potential for CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5. ODV is primarily cleared by biliary secretion, is not 
significantly metabolized, and is not expected to be involved with clinically significant 
drug-drug interactions associated with the CYP450 enzyme system. ACH is not a substrate or 
inhibitor of transporters such as MDR1 (P-gp), OATP1B1/1B3, OAT1/3, OCT2, BCRP, MRP2, 
MRP3, and BSEP. 
No clinically significant drug-drug interaction was observed between ODV and sovaprevir, 
montelukast, 
atazanavir/ritonavir, 
efavirenz/emtricitabine/tenofovir 
disoproxil 
fumarate, 
darunavir/ritonavir, or raltegravir. 
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.  
1.3.1 
Summary of Cardiac Safety in Animal Studies 
In vivo, no cardiac effects occurred at exposure levels (Cmax and AUC) about 6 times the target 
clinical exposure of ODV (when administered at a dose of 25 mg qd in combination with SMV 
75 mg qd and AL-335 800 mg qd). After repeated dosing of ODV in rats and dogs with exposure 
levels (Cmax and AUC) 14 times the target clinical exposure, increased heart weights were noted. 
In repeated dose studies in the dog, administration of ODV, at similar exposure levels, was 
associated with ECG changes (prolonged PR intervals and/or 1st degree AV block, prolonged 
QRS and QT intervals) and decreased heart rate. Echocardiography was performed in the 
26-week toxicity study in the dog and revealed progressive left ventricular dilatation, eccentric 
hypertrophy and minor reduction 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. 
Evaluation of the results from an additional 8-week repeat dose (70 mg/kg orally) mechanistic 
study in the telemetered dog is currently ongoing. In this study, ODV was administered at a dose 
corresponding to approximately 200 times a 25-mg dose in humans. Preliminary data showed a 
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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. The clinical relevance of these 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). 
1.3.2 
Previous Clinical Experience for ODV 
In clinical studies of ODV, including administration of single 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 (LD) on Day 1, but ODV has been used successfully without a 
LD in a recent Phase 2a study, ACH102-017.  
Odalasvir has been studied in combination with other anti-viral agents such as RBV, sovaprevir, 
and sofosbuvir, and has been well-tolerated in each of these settings. Specifically, after single 
(Studies ACH102-001, ACH102-003, ACH102-010, ACH102-015, ACH102-020) and multiple 
dosing (Studies ACH102-001, ACH102-008, ACH102-009, ACH102-011, ACH102-012, 
ACH102-013 and ACH786-001) of ODV in healthy volunteers and single (Study ACH102-002) 
and multiple dose studies in HCV-infected subjects (Studies ACH102-005 and ACH102-007), no 
dose-related trends in treatment-emergent AEs were observed. In placebo-controlled studies in 
healthy volunteers, no differences in the frequency of treatment-emergent AEs (preferred terms) 
were observed between the active treatment and the placebo group. In a placebo-controlled study 
in chronic hepatitis C (CHC)-infected subjects (Study ACH102-007), headache, nausea, bilirubin 
increases, and anemia were safety findings that occurred more frequently in subjects treated with 
ODV (150 mg LD followed by 50 mg qd)+sovaprevir (200 or 400 mg qd) + RBV (1,000 or 
1,200 mg/day; twice daily [bid] regimen) treatment compared to placebo-treated subjects. 
However, these are known to occur with RBV administration and none led to permanent 
treatment discontinuation. RBV dosing was interrupted or the dose was reduced in 5 (6.6%) 
subjects on active treatment. 
Overall, in the approximately 440 ODV-treated subjects with data available as of 
21 March 2016, the majority of treatment-emergent AEs were Grade 1 or 2 in severity. No 
Grade 4 treatment-emergent AEs have been reported. Five Grade 3 treatment-emergent AEs 
were reported in 4 subjects. One healthy volunteer (Study ACH102-009) experienced a Grade 3 
asymptomatic elevation of aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT; 519 and 518 U/L, respectively), which were considered probably related to ODV, and led 
to study drug discontinuation. Another healthy volunteer (Study ACH102-001) experienced a 
Grade 3 elevation of creatine phosphokinase (7,729 U/L), which was considered unrelated to 
ODV. A Grade 3 worsening of anemia and Grade 3 Wenckebach phenomenon was reported in 
Study ACH102-005 in subjects with CHC. Both events were considered unrelated to ODV by 
the investigator and did not lead to study drug discontinuation. Except for the above mentioned 
subject in Study ACH102-009, no subjects discontinued ODV treatment due to an AE in any of 
the studies. 
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Overall, SAEs were reported in 3 subjects that were dosed with ODV in studies outside of the 
current study. One healthy volunteer, who received a single 600 mg dose of ODV during Study 
ACH102-001 developed a gastroenteritis, which was considered unrelated to ODV, requiring 
hospitalization. One subject with CHC who had received ODV (150 mg LD; 50 mg maintenance 
dose) + sovaprevir (400 mg) + RBV (weight-based 1,000 or 1,200 mg dose) in Study ACH102-
007 experienced chest pain on Day 15. The subject was hospitalized for cardiac evaluation, 
which was negative. A third subject experienced an SAE of intervertebral disc protrusion that 
occurred more than 28 days after the end of treatment (EOT) visit in Study ACH102-017, and 
was considered unrelated to ODV and sofosbuvir. 
Cardiac Safety 
In the placebo-controlled studies ACH102-001, ACH102-002 and ACH786-001 in healthy 
volunteers and ACH102-007 in CHC-infected subjects, no notable trends in mean cardiac 
intervals and durations over time as compared with placebo were noted for ODV dosing groups. 
However, in the multiple-dose, placebo-controlled portion of Study ACH102-001, in healthy 
volunteers, PR categorical outliers were noted only in higher dose ODV groups. A total of 4 of 
32 (12.5%) subjects who received ODV had treatment-emergent PR values >200 msec, as 
compared with none of the eight subjects that received placebo. When ODV was co-administered 
with deldeprevir (also known as ACH-0142684), an investigational HCV protease inhibitor, in 
Study ACH786-001, a higher number of subjects with PR >200 msec was noted in the active 
treatment groups (N=7; 2 subjects during ACH-0142684 monotherapy, 2 subjects during ODV 
monotherapy, and 3 subjects during ACH-0142684 + ODV treatment) as compared with 
placebo(N=0). 
Electrocardiogram cardiac monitoring in Phase 1b/2a studies ACH102-005 and ACH102-007 in 
HCV-infected subjects did not identify any clinically significant trends in ECG parameters. In 
contrast to the placebo-controlled studies in healthy volunteers, no trends in PR categories or 
other ECG findings were noted with weekly ECG monitoring in the placebo-controlled, 12-week 
sovaprevir/RBV co-administration study (ACH102-007) in CHC-infected subjects. Cardiac 
monitoring in Study ACH102-005 in HCV-infected subjects did not identify any clinically 
significant trends in ECG parameters. In Study ACH102-005 one treatment-emergent PR 
prolongation was observed; by Week 12 this event had evolved to a transient type 1 
second-degree AV block (Wenckebach). 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.  
Echocardiograms were performed in Study ACH102-007. There were no clinically significant 
echocardiogram findings and no treatment-related trends in echocardiographic parameters. 
Efficacy 
A summary of antiviral effect and efficacy data of ODV from clinical studies with ODV as 
monotherapy and ODV in combination with DAAs other than AL-335±SMV is provided below.  
In Study ACH102-002, 18 subjects with GT HCV infection were administered single doses of 
ODV, and the mean (range) maximal HCV RNA decrease from baseline (log10 IU/mL), was 4.04 
(3.32 to 4.62) in the 25 mg dose group, 3.78 (3.35 to 4.16) in the 50 mg dose group, 3.52 (2.91 to 
3.98) in the 150 mg dose group, and 3.93 (3.40 to 4.60) in the 300 mg dose group. 
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In Study ACH102-005, 8 subjects with GT1b HCV infection and interleukin 28B (IL28B) 
genotype CC were administered ODV as 225 mg LD followed by 75 mg qd and weight-based 
RBV (1,000 or 1,200 mg daily) for 12 weeks. Six out of 8 subjects had a rapid decline in HCV 
RNA with HCV RNA <lower limit of quantification (LLOQ) by Week 3, with maintenance of 
viral suppression through the EOT at Week 12. Of these 6 subjects, 5 achieved SVR 4 weeks 
after planned EOT (SVR4), 4 achieved SVR 12 weeks after planned EOT (SVR12), and 
3 achieved SVR 24 weeks after planned EOT (SVR24). The remaining 2 subjects had a slower 
but continuous decline in HCV RNA over the 12-week treatment period with HCV RNA 
>LLOQ at EOT. There were no instances of on-treatment viral breakthrough in this study. 
Study ACH102-007 was a study in treatment-naïve subjects with GT1 HCV infection (8 GT1b 
and 12 GT1a-infected subjects) who received ODV (150 mg LD on Day 1 followed by a 50 mg 
qd dose) in combination with weight-based RBV, and sovaprevir (200 mg in Group 1; 400 mg in 
Group 2) for 12 weeks. For both Group 1 and Group 2, administration of sovaprevir, ODV and 
RBV resulted in a rapid virologic response with HCV RNA <LLOQ by Week 1-2 in all active 
subjects who received at least 2 weeks of study drugs, while placebo subjects had little or no 
change in HCV RNA. Of the 12 GT1a-infected subjects overall, 7 subjects (58.3%) had 
undetectable HCV RNA by Week 4 (rapid virologic response [RVR]). Seven GT1a-infected 
subjects experienced virologic failure with viral breakthrough in 6 subjects and relapse in 
1 subject. In addition, 1 subject withdrew consent at Week 1 (personal reasons) resulting in a 
SVR4, SVR12 and SVR24 of 33% in HCV GT1a-infected subjects. Of the 8 GT1b-infected 
subjects, all subjects (100%) had undetectable HCV RNA at Week 4 and at Week 12 and 
achieved SVR4, SVR12 and SVR24.  
Study ACH102-017 was a Phase 2, open-label, randomized, controlled, partial crossover study 
to evaluate the efficacy, safety, and tolerability of 8 weeks (Group 1) or 6 weeks (Group 2 and 
Group 3) of ODV (50 mg qd; fasted; without LD) and SOF (400 mg qd) in treatment-naïve 
subjects with GT1 HCV infection. All subjects (N=30) on active treatment in Group 1 (8-week 
treatment) Group 2 and Group 3 (6-week treatment) achieved SVR12 and SVR24, i.e., 
12 subjects achieved SVR24 after 8 weeks of treatment with SOF and ODV and 18 subjects 
achieved SVR24 after 6 weeks of treatment with SOF and ODV. The efficacy data suggest the 
adequacy of the 6-week regimen with the combination of ODV and SOF. 
A complete summary of the clinical characteristics of ACH-0143102 and clinical data obtained 
with regimens not including AL-335 co-administration can be found in the Investigator’s 
Brochure and Addenda. 
1.4 
SMV Background 
SMV is an orally active, small molecule inhibitor of the NS3/4A protease of HCV and indicated 
for the treatment of GT1 and GT4 chronic HCV infection, including subjects with Child Pugh A 
cirrhosis, as a component of a combination antiviral treatment regimen. SMV is available as a 
hard capsule for oral administration. The recommended dose is one 150 mg capsule taken qd 
with food. Each capsule contains 154.4 mg of SMV sodium salt, which is equivalent to 150 mg 
of SMV. The capsules contain the following inactive ingredients: colloidal anhydrous silica, 
croscarmellose sodium, lactose monohydrate, magnesium stearate, and sodium lauryl sulphate. 
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SMV is highly protein-bound in plasma (>99.9%) at pharmacologically relevant concentrations. 
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, the Tmax was 4 to 
6 hours. 
In CHC GT1-infected subjects, the exposure was generally greater than observed in healthy 
subjects. In subjects with CHC, the terminal elimination half-life was approximately 41 hours, a 
profile that supports a qd dosing regimen. Renal clearance plays an insignificant role in the 
elimination of SMV and its metabolites. 
A number of Phase 1 PK and drug-drug interaction studies have been conducted with SMV and 
are summarized in the Investigator’s Brochure including the following: the SMV-methadone 
interaction study (C110) that demonstrated no interaction between SMV and methadone and the 
thorough QT interval corrected for heart rate (QTc) study (Study C117) that demonstrated no 
effect of SMV upon the QT interval in humans. 
Cytochrome P450 (CYP) 3A enzymes are mainly involved in the metabolism of SMV, so plasma 
concentration will significantly increase if taken with medications that are strong CYP3A4 
inhibitors (e.g., macrolides, azole antifungal agents, ritonavir) and will significantly decrease if 
taken with strong CYP3A4 inducers (e.g., efavirenz, rifampicin). Hepatic uptake of SMV is 
mediated by OATP1B1, inhibitors of this transporter may increase plasma concentrations of 
SMV (e.g., cyclosporine). 
SMV is a mild inhibitor of intestinal (but not hepatic) CYP3A activity and a mild inhibitor of 
CYP1A2, which is only relevant for drugs solely metabolized by these enzymes, and having a 
narrow therapeutic index (e.g., certain anti-arrhythmics). In addition, drug-drug interaction 
studies with transporter substrates suggest that SMV is a mild inhibitor of P-gp and a moderate 
inhibitor of organic anion-transporting polypeptide (OATP)1B1 in vivo. Thus, co-administering 
SMV with medications that are substrates for P-gp or OATP (such as statins) may lead to 
increased plasma concentrations of these medications. 
SMV is primarily metabolized by the liver. Compared to HCV-uninfected subjects with normal 
hepatic function, the mean steady-state AUC of SMV was 2.4-fold higher in HCV-uninfected 
subjects with moderate hepatic impairment (Child-Pugh Class B) and 5.2-fold higher in 
HCV-uninfected subjects with severe hepatic impairment (Child-Pugh Class C). No dose 
adjustment of SMV is necessary in patients with mild hepatic impairment (Child-Pugh Class A). 
1.4.1 
Previous Clinical Experience for SMV 
Efficacy 
For approval, SMV was investigated in three Phase 3 studies involving 1,178 patients with HCV 
of GT1. The first 2 studies included treatment-naïve patients, while the third included patients 
who relapsed following treatment with interferon-based therapy. All 3 studies compared SMV 
with placebo when taken in combination with pegylated interferon alfa (PegIFN) and RBV. 
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The combined results of the first 2 studies demonstrated that around 80% (419 out of 521) of 
patients taking SMV achieved HCV RNA levels <LLOQ by 12 weeks after the end of treatment, 
compared with 50% (132 out of 264) of patients on placebo. In the third study, around 80% 
(206 out of 260) of patients taking SMV achieved HCV RNA levels <LLOQ by 12 weeks after 
the end of treatment, compared with around 37% (49 out of 133) of patients on placebo. An 
analysis of these studies showed that SMV was less effective in a subgroup of patients infected 
with HCV GT1a who harbor an NS3 Q80K polymorphism at baseline. Additional studies 
involving patients with HCV of GT4 and patients with HIV co-infection showed results 
consistent with those in patients with GT1. 
SMV taken together with sofosbuvir has been investigated in the Phase 2 study 
TMC435HPC2002 (COSMOS) which evaluated the efficacy and safety of 12 or 24 weeks of 
SMV 150 mg qd in combination with sofosbuvir 400 mg qd, with and without RBV, in HCV 
GT1-infected subjects with METAVIR F0-F2 who were prior null responders to PegIFN/RBV 
therapy (Cohort 1, N=80) and subjects with METAVIR F3-F4 who were prior null responders to 
PegIFN/RBV therapy or treatment-naïve (Cohort 2, N=87). The results of this study 
demonstrated SVR12 rates of ≥90%, irrespective of treatment duration (12 or 24 weeks), use of 
RBV or treatment history (prior null responders to the combination of PegIFN and RBV or 
treatment-naïve)  
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 GT2, 4, 5, and 6. For 
the primary endpoint at Day 8, the mean (±standard error [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 GT3. The efficacy in HCV GT4-infected subjects was 
confirmed in the Phase 3 study HPC3011. 
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 HCV GT1 treatment-naïve and 
treatment-experienced subjects and the exposure at this dose was similar to the exposure of 
150 mg qd in Caucasian subjects.  
In HCV GT1b treatment-naïve subjects from China and South Korea, SMV 100 mg and 150 mg 
were found equally efficacious, with efficacy data in line with efficacy data previously obtained 
in mainly Caucasian treatment-naïve HCV GT1b-infected subjects dosed with SMV 150 mg qd. 
Safety 
The most common AEs reported in the Phase 3 trial of SMV with PegIFN and RBV (occurring 
with at least 3% higher frequency compared to placebo) during the first 12 weeks of treatment 
included: rash (including photosensitivity), pruritus, nausea, myalgia, and dyspnea. Most of the 
rash events were of mild or moderate severity (Grade 1 or Grade 2). Severe (Grade 3) rash 
occurred in 1% of SMV-treated subjects and there were no reports of life-threatening (Grade 4) 
rash. Discontinuation of SMV or placebo due to rash occurred in 1% of SMV-treated subjects, 
compared to less than 1% of placebo-treated subjects. The frequencies of rash and 
photosensitivity reactions were higher in subjects with higher SMV exposures. Most 
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photosensitivity reactions were of mild or moderate severity (Grade 1 or 2). Two SMV-treated 
subjects experienced photosensitivity reactions which resulted in hospitalization. No 
life-threatening photosensitivity reactions were reported. 
All dyspnea events reported were of mild or moderate severity (Grade 1 or 2), there were no 
Grade 3 or 4 dyspnea events reported and no subjects discontinued treatment due to dyspnea. 
Sixty-one percent (61%) of dyspnea events occurred in the first 4 weeks of treatment with SMV. 
The only difference between treatment groups for laboratory parameters was an elevation in 
bilirubin. Elevations in bilirubin were predominately mild to moderate (Grades 1 or 2) in 
severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin 
occurred early after treatment initiation, and normalized upon cessation of SMV. Bilirubin 
elevations were generally not associated with elevations in liver transaminases. Consult the 
investigator brochure for SMV for further information.  
Clinical Pharmacology 
SMV is orally bioavailable and Cmax is typically achieved between 4 to 6 hours post dose. 
Steady-state is reached after 7 days of daily treatment with 150 mg of SMV. Plasma exposure of 
SMV in HCV-infected subjects is about 2- to 3-fold higher compared with that observed in 
HCV-uninfected subjects. 
SMV is highly protein-bound in plasma (>99.9%) at pharmacologically relevant concentrations. 
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. 
Administration of SMV with food to healthy subjects increased the relative bioavailability by 
61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, 
respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively 
(Janssen Therapeutics 2016). 
1.5 
Rationale for the Study and Study Design 
AL-335 is a nucleotide analog being developed for the treatment of HCV. Data from several 
clinical trials have demonstrated the potential for the effective combination of nucleotide analogs 
with NS5A or NS3 inhibitors for the treatment of chronic HCV infection (Lawitz et al. 2014). 
This study is designed to determine the initial safety and efficacy of concomitant administration 
of ODV (NS5A inhibitor), AL-335 (nucleotide analog inhibitor), ±SMV (NS3 protease 
inhibitor), over a 4- to 12-week treatment period in treatment-naïve and treatment experienced 
subjects with CHC. The results of this study will assist in determining the design of subsequent 
studies.  
1.6 
Rationale for Permitting Women of Child Bearing Potential 
The embryo-fetal developmental studies conducted with AL-335 and ODV in rats and rabbits do 
not indicate significant risk to a fetus when given to animals over critical period of 
organogenesis. Exposure multiples 1.8-fold (rat) to 5-fold (rabbit) of the major analyte 
ALS-022227 were obtained in these studies compared with human exposure at 800 mg AL-335. 
For ODV, 0.5-fold (rabbit) to 21-fold (rat) multiples of the exposure were obtained in these 
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studies as compared with the human exposure of 50 mg qod ODV (see Investigator’s Brochure 
for details). In addition, AL-335 did not have any adverse effects/disturbances in the 
reproductive process from pre-mating to conception and from conception to implantation in rats 
up to the highest dose of 1000 mg/kg/day (2-fold above human exposures). SMV is a marketed 
product with Pregnancy C category (see Package Insert). Therefore, highly effective 
contraception in heterosexually active subjects and/or their partners is sufficient to protect 
subjects of child bearing potential.  
1.7 
Risk-Benefit Assessment 
In vitro and in vivo studies, including available data from Cohorts 1-3 in this study, indicate that 
the planned combinations of AL-335 and ODV±SMV have the potential to successfully treat 
HCV infection in the populations being studied in this trial. In subjects with GT1 and 2 infection, 
all 3 study drugs have demonstrated significant antiviral activity in vitro/in vivo and at least 
in vitro, respectively. In GT3 subjects, SMV is not expected to have any direct antiviral activity; 
however, its boosting effects on AL-335/metabolites and ODV exposures may enhance the 
antiviral activity of AL-335 and ODV. Furthermore, in the event unacceptable levels of 
treatment failures were to occur for a given regimen or population (see Section 4.8.1), this 
protocol is designed to detect these failures early and discontinue further evaluation of 
potentially inadequate regimens. Finally, any subject that does experience treatment failure will 
be further characterized (i.e., viral RNA will be sequenced) and, based on this analysis, enrolled 
in a retreatment protocol or provided an appropriate standard of care antiviral therapy. 
With respect to safety, available data to date in 121 subjects who received at least one dose of 
study drugs, suggest that these treatment regimens are generally well tolerated as determined by 
adverse events, laboratories, ECGs, echocardiograms, physical examination, and vital signs. 
Additionally, precautions to avoid and detect early any toxicities potentially associated with 
individual study drugs (e.g., cardiac toxicity with ODV, photosensitive rash and drug-drug 
interactions with SMV) are extensively incorporated into the protocol, thereby minimizing risk 
to subjects. Examples of these precautions include: 
• Continuous AE assessments  
• At least biweekly safety labs (through completion of dosing then at SVR4 visit) 
• Weekly ECGs (through completion of dosing then at SVR4 visit) 
• Monthly echocardiograms (through completion of dosing then at SVR4 visit) 
• Weekly physical examinations and vital signs (through completion of dosing then at 
SVR4 visit) 
• Education on sun avoidance and skin protection 
• Extensive list of prohibited medications to minimize DDI potential 
 
In summary, the proposed combinations of study treatments in planned patient populations can 
be supported on the basis of the following points:  
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• High SVR rates observed in the relevant cohorts evaluated to date 
• An acceptable safety profile to date 
• The incorporation of intensive surveillance measures to detect early futility and to be able 
to modify or discontinue treatment regimens associated with any 
• Unacceptable treatment failures 
• Emerging safety signals  
 
2.0 
STUDY DESIGN 
2.1 
Summary 
This open-label study will assess the safety, pharmacokinetics and efficacy of the orally 
administered combination of AL-335 and ODV, with or without SMV in treatment-naïve and 
treatment experienced subjects with CHC infection. Up to 320 subjects with CHC GT1 or 2 or 3 
infection will be enrolled to receive up to 1,200 mg qd of AL-335 in combination with ODV up 
to 50 mg qd or qod, with or without up to150 mg qd SMV.  
Based on emerging safety, PK, and efficacy data, the following study parameters may be 
changed for ongoing and future cohorts after obtaining agreement from the Sponsor and the 
Principal Investigator:  
• Treatment duration: 4-12 weeks 
• Dose levels: 
o  AL-335: 400-1,200 mg 
o ODV: 25-50 mg (dosed either qd or qod) 
o SMV: 75-150 mg (if evaluated in a cohort) 
• Genotype: GT1 and/or GT2 and/or GT3; Cohorts may also be limited to specific subtypes 
(e.g., GT1a only) or may include all subtypes  
• Cohort size: 10-20 subjects. In any ongoing cohort in which a dosing regimen is modified 
(e.g. treatment duration is extended) due to apparently insufficient efficacy/safety, the 
cohort size may be increased such that 20 subjects at the final dosing regimen are 
enrolled in that cohort. 
• Population: Treatment-naïve non-cirrhotic HCV-infected subjects and treatment naïve or 
treatment 
experienced 
HCV-infected 
subjects 
with 
compensated 
cirrhosis 
(decompensated cirrhosis prohibited) 
• Viral load: A viral load threshold may be included in determining eligibility for a cohort 
if higher viral loads are projected to have unacceptable efficacy. This threshold may be 
derived from emerging data (e.g. prior cohorts), medical literature, etc. 
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• Number of cohorts: Up to 16 cohorts (maximum N=320 subjects) with the above defined 
constraints may be enrolled. 
The planned study design is depicted in the study schema in Section 2.2.  
The initial 8-week treatment cohort (Cohort 1) will consist of at least 50% HCV GT1a. After 
4 weeks of treatment in the 8 week treatment cohort, safety and viral load from at least 16 of 
20 subjects and available PK data will be reviewed by the Sponsor in consultation with the 
Principal Investigator prior to initiation of enrollment of additional cohorts. If necessary, the 
review may be extended to include the full PK data set from the Week 2 intensive PK 
assessment.  
After the initial cohort (Cohort 1), subsequent cohorts may be enrolled concurrently or in a 
staggered fashion. Effective as of approval of protocol version 7, prior to evaluating a given 
treatment regimen in subjects with cirrhosis or for a shorter duration, efficacy, safety, and 
available PK data for that treatment regimen in subjects without cirrhosis and/or for a longer 
duration will be reviewed. Specifically, data from at least 10 subjects at the SVR4 time point will 
be reviewed and, if acceptable (see Section 4.8), subsequent cohorts evaluating shorter durations 
and/or subjects with cirrhosis will be initiated. The timing of initiating enrollment in these 
subsequent cohorts will be coordinated such that SVR12 data from at least 10 subjects in the 
earlier cohort will be available before the end of treatment visit occurs for the first subject in the 
subsequent cohort. This timing is designed to enable extension of the treatment duration in the 
subsequent cohort if the earlier cohort is determined to have insufficient efficacy.  
Based on data available as of 17 February 2017, the following cohorts have been completed, 
initiated or are planned (Table 2-1). Available VK data are also included. Safety, viral load and 
PK data from dosing regimens in subjects without cirrhosis and/or dosed for longer treatment 
durations will be evaluated and, if they indicate an adequate safety and efficacy profile, dosing 
with the same regimen in cohorts with cirrhosis or for shorter treatment durations will be 
permitted. Cohorts 6 through 12 are currently open for enrollment or planned at the time of this 
protocol finalization. The cohort regimens will only change if emerging data requires they be 
altered for safety purposes. Some planned cohorts may not be enrolled if emerging data are not 
supportive or suggest the cohort is not necessary to achieve the study’s objectives. 
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Table 2-1. 
Completed, Initiated, and Planned Cohorts^ with Available VK Data 
 
^ N=10-20 per cohort; In ongoing cohorts in which a dosing regimen is modified (e.g. treatment duration is 
extended) due to apparently insufficient efficacy/safety, the cohort size may be increased such that 20 subjects at 
the final dosing regimen are enrolled in that cohort. 
 
This protocol permits enrollment of up to 16 cohorts. The maximum permissible enrollment in 
this study is up to 320 subjects. 
Safety and tolerability will be evaluated on an ongoing basis through assessment of AEs, blood 
and urine sample analyses, collection of ECG, echocardiograms, vital signs and physical 
examinations. PK data will be routinely reviewed as it becomes available. 
All enrolled subjects will be monitored from Day 1 through end of follow up for on treatment 
failure or relapse as defined by the criteria outlined in Sections 8.2.2–8.2.4. The Sponsor will 
provide the Investigator with the results of the resistance evaluation to enable them to evaluate 
the most appropriate therapeutic option for any subject that experiences relapse. Where 
necessary, the Sponsor will offer appropriate retreatment within a separate protocol or, if the 
subject is unable or unwilling to participate in that trial, the Sponsor will provide reimbursement 
for locally available HCV treatment for any subjects that experience on treatment failure or 
relapse, subject to local regulations. Alternatively, where possible, subjects will be allowed to 
enroll in a subsequent clinical trial subject to meeting the relevant entry criteria. 
PK samples will be obtained at a single time point prior to dosing at all routine study visits while 
subjects are receiving study medication as well as at Weeks 3 and 6, 2-4 hours postdose, and at 
Weeks 4 and 8, 6-8 hours postdose. In addition, for a subgroup of up to 250 subjects, additional 
PK samples will be obtained at Week 2 for all treatment groups.  
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2.2 
Study Schema 
The study schema is presented in Figure 2-1. Study procedures are listed in Section 6.0 and 
depicted for the 8-week treatment group or 12-week treatment group in Table 6-1; the schedule 
of events for a 6-week treatment group can be found in Table 6-2 and for a 4-week treatment 
group in Table 6-3. A schedule for the post dosing follow-up period for all cohorts can be found 
in Table 6-4. 
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Figure 2-1 
Study Schema 
 
See Section 6.0 for details of Study Procedures. 
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3.0 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
The primary objective of this study is as follows: 
• To evaluate the safety and tolerability of AL-335 in combination with ODV with or 
without SMV in subjects with GT1 or GT2 or GT3 CHC infection 
3.1.2 
Secondary Objectives 
The secondary objectives of this study are as follows: 
• To evaluate the efficacy of treatment with AL-335 in combination with ODV±SMV in 
subjects with GT1 or GT2 or GT3 CHC infection  
• To evaluate the pharmacokinetics of AL-335 (and metabolites), ODV±SMV in plasma 
• To evaluate the viral kinetics of HCV RNA in subjects with GT1 or GT2 or GT3 CHC 
infection treated with AL-335 in combination with ODV±SMV 
• To evaluate the effect of baseline host and disease-related characteristics on treatment 
outcome  
• To evaluate the impact of the presence of an (NS) 3 polymorphism (e.g., Q80K; 
SMV-containing arms only) and/or NS5A and NS5B polymorphisms at baseline on 
treatment outcome  
• To evaluate the viral resistance profile after ≤12 weeks administration of AL-335 in 
combination with ODV±SMV 
3.2 
Study Endpoints 
3.2.1 
Primary Endpoint 
• Safety data including but not limited to tabulation of AEs, physical exam, vital signs, 
12-lead ECGs, echocardiograms, and clinical laboratory results (including chemistry, 
hematology, and urine) 
3.2.2 
Secondary Endpoints 
• The proportion of subjects who have a sustained virologic response (SVR; i.e., HCV 
RNA concentration <LLOQ (<15 IU/mL) at 4, 8, 12, 18 and 24 weeks after the last actual 
dose of treatment  
• PK parameters for AL-335 (and metabolites), ODV and SMV in plasma  
• The proportion of subjects who experience virologic relapse during the follow-up period. 
• The proportion of subjects who have on treatment failure while receiving study 
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medication 
• Viral kinetics, as determined at different timepoints during treatment by the proportion of 
subjects who achieve 
- HCV RNA <LLOQ Undetectable  
- HCV RNA <LLOQ  
• Time to achieve undetectable HCV RNA and <LLOQ HCV RNA 
• The amino acid sequence of the NS5A, NS5B and NS3/4A proteins at baseline and 
post-baseline in subjects who fail treatment 
• Effect of various baseline and host disease-related characteristics on treatment outcome 
4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Study Population 
The target population will consist of treatment-naïve and treatment experienced male and female 
subjects (18-70 years of age, inclusive) with CHC infection. Up to 320 subjects will be enrolled 
into up to 16 treatment arms. 
4.2 
Inclusion Criteria 
Main Inclusion Criteria for All Subjects: 
1. Subject has provided written consent. 
2. In the Investigator’s opinion, the subject is able to understand and comply with 
protocol requirements, instructions, and protocol-stated restrictions and is likely to 
complete the study as planned. 
3. Male or female, 18–70 years of age. 
4. Body mass index (BMI) 18–35 kg/m2, inclusive.  
5. A woman of childbearing potential must have a negative serum (β-human chorionic 
gonadotropin) pregnancy test at screening.  
6. Female subjects must either: 
• not be of childbearing potential defined as:  
i. 
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 (per reference laboratory), OR 
ii. 
Surgically 
sterile 
(e.g., 
underwent 
total 
hysterectomy, 
bilateral 
oophorectomy, or bilateral tubal ligation/bilateral tubal clips without 
reversal operation), or otherwise incapable of becoming pregnant, 
• OR 
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i. 
be of childbearing potential AND 
ii. 
not heterosexually active (e.g., abstinent or homosexual) from screening 
until 6 months after study drug administration (or longer, if dictated by 
local regulations), OR 
iii. 
if heterosexually active  
o 
have a vasectomized partner (confirmed sterile per verbal account 
of the subject), OR 
o 
using an acceptable method of birth control from screening and 
agree to continue to use the same method of contraception 
throughout the study and for 6 months after study drug 
administration (or longer, if dictated by local regulations). 
Acceptable methods of birth control include: oral hormone-based 
contraceptives, an IUD, being either hormonal (i.e., IUS) or non-
hormonal, other non-oral hormone-based contraception methods 
(e.g., injectable, implants, transdermal system, vaginal ring), or a 
double-barrier method (eg, male condom + either a diaphragm or 
cervical cap with or without spermicide).   Condom use by male 
partners with reproductive potential is required in all circumstances 
except when female subjects are using acceptable birth control 
methods which are long term in nature and do not require high 
degrees of compliance (e.g. IUDs, depot-form injectables, 
implants).     
o 
See also the NOTES regarding contraception considerations that 
apply to men and women at the bottom of Inclusion #7 
7. Male subjects must either: 
• be surgically sterile (had a vasectomy), or otherwise incapable of fathering a 
child, OR 
• not be heterosexually active (e.g., abstinent or homosexual) from enrollment (Day 
1) in the study until at least 6 months after study drug administration, OR 
• if heterosexually active: 
o have a partner who is postmenopausal (2 years amenorrhea), surgically sterile 
(e.g., has had a total hysterectomy, bilateral oophorectomy, or bilateral tubal 
ligation/bilateral tubal clips without reversal operation), or otherwise 
incapable of becoming pregnant OR 
o be practicing an acceptable method of birth control from enrollment in the 
study (Day 1) and agree to continue to use the same method of contraception 
throughout the study and for at least 6 months after study drug administration 
(or longer, if dictated by local regulations). An acceptable method of birth 
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control for male subjects is a double-barrier method (e.g., male 
condom+either diaphragm or cervical cap with or without spermicide).  
 
NOTE 1: Male subjects with a female partner who uses hormonal contraceptives 
(oral, injectable, implants) or a 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 2: 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 3: A male and female condom should not be used together due to risk of 
breakage or damage caused by latex friction. 
NOTE 4: Contraceptive use by men and 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. 
8. Subjects must agree to refrain from sperm/egg donation from start of dosing through 
6 months after the completion of study drug administration. 
9. GT1a or 1b or GT2 or 3 CHC, depending on cohort, with positive HCV antibody and 
a positive HCV RNA at screening including documentation of CHC infection for at 
least 6 months. Genotype testing must occur at a screening visit. NOTE: GT1 
patients are eligible for inclusion even if they cannot be successfully subtyped unless 
a specific subtype is required for a cohort. 
10. Screening HCV RNA viral load ≥50,000 IU/mL, except for subjects with 
compensated cirrhosis (Child-Pugh Class A) who may have HCV RNA viral load 
≥104 IU/mL. 
11. Treatment naïve (i.e., no prior exposure to any approved or investigational drug(s) 
including direct-acting antivirals, and interferon-based treatment regimens) or, in 
subjects with cirrhosis, treatment experienced (defined as subjects who experienced 
virologic relapse after receiving a full course of pegylated interferon+ribavirin 
(peg/riba) treatment).  Prior use of any direct acting antiviral in combination with 
peg/riba is not permitted. 
12. Fibroscan, collected within 6 months of baseline visit, with liver stiffness score 
≤12.5 kPa to be eligible (except for subjects with cirrhosis, see below). 
• Subjects with compensated cirrhosis must meet the Child-Pugh Class A definition 
(see Appendix G) and at least one of the following criteria: 
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iii. Liver biopsy result indicating the presence of cirrhosis (e.g., Metavir F4; 
Ishak >5) or 
iv. Fibroscan evaluation with a liver stiffness score >12.5 kPa 
13. Subject is otherwise in good health as deemed by the investigator, based on the 
findings of a medical evaluation including medical history, physical examination, 
laboratory tests and ECG. 
14. Willing to avoid prolonged sun exposure and use of tanning devices while taking 
SMV and through 4 weeks of follow up. Subjects should also be advised to use a 
broad-spectrum sunscreen and lip balm of at least sun protection factor >30 to help 
protect against potential sunburn. 
4.3 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. 
Pregnant, planning on becoming pregnant (during treatment and up to 6 months 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 6 months 
after the EOT) 
2. 
Other than CHC with or without compensated cirrhosis, clinically significant 
cardiovascular, respiratory, renal, gastrointestinal, hematologic, neurologic, thyroid 
or any other medical illness or psychiatric disorder, as determined by the 
Investigator and/or Sponsor’s Medical Monitor. 
3. 
History or other clinical evidence of significant or unstable cardiac disease 
(e.g., angina, congestive heart failure, myocardial infarction, diastolic dysfunction, 
significant arrhythmia, coronary heart disease, and/or clinically significant ECG 
abnormalities), moderate to severe valvular disease or uncontrolled hypertension at 
screening. 
4. 
Screening echocardiogram ejection fraction <55% or any other echocardiographic 
finding suggestive of clinically relevant cardiomyopathy. 
5. 
Creatinine clearance of <60 mL/min (Cockcroft-Gault). 
6. 
Positive test for HAV IgM, HBsAg, or HIV Ab.  
7. 
Abnormal screening laboratory results that are considered clinically significant by 
the investigator. 
8. 
History of clinical hepatic decompensation, e.g., variceal bleeding, spontaneous 
bacterial peritonitis, ascites, hepatic encephalopathy or active jaundice within the last 
year. 
9. 
Any condition that, in the opinion of the investigator, would compromise the study’s 
objectives or the well-being of the subject or prevent the subject from meeting the 
study requirements. 
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10. Participation in an investigational drug trial or having received an investigational 
vaccine within 30 days or 5 half-lives (whichever is longer) prior to study 
medication. 
11. Clinically significant abnormal screening ECG findings (e.g., PR >200 msec, QRS 
interval >120 msec or corrected QT interval (QTc) >450 msec for male subjects and 
>470 msec for female subjects), based on an average of triplicate ECGs. Any 
evidence of heart block or bundle branch block is also exclusionary. 
12. History or family history of abnormal ECG intervals, for example prolonged QT 
syndrome (torsade de pointes) or sudden cardiac death. 
13. The subject has a positive prestudy drug screen, including methadone unless the 
drug is prescribed by the subject’s physician. The list of drugs that should be 
screened for includes amphetamines, barbiturates, cocaine, opiates, phencyclidine 
(PCP), and benzodiazepines.  Drug use without a physician prescription may be 
permitted on a case by case basis after review by the Sponsor in consultation with 
the investigator. 
14. Laboratory abnormalities including: 
• Hematocrit <0.34 
• White blood cell counts <3,500/mm3 (<1,000/mm3 for subjects with 
compensated cirrhosis) 
• Absolute neutrophil count <1,000/mm3 (<750/mm3 for subjects with 
compensated cirrhosis) 
• Platelets ≤120,000/mm3 (platelets <70,000/mm3 for subjects with 
compensated cirrhosis) 
• Glycosylated hemoglobin (HbA1C) >55 mmol/mol or 7.2% 
• Prothrombin time ≥1.5 × ULN 
• Albumin ≤32 g/L, bilirubin ≥1.5 mg/dL at screening (subjects with 
documented Gilbert’s disease allowed) 
• Serum ALT concentration ≥5× ULN 
• CK >1.5× ULN 
A single repeat laboratory evaluation under appropriate conditions (e.g., fasted, no 
antecedent exercise) is allowed for eligibility determination. 
15. Any condition possibly affecting drug absorption (e.g., gastrectomy or other 
significant gastrointestinal tract surgery, such as gastroenterostomy, small bowel 
resection, or active enterostomy). 
16. Clinically significant blood loss or elective blood donation of significant volume 
(i.e., >500 mL) within 60 days of first dose of study drug; >1 unit of plasma within 7 
days of first dose of study drug. 
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17. Evidence of clinically relevant active infection that would interfere with study 
conduct or its interpretation. 
18. History of regular alcohol intake >10 standard drinks per week of alcohol for 
females and >15 standard drinks per week for males (one unit is defined as 10 g 
alcohol) within 3 months of the screening visit. 
19. The use of prohibited medications, including prescription, over-the-counter (OTC) 
medications, herbal medications, inducers or inhibitors of CYP450 enzymes or drug 
transporters (including P-gp) within 14 days prior to the first dose of study 
medication is excluded, unless previously approved by the Sponsor’s Medical 
Monitor. NOTE: Chronic medication use is permitted so long as they are medically 
necessary, deemed acceptable by the Principal Investigator and Medical Monitor, 
and not Prohibited Medications (see Section 5.12).  
20. Hypersensitivity to the active substances (including sulfa allergy) or to any of the 
excipients of AL-335, ODV or SMV. 
21. Evidence on recent (within 6 months) liver ultrasound of hepatic mass or lesion 
concerning for malignancy (subjects with cirrhosis only). 
4.4 
Subject Screening and Enrollment 
Screening procedures will occur when a subject signs and dates an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Ethics Committee (EC) approved informed consent 
form (ICF) and provides authorization to use protected health information. The ICF will be 
completed prior to any study-specific procedures. The use of a site-specific generic consent 
form, approved by the local EC, may be used prior to approval of the study specific consent form 
at the Sponsor’s discretion.  
To enroll, the investigator will verify eligibility according to all inclusion and exclusion criteria 
(Sections 4.2 and 4.3). Any questions regarding eligibility should be addressed to the Sponsor’s 
Medical Monitor prior to enrollment.  
4.4.1 
Screening Examination 
A screening examination should be performed between -50 and -1 days before the start of the 
study. Subjects must fulfill all entry criteria to be accepted into the study. 
A screen failure log must be maintained by the investigator.  
At the screening examination, the procedures outlined in Table 6-1 through Table 6-3 will be 
performed to establish each candidate’s general health and qualifications for enrollment into the 
study. 
For re-screened subjects who were previously screened in the study and found to be eligible  but 
were not enrolled due to limited cohort slot enrollment availability or other nonmedical reasons 
or were ineligible under a prior protocol version but became eligible under an approved later 
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version of the protocol, the screening procedures outlined in Table 6-1 through Table 6-3 should 
be repeated with the exclusion of the following: 
• Echocardiogram (as long as the most recent study echocardiogram was obtained within 
the past 4 months) 
• HCV genotype 
• Hepatitis and HIV screen 
• IL28B genotype 
4.5 
Subject Completion 
A subject will be considered to have completed the study if he or she has completed the 
assessments at the Week 24 follow-up visit.  
4.6 
Subject Discontinuation 
The primary consideration in any determination to discontinue a subject’s participation must be 
the health and welfare of the subject. Reasons for discontinuation may include, but are not 
limited, to the following: 
• An AE or SAE, drug reaction, or complication, whether related or not to study drug, 
which precludes continuation of treatment with study drug. This includes the 
development of allergic reactions or other potentially serious drug reactions to the study 
medication. 
• Noncompliance with study drug dosing.  
• Noncompliance with study procedures. 
• Lost to follow up. 
• Subject’s right to withdraw consent at any time during the study, with or without a stated 
reason. 
• The principal investigator’s opinion that it is not in the subject’s best interest to continue 
study participation. 
• Sponsor’s decision to terminate the study (e.g., see section 4.7). 
Subjects are free to discontinue their participation at any time during this clinical trial. The 
investigator has the right to remove any subject from treatment with study drug or participation 
in the study. However, Alios requests that the investigator consult with the Sponsor’s Medical 
Monitor before prematurely removing a subject. For subjects that discontinue study drug 
prematurely, sites are strongly encouraged to follow these subjects as prescribed in this protocol 
as much as possible as this is the primary mechanism to ensure subject safety. 
Any subject who decides to discontinue participation in the study, or meets the discontinuation 
criteria specified below, should undergo early discontinuation procedures (Section 4.6.2).  
4.6.1 
Subject Treatment Discontinuation Criteria 
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If a subject's study drug treatment must be discontinued before the end of the treatment regimen, 
this will not result in automatic withdrawal of the subject from the study. 
A subject's study drug treatment (AL-335, SMV and ODV) must be permanently discontinued if: 
• The investigator believes that for safety reasons (e.g., AE), it is in the best interest of the 
subject to discontinue study drug treatment. 
• The subject becomes pregnant. 
• The subject has evidence of muscle injury (Section 7.5.1) or cardiac toxicity 
(Section 7.5.2 and 7.5.3).  
• The subject has a Grade 4 rash; see Section 7.6. 
• The subject has a Grade 3 or 4 allergic reaction; see Section 7.7. 
• The subject has a confirmed Grade 4 ALT and/or AST value that is >2× the baseline 
value; see Section 7.9. 
• 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 Sections 7.8 
and 7.9. 
• The subject has severe worsening of hepatic disease. 
• The subject has a confirmed diagnosis of pancreatitis. 
• The subject has a Grade 4 AE or laboratory abnormality at least possibly related to 1 of 
the study drugs and which is considered clinically significant (laboratory abnormalities 
only). 
• The subject requires treatment with any of the medications reported on the list of 
disallowed medications; see Section 5.12. 
• The subject experiences inadequate virologic response or viral breakthrough (refer to 
Definitions) 
• An event occurs which triggers the study treatment stopping criteria (Section 4.7.1) 
4.6.2 
Procedures for Subjects Who Discontinue Treatment 
Subjects who discontinue from treatment should undergo the Study Completion procedures 
tabulated in Section 6.1 for the purpose of safety monitoring within 7 days after their last dose of 
study medication. Any subject that discontinues with ongoing AEs should be followed until 
resolution of their AE(s) or until the investigator has determined that the AE(s) has stabilized. In 
addition subjects should be followed up per Table 6-4 off treatment for up to 24 weeks, or when 
commencing therapy if earlier.  
4.6.3 
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 
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If a subject is lost to follow up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. 
Subjects who withdraw consent during the treatment or follow-up phase will be offered an 
optional safety follow-up visit, at which the assessments from the Week 4 follow-up visit need to 
be performed. 
Subjects who withdraw consent from the PK substudy (see Section 6.2.1) 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 current study 
first. 
Subjects who discontinue may withdraw consent for use of their samples for future research 
(refer to Section 11.7). 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. 
4.6.4 
Documentation of Discontinuation of Subjects 
Document the reasons for early discontinuation of any subject from the study on the appropriate 
case report form (CRF). If the reason for early discontinuation is an AE or an abnormal 
laboratory value, record the specific event or test result on the AE CRF, and monitor the subject 
until the event is resolved or deemed stable by the investigator. 
4.7 
Study Discontinuation 
The Sponsor has the right to terminate this study or remove a participating site at any time. 
Reasons for terminating the study or site may include, but are not limited to, the following:  
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects as described in section 4.7.1 Study Treatment Stopping Criteria.  
• Subject enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 
• Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study. 
• A decision from the IRB/IEC, or regulatory authority to terminate the study. 
• The Sponsor may also opt to not conduct any of Cohorts7–15 if they are considered 
redundant or to otherwise not contribute to the achievement of the study’s objectives. 
4.7.1 
Study Treatment Stopping Criteria 
The occurrence of any one of the following treatment emergent events in any ongoing study 
using ODV at therapeutic doses: 
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• 
2nd degree Mobitz Type 2 or 3rd degree heart block; 
• 
drop in ejection fraction (EF) by ≥10 points with absolute EF <50%; 
• 
a cardiac event that is serious, severe or life-threatening; 
will lead to stop of recruitment and dosing in all subjects in the current study if adjudicated by 
the Sponsor, in consultation with the Investigator, 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 Sponsor in consultation with the 
Investigator will take place within 72 hrs 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. 
4.8 
Futility Criteria 
4.8.1 
Predefined Criteria to Determine the Futility of an Individual Treatment 
Regimen 
The futility of any of the regimens evaluated in the study will be assessed by the Sponsor based 
on predefined criteria, as detailed below. Once a predefined futility criterion is met, appropriate 
action will be taken by the Sponsor, which may include halting the enrollment of individual 
treatment arms and/or extending treatment duration of subjects who have not yet reached end of 
treatment at that time. Futility criteria will be in place during the entire conduct of the study. The 
Sponsor will evaluate the futility criteria and notify the Principal Investigator if a futility 
criterion is met. 
The objective of the futility criteria is to detect futile regimens as early as possible and ideally 
within a timeframe that would allow the Sponsor to take action (i.e., while recruitment or 
treatment phase is ongoing). The futility criteria will take into account post-treatment failure for 
virologic reasons (viral relapse; see Definitions of Terms). For confirmation of viral relapse, an 
HCV RNA retest should be scheduled (see Sections 6.2.3 and 6.2.4). However, the Sponsor may 
evaluate futility criteria based on the original test results without waiting for the retest results. 
The futility criteria will have been met: 
• If >2 subjects in any 1 cohort experience viral breakthrough or inadequate virologic 
responsewhile recruitment is ongoing. Further recruitment in the cohort will then be 
discontinued 
• If ~15% of subjects in a cohort experience relapse at any available timepoint during the 
follow-up phase (at 24 weeks after actual end of study drug treatment or earlier for 
subjects who have not yet reached the 24 weeks after actual end of study drug treatment 
visit).  
If the futility criterion is met for a regimen evaluated in a historically easier to treat 
population (e.g., subjects with GT1 infection without cirrhosis), then that regimen will not be 
evaluated in historically more difficult to treat populations (e.g., subjects with GT1 infection 
and with cirrhosis).  
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If a drug regimen evaluating a particular treatment duration is found to be futile in a 
population, a shorter duration of that drug regimen will not be assessed in that population. 
Also, shorter duration cohorts (e.g., 6 weeks) will only be initiated if supported by viral 
kinetic data from longer duration cohorts in the same patient population. Supportive data are 
defined as viral load below the limit of quantification for ≥80% of subjects at Week 6 in an 
8-week cohort. A similar paradigm will be applied for cohorts of 4 weeks’ duration based on 
4-week data from cohorts of 6 weeks’ duration.  
5.0 
DOSING REGIMEN 
5.1 
Rationale for Dosage Selection 
5.1.1 
AL-335 
A dose of 400 to 1,200 mg qd for AL-335 has been selected for this study. These doses are based 
on safety and PK data from Study AL-335-601 (Section 1.2.1.1), Study AL-335-602 
(Section 1.2.1.2), and preliminary data from Cohorts 1-3 in Study AL-335-604 (Section 1.2.1.2). 
In these studies, single and multiple doses up to 1,200 mg have been well tolerated and 
preliminary information on the impact of ODV and SMV dosing on the pharmacokinetics of 
AL-335 and its metabolites is known. 
Evaluation of higher doses of AL-335 up to 1,200 mg qd is considered justified because: 
• AL-335 and its metabolite exposures appear to increase less than dose proportionally for 
AL-335 doses >800 mg 
• Higher doses of AL-335 may be needed to increase antiviral activity 
• It is anticipated that the 1,200 mg qd dose of AL-335, even in the setting of a drug–drug 
interaction with SMV and/or ODV, will deliver mean projected exposure of ALS-022227 
that will not exceed the NOAEL established in nonclinical studies. 
• The safety and pharmacokinetics of a dose that will deliver exposures ≤2-fold those 
already evaluated in this and earlier studies can be safely evaluated in this study given the 
intensive nature of the safety/PK assessments defined in the Schedule of Events 
(Section 6.0).  
5.1.2 
Simeprevir 
A dose of 75 to 150 mg for SMV has been selected for this study. In a drug-drug interaction 
study in healthy volunteers (AL-335-602), PK results suggest ODV increases SMV exposure 
(AUC) 1.8-fold. It is anticipated that the 100 mg dose of SMV, along with the interaction of 
ODV, will result in exposures of SMV approximately similar to 150 mg (the approved dose) 
without interaction; a dose that has demonstrated to be efficacious and well tolerated in patients 
with CHC. Similarly, it is anticipated that the 75 mg dose of SMV, along with the interaction of 
ODV, will result in exposures of SMV approximately similar to 100 mg (the approved dose in 
Japan) without interaction; this dose has also been demonstrated to be efficacious and well 
tolerated in patients with CHC. For a 150 mg dose of SMV, even in the setting of a drug-drug 
interaction with ODV, the projected SMV exposures are expected to be within the range of 
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exposures seen in patients with mild (Child Pugh A) cirrhosis, a population in which the 150 mg 
SMV dose is approved without dose adjustment.  
5.1.3 
Odalasvir 
A daily dose of 12.5 to 50 mg for ODV has been selected for this study. In prior studies, a 50 mg 
daily dose of ODV given as a liquid filled capsule has been shown to be well tolerated and have 
clinical efficacy in combination with another nucleotide (sofosbuvir) in patients infected with 
HCV. Also, when a liquid filled capsule of ODV was given as monotherapy in a prior study, a 
single dose of 25 to 300 mg demonstrated similar antiviral effects. Taken into account these data 
and emerging efficacy data from Study AL-335-604, it is possible total daily doses <25 mg of 
ODV administered as a tablet may also be efficacious. Because only 25-mg and 50-mg ODV 
tablets are available for this study, dosing with 25 mg ODV qod may be administered if a 
decision is made to evaluate the efficacy of ODV using the equivalent of a 12.5 mg daily dose.  
5.1.4 
Dosing Regimens for Patients With Mild (Child Pugh A) Cirrhosis 
AL-335 and its metabolites appear to have similar steady state exposures in cirrhotic vs, 
non-cirrhotic patients (Study AL-335-601). Furthermore the 800 mg dose of AL-335 has been 
well tolerated and may deliver more antiviral activity than a 400 mg dose (see Section 1.2.1.1). 
As a result, the AL-335 dose for the first cohort of subjects with cirrhosis will be 800 mg qd.  
ODV has not been studied in CHC subjects with compensated cirrhosis; however, other drugs in 
the same drug class are known to have lower exposures in patients with cirrhosis compared to 
patients without cirrhosis. As a result, it is not expected that a 50 mg dose of ODV will deliver 
higher exposures in patients with vs. those without cirrhosis. Nevertheless, as a precaution, the 
ODV dose for the first cohort of subjects with cirrhosis will be 25 mg qd or 50 mg qod. 
Because SMV is primarily cleared by the liver, the SMV dose for the first cohort of subjects with 
cirrhosis will be the lowest possible qd dose (75 mg). 
After the safety and PK data of all 3 drugs has been evaluated in the first cohort of subjects with 
compensated cirrhosis, the dose limits defined in Sections 5.1.1 through 5.1.3 may then be 
explored if supported by emerging data. 
5.2 
Description of Study Drug and Background Therapy 
5.2.1 
AL-335 
AL-335 will be supplied as tablets containing 400 mg of AL-335 and microcrystalline cellulose 
(filler), croscarmellose sodium (disintegrant), and magnesium stearate (lubricant). A second 
formulation of AL-335 may be supplied as well and these tablets contain 100 mg of AL-335 and 
microcrystalline cellulose (filler), croscarmellose sodium (disintegrant), and magnesium stearate 
(lubricant). AL-335 will be supplied to the site in open-label containers and stored at controlled 
room temperature.  
5.2.2 
Simeprevir 
SMV 75 mg capsules will be supplied as red hard gelatin capsules. SMV 100 mg capsules will 
be supplied as hard gelatin, white capsules with black "TMC435" print. SMV 150 mg capsules 
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will be supplied as hard gelatin, white capsules with black “TMC435 150” print. Each capsule 
contains 75, 100, or 150 mg of SMV along with sodium lauryl sulphate, magnesium stearate, 
anhydrous colloidal silica, croscarmellose sodium, and lactose monohydrate. SMV capsules will 
be supplied to the site in open-label containers and stored at controlled room temperature. 
5.2.3 
Odalasvir 
ODV will be supplied as film-coated tablets containing 25 or 50 mg of ODV active drug 
substance, poloxamer 407, copovidone, silicified microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate and white film coating (polyvinyl alcohol, titanium dioxide, 
macrogol/polyethylene glycol, and talc). 
5.3 
Dose Preparation and Administration 
Study medication will be dispensed by the licensed investigational pharmacist or other 
authorized personnel with appropriate training.  
Subjects will be told to take each dose of AL-335, SMV, or ODV with food (or up to 15 minutes 
after completion of a meal) once a day at approximately the same time each day. On Day 1, 
study medication should be administered after all baseline assessments have been completed. On 
subsequent study visits where biochemistry assessments are scheduled, subjects will be required 
to fast for at least 8 hours overnight. Subjects will receive study medications at the clinical trial 
site after receiving a meal following the biochemistry blood draw.  
5.4 
Treatment Delay or Interruption 
No treatment delay or interruptions are allowed without consultation of the Sponsor’s Medical 
Monitor.  
5.5 
Missed Doses 
In the event of a missed dose, after discussion with the Sponsor Medical Monitor, a subject’s 
study drug regimen may be resumed if the proposed time of administration of study drug is 
≤12 hours since the planned time of the missed dose for AL-335, SMV, or ODV. If more than 12 
hours (AL-335, SMV, ODV) have passed since the missed dose, the subject should skip the 
missed dose and resume dosing at the next planned time. 
5.6 
Overdoses 
In the event that a subject takes an accidental overdose of ≤200% of the planned dose and the 
subject is asymptomatic and deemed clinically stable, continued dosing is permissible after a 
discussion with the Sponsor Medical Monitor. 
5.7 
Dose Modifications 
The dose of AL-335, SMV or ODV may be modified in subsequent cohorts based on safety, 
efficacy and PK data from prior cohorts. Cohorts 1b, 2 to 15 may or may not include SMV. 
Mean projected plasma exposures of ALS-022399, ALS-022227, and ODV at the doses selected 
in study cohorts will not exceed NOAEL exposures obtained from nonclinical toxicology 
studies. SMV doses will not exceed the approved dose. 
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If any of the individual study drugs is discontinued, unless specific requirements are already 
defined in this protocol, the investigator must contact the Medical Monitor to assess the need to 
stop all study drugs.  
5.8 
Ordering Study Drug 
To order study drug, refer to the Pharmacy Manual. 
5.9 
Drug Accountability 
Study site personnel will maintain adequate records of the receipt and disposition of all study 
medication shipped to the site. Records must include dates, lot numbers, quantities received, 
quantities dispensed and the identification number of each subject who has received each lot of 
study drug. 
The investigator will not supply study drug to any person not authorized to receive it. 
5.10 
Disposition of Used, Partially Used, and Unused Study Medication Containers 
All used and unused study drug supplied by Alios BioPharma must be retained by the 
pharmacist. Periodically throughout and at the conclusion (or suspension, termination, or 
discontinuation) of the study, a representative of Alios BioPharma or its designated agent will 
conduct inventories and accountability of study materials. Once accountability is completed, an 
Alios BioPharma representative or designee will authorize the return of all used and unused 
study medication containers to a designated facility. For study medication containers returned to 
Alios BioPharma or its designated agent, records will include dates, lot numbers, and quantities 
of study drug returned. Local destruction of study drug is permitted where appropriate methods 
of destruction are available. 
5.11 
Concomitant Medications 
Medications not explicitly prohibited (see Section 5.12) may be used as concomitant 
medications, where the investigator feels it appropriate to do so. For analgesia and anti-pyretic 
therapy, investigators are encouraged to use low doses of ibuprofen (or equivalent) on an as 
needed basis. Questions related to medications to treat AEs should be discussed with the medical 
monitor, whenever feasible, to minimize the risk of unintended drug–drug interactions. All 
medications, prescription and OTC, including vitamins and herbal products taken within 30 days 
of study screening and during the study, will be recorded in the CRF with indication, dose 
information and dates of administration.  
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 
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drug-drug interaction associated with the CYP enzyme system. ODV is neither a substrate nor an 
inhibitor of transporters such as OATP1B1/3, BCRP, MRP2, MRP3, and BSEP. ODV is a 
low-affinity substrate of 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/MDR1 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.  
The concomitant medications in Table 5-1 are allowed, but should be used with caution and be 
administered at the lowest possible dose, with monitoring of AEs and desired efficacy. 
Table 5-1. 
Concomitant Medication to be Administered With Caution 
• 
P-gp substrates with a narrow therapeutic index  
• 
Acid-reducing agents - antacids (e.g., aluminum and magnesium hydroxide) should be administered 4 hours 
apart; H2-receptor antagonists (e.g., cimetidine, famotidine, nizatidine, ranitidine) may be administered 
simultaneously with or 12 hours apart from study drugs at a dose that does not exceed doses comparable to 
famotidine 40 mg twice daily) 
• 
Analgesics: ergaloid mesylates, ergotamine tartrate, dihydroergotamine, and methylergonovine 
• 
Lipid-lowering drugs - atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin 
• 
Phosphodiesterase type 5 inhibitors - sildenafil, tadalafil, vardenafil 
• 
Sedatives/anxiolytics - lorazepam, midazolam, oxazepam, triazolam 
• 
Warfarin 
Note: This list of permitted (with caution) medications is subject to change based on emerging information related to 
the study drugs (e.g., transporter study results) or other medications (e.g., new information from the medical 
literature). The most up-to-date list of permitted (with caution) medications can be found in the study manual or 
a note to file. 
5.12 
Prohibited Medications 
An overview of prohibited medications is presented in Table 5-2.  
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Table 5-2. 
Prohibited Medications 
Prohibited Medications include potent and moderate CYP3A4 inducers/inhibitors, P-gp inhibitors, CYP3A 
substrates with a narrow therapeutic index, and drugs known to prolong the QT interval. Drugs in these 
categories and which are prohibited include (by class) 
• 
Anti-arrhythmics – amiodarone (prohibited from 3 months prior to first dose), digoxin, disopyramide, 
dronedarone, flecainide, mexilitine, systemic lidocaine, propafenone, quinidine 
• 
Anti-epileptics - carbamazepine, oxcarbazapine, (fos)phenytoin, phenobarbital 
• 
Anti-infectives - clarithromycin, erythromycin, fluconazole, itraconazole, posaconazole, telithromycin, 
troleandomycin, voriconazole 
• 
Antiretrovirals - atazanavir, cobicistat, delavirdine, darunavir, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, tipranavir 
• 
Anti-tuberculosis drugs - rifabutin, rifampin, rifapentine 
• 
Beta-blockers 
• 
Calcium-channel blockers - amlodipine, bepridil, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, 
verapamil 
• 
Immunomodulators - cyclosporine, interleukins, or systemic corticosteroids at an immunosuppressive dose 
• 
Dexamethasone (if administered systemically and more than one dose) 
• 
Antihistamines - astemizole, terfenadine 
• 
Cisapride 
• 
Proton pump inhibitors -(dex)lansoprazole, (es)-omeprazole, pantoprazole, rabeprazole 
• 
Herbal or nutritional products intended for liver disease including HCV (e.g., silibinin, silybin, silymarin (milk 
thistle)) 
• 
Miscellaneous - products containing Hypericum perforatum (St. John’s Wort) 
Note: The list of prohibited 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. 
 
These medications are prohibited from 14 days prior to initiation of treatment through the last 
study visit with the exception of amiodarone (prohibited from 3 months prior to first dose). 
Subjects that receive a prohibited medication should be discussed as soon as practical with the 
Medical Monitor. Study treatment may be discontinued if a subject receives a prohibited 
medication. Subjects that discontinue study drug due to use of a prohibited medication will be 
followed up as outlined in Section 4.6.1. 
In addition to the medications outlined in Table 5-2, drugs which are known to prolong the QTc 
interval (see https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf) may not be 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 (e.g., 
methadone, citalopram) are permitted as prior/concomitant medications if they have been 
administered chronically (at least 2 months prior to enrollment), the dose is stable (for at least 
4 weeks prior to enrolling), and the subject’s QTc interval is normal (see Inclusion/Exclusion 
criteria).  
Note: The list of prohibited medications in Table 5-2 is subject to change based on emerging 
information related to the study drugs (e.g., transporter study results) or other medications (e.g., 
new information from the medical literature). The most up to date list of prohibited/concomitant 
medications can be found in the study manual or a note to file. 
5.13 
Special precautions 
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SMV is known to be associated with rashes including photosensitivity reactions. Investigators 
must advise study participants taking SMV of the need to avoid prolonged sun exposure or 
tanning devices. When these subjects are exposed to sunlight they should take appropriate 
precautions (examples include long sleeve shirts, long pants, hats, sunscreen with sun protection 
factor >30). 
5.14 
Special Dietary Requirements 
During the study, subjects will be advised to adhere to the following dietary requirements: 
• Subjects should be requested to refrain from significant alcohol consumption from 
screening up to and including the Week 12 follow-up visit.  
• Grapefruit, grapefruit juice, and seville orange will not be permitted within 14 days prior 
to administration of study drug(s) (Day 1) and throughout the study until follow-up 
Week 4.  
• Subjects should be requested to refrain from any strenuous activities through study 
follow-up Week 4. Light ambulatory activities will be permitted. 
6.0 
STUDY PROCEDURES 
6.1 
Schedule of Events 
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Table 6-1. 
Schedule of Events for 8 or 12*-Week Treatment Groups  
Interval 
 
Assessments 
Day 
Week** 
Screen 
-50 to -1 
1 
2 
3 
1 
2 
3 
4 
5 
6 
7 
8 
AL-335+ODV±SMV 1 
 
< ----------------------------------------------------------------------------------------------------------> 
Obtain informed consent before study procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height, Weight, BMI2 
X 
 
 
 
 
 
 
 
 
 
 
X 2 
Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram 
X  
 
 
 
 
 
 
X (±3 days) 
 
 
 
X (±3 days) 
Triplicate 12-Lead electrocardiogram 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam and vital signs 3 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis and HIV screen (HBsAg, HBsAB, HBcAb, 
HCVAb, HIVAb) 
X 
 
 
 
 
 
 
 
 
 
 
 
Alpha-fetoprotein, glycosylated HbA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
Liver Ultrasound (subjects with cirrhosis) 
X 
 
 
 
 
 
 
 
 
 
 
 
HCV genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
IL28B genotype 
 
X 
 
 
 
 
 
 
 
 
 
 
Enrollment 4 
 
X 
 
 
 
 
 
 
 
 
 
 
AE & Conmed Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Cohorts 1b, 2 to 16 may or may not include SMV. Dosing frequency will be qd except possibly for ODV which may also be dosed qod. 
2  Weight only collected at last treatment visit. 
3  Complete Physical Exams, including vital signs (BP, HR, RR, body temperature), are to be done at screening, predose on Day 1, early termination, safety follow-up 
visits. Symptom directed physical exams and vitals are to be collected as necessary at all other visits.  
4  Enrollment may take place up to 4 days before first dose.  
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Protocol No. AL-335-604 
Version 10.0, 03 May 2017 
 
Table 6-1. 
Schedule of Events for 8 or 12*-Week Treatment Groups  
Interval 
 
Assessments 
Day 
Week** 
Screen 
-50 to -1 
1 
2 
3 
1 
2 
3 
4 
5 
6 
7 
8 
PK Samples 5 
 
X 
 
 
 
X 
X 
X 
 
X 
 
X 
Hematology 6 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
Serum Chemistries 6 
X 
X 
 
 
X 
X 
 
X 
  
X 
  
X 
Urinalysis 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
ALT/AST 6 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
HCV RNA concentrations 7  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma for drug resistance monitoring 8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 9 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Optional stored serum sample 10 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
5  A single predose PK sample will be collected at each indicated visit for AL-335 (and metabolites), ODV and SMV concentrations for all subjects. In addition, PK 
samples will be collected at Weeks 3 and 6, 2-4 hours postdose, and at Weeks 4 and 8, 6-8 hours postdose. Subjects in the intensive PK subset will have the 
following samples collected at the Week 2 visit Predose (within 0.5 hour) and 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose. 
6 
Blood for routine safety evaluations should be collected in a fasted state. 
7 
Plasma for HCV RNA analysis to be collected predose at Day 1. 
8 
Plasma collected for HCV RNA resistance monitoring will be collected at the same time as HCV RNA quantification. The Day 1 samples must be collected predose. 
9 
Heterosexually active women of childbearing potential. A highly sensitive pregnancy test (e.g., urine or plasma) must be conducted immediately (within 4 days) 
prior to initiating treatment on Day 1 (local results may be used for this eligibility determination)  
10  For additional safety investigations as needed. 
* If a 12-week regimen is evaluated, the Week 5, 6, 7, and 8 visits will be repeated at Weeks 9, 10, 11, and 12, respectively. 
** Weekly visit may occur ±1 day from the expected visit date. 
 
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Version 10.0, 03 May 2017 
 
Table 6-2. 
Schedule of Events for a 6-Week Treatment Group 
Interval 
 
Assessments 
Day 
Week* 
Screen 
-50 to -1 
1 
2 
3 
1 
2 
3 
4 
5 
6 
AL-335+ODV±SMV 1 
 
< --------------------------------------------------------------------------------------------------------> 
Obtain informed consent before study procedures 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Height, Weight, BMI 2 
X 
 
 
 
 
 
 
 
 
X 2 
Drug Screen 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Echocardiogram  
X (±3 days) 
 
 
 
 
 
 
X (±3 days) 
 
X (±3 days) 
Triplicate 12-Lead electrocardiogram 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Physical Exam and vital signs 3 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Hepatitis and HIV screen (HBsAg, HBsAB, HBcAb, 
HCVAb, HIVAb) 
X 
 
 
 
 
 
 
 
 
 
Alpha-fetoprotein, glycosylated HbA1C 
X 
 
 
 
 
 
 
 
 
 
HCV genotype 
X 
 
 
 
 
 
 
 
 
 
IL28B genotype 
 
X 
 
 
 
 
 
 
 
 
Enrollment 4 
 
X 
 
 
 
 
 
 
 
 
AE & Conmed Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Cohorts 1b, 2 to 16 may or may not include SMV. Dosing frequency will be qd except possibly for ODV which may also be dosed qod. 
2  Weight only collected at Week 6. 
3  Complete Physical Exams, including vital signs (BP, HR, RR, body temperature), are to be done at screening, predose on Day 1, early termination, safety follow-up 
visits. Symptom directed physical exams and vitals are to be collected as necessary at all other visits.  
4  Enrollment may take place up to 4 days before first dose.  
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AL-335 
Protocol No. AL-335-604 
Version 10.0, 03 May 2017 
 
Table 6-2. 
Schedule of Events for a 6-Week Treatment Group 
Interval 
 
Assessments 
Day 
Week* 
Screen 
-50 to -1 
1 
2 
3 
1 
2 
3 
4 
5 
6 
PK Samples 5 
 
X 
 
 
 
X 
X 
X 
 
X 
Hematology 6 
X 
X 
 
 
X 
X 
 
X 
 
X 
Serum Chemistries 6 
X 
X 
 
 
X 
X 
 
X 
  
X 
Urinalysis 
X 
X 
 
 
X 
X 
 
X 
 
X 
ALT/AST 6 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
HCV RNA concentrations 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma for drug resistance monitoring 8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 9 
X 
 
 
 
 
 
 
X 
 
 
Optional stored serum sample 10 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
5  A single predose PK sample will be collected at each indicated visit for AL-335(and metabolites), ODV and SMV concentrations for all subjects. In addition, PK 
samples will be collected at Weeks 3 and 6, 2-4 hours postdose, and at Week 4, 6-8 hours postdose. Subjects in the intensive PK subset will have the following 
samples collected at the Week 2 visit Predose (within 0.5 hour) and 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose. 
6  Blood for routine safety evaluations should be collected in a fasted state. 
7  Plasma for HCV RNA analysis to be collected predose at Day 1. 
8  Plasma collected for HCV RNA resistance monitoring will be collected at the same time as HCV RNA quantification. The Day 1 samples must be collected predose. 
9  A highly sensitive pregnancy test (e.g., urine or plasma) must be conducted immediately (within 4 days) prior to initiating treatment on Day 1 (local results may be 
used for this eligibility determination) 
10  For additional safety investigations as needed. 
* Weekly visit may occur ±1 day from the expected visit date. 
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Version 10.0, 03 May 2017 
 
Table 6-3. 
Schedule of Events for a 4-Week Treatment Group 
Interval 
Assessments 
Screen 
-50 to -1 
Day 1 
Day 2 
Day 3 
Week 1* 
Week 2* 
Week 3* 
Week 4* 
AL-335+ODV±SMV 1 
 
< -------------------------------------------------------------------------------------------------------------- > 
Obtain informed consent before study procedures 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Height, Weight, BMI 2 
X 
 
 
 
 
 
 
X 2 
Drug Screen 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Echocardiogram 
X (±3 days) 
 
 
 
 
 
 
X (±3 days) 
Triplicate 12-Lead electrocardiogram 
X 
X 
 
 
X 
X 
X 
X 
Physical Exam and vital signs 3 
X 
X 
 
 
X 
X 
X 
X 
Hepatitis and HIV screen (HBsAg, HBsAB, 
HBcAb, HCVAb, HIVAb) 
X 
 
 
 
 
 
 
 
Alpha-fetoprotein, glycosylated HbA1C 
X 
 
 
 
 
 
 
 
HCV genotype/subtype 
X 
 
 
 
 
 
 
 
IL28B genotype 
 
X 
 
 
 
 
 
 
Enrollment 4 
 
X 
 
 
 
 
 
 
AE & Conmed Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
1 Cohorts 1b, 2 to 16 may or may not include SMV. Dosing frequency will be qd except possibly for ODV which may also be dosed qod. 
2  Weight only collected at Week 4. 
3  Complete Physical Exams, including vital signs (BP, HR, RR, body temperature), are to be done at screening, predose on Day 1, early termination, safety follow-up 
visits. Symptom directed physical exams and vitals are to be collected as necessary at all other visits. Vital signs will be collected at all visits indicated. 
4  Enrollment may take place up to 4 days before first dose.  
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Protocol No. AL-335-604 
Version 10.0, 03 May 2017 
 
Table 6-3. 
Schedule of Events for a 4-Week Treatment Group 
Interval 
Assessments 
Screen 
-50 to -1 
Day 1 
Day 2 
Day 3 
Week 1* 
Week 2* 
Week 3* 
Week 4* 
PK Samples 5 
 
X 
 
 
X 
X 
X 
X 
Hematology 6 
X 
X 
 
 
X 
X 
 
X 
Serum Chemistries 6 
X 
X 
 
 
X 
X 
 
X 
Urinalysis 
X 
X 
 
 
X 
X 
 
X 
ALT/AST 6 
X 
X 
 
 
X 
X 
X 
X 
HCV RNA concentrations 7 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma for drug resistance monitoring 8 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 9 
X 
 
 
 
 
 
 
X 
Optional stored serum sample 10 
X 
X 
 
 
X 
X 
X 
X 
 
5  A single predose PK sample will be collected at each indicated visit for AL-335 (and metabolites), ODV and SMV concentrations for all subjects. In addition, PK 
samples will be collected at Week 3, 2-4 hours postdose, and at Week 4, 6-8 hours postdose. Subjects in the intensive PK subset will have the following samples 
collected at the Week 2 visit Predose (within 0.5 hour) and 0.5, 1, 2, 3, 4, 6, 9, and 24 hours postdose. 
6  Blood for routine safety evaluations should be collected in a fasted state. 
7  Plasma for HCV RNA analysis to be collected predose at Day 1, 2 and 3.  
8  Plasma collected for HCV RNA resistance monitoring will be collected at the same time as HCV RNA quantification. The Day 1 samples must be collected predose. 
9  A highly sensitive pregnancy test (e.g., urine or plasma) must be conducted immediately (within 4 days) prior to initiating treatment on Day 1 (local results may be 
used for this eligibility determination) 
10  For additional safety investigations as needed. 
* Weekly visit may occur ±1 day from the expected visit date. 
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Version 10.0, 03 May 2017 
 
Table 6-4. 
Schedule of Events for Post-dosing (Safety and Virology) Follow-up Visits (All Treatment Cohorts) 
Post-dosing Follow-up 
Assessment 
Early 
Termination 
(ET) Visit 1 
Safety Follow-up Visit 
4 Weeks (±1 week) 
After the Last Actual 
Dose of Study Drug 
Virology Follow-up Visits (After end of Treatment 2 OR  
After Time of Treatment Failure [if earlier]) 3 
Week 24 
(±2 weeks) 
Week 4 
(±1 week) 4 
Week 8 
(±1 weeks) 
Week 12 
(±2 weeks) 
Week 18 
(±2 weeks) 
Physical Exam 5 
X 
X 
 
 
 
 
 
Echocardiogram 
X 
X 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
Triplicate 12 Lead ECG 
X 
X 
 
 
 
 
 
Liver Ultrasound (subjects with 
cirrhosis) 
 
 
 
 
 
 
X 
Serum Chemistry w/ ALT & AST 
X 
X 
 
 
 
 
 
Hematology 
X 
X 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
HCV RNA concentration 
X 
X 
X 
X 
X 
X 
X 
Plasma for drug resistance monitoring 
X 
X 
X 
X 
X 
X 
X 
AE & Conmed Evaluation 
X 
X 
X 
X 
X 
X 
X 
PK Samples 6 
X 
X 
X 
X 
X 
X 
X 
1  Subjects who prematurely discontinue from their assigned study treatment should return to the clinic as soon as possible for an Early Termination Visit. If the timing 
of the Early Termination Visit coincides with the Safety Follow up Visit, then assessments for the Early Termination Visit should be conducted. 
2  For subjects with less than lower limit of quantitation (<LLOQ) HCV RNA at actual end of treatment (EOT) (if prematurely discontinued treatment, discontinuation 
was for reasons other than on-treatment virologic failure (e.g., AE). 
3  See “Definitions” in the beginning of the protocol for definition of on treatment failure.   No subject will be followed for more than 24 weeks.  
4  Note: The Week 4 Virology Follow up Visit will coincide with the Safety Follow-up Visit for most subjects and may be replaced by the Safety Follow-up Visit in 
these cases; it will not coincide for subjects who have relapse or for subjects who discontinue early with <LLOQ HCV RNA. 
5 
Complete Physical Exams, including vital signs (BP, HR, RR, body temperature), are to be done at screening, predose on Day 1, early termination, safety follow-up 
visits. Symptom directed physical exams and vitals are to be collected as necessary at all other visits. 
6  PK sampling will be conducted for ODV at the time of visit.  
7  Heterosexually active women of childbearing potential. 
8 
For additional safety investigations as needed. 
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Pregnancy test7 
X 
X 
 
X 
X 
 
X 
Optional stored Serum Sample8 
X 
X 
 
 
 
 
 
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6.2 
On-study Evaluations and Procedures 
Where multiple procedures are scheduled at the same timepoint(s) relative to dosing, the 
following order of events should be adhered to, where possible: 
• Obtain ECGs first and then vital signs, as close as possible to scheduled times but prior to 
blood specimen collections.  
• All other procedures should be obtained as close as possible to the scheduled time, and 
may be obtained before or after blood specimen collection 
6.2.1 
Pharmacokinetic Blood Sampling 
Blood samples for PK analysis will be collected at the scheduled times via an indwelling catheter 
and/or direct venipuncture. Saline or heparin flushes may be used to maintain viability of 
indwelling catheters. Additional information may be found in the Pharmacokinetic Sample 
Processing Manual. 
The total volume of blood required for the intensive PK profile is up to 90 mL per subject, and 
approximately 20 mL for all other subjects 
Blood samples will be assessed for plasma concentrations of ALS-022335, ALS-022399 and 
ALS-022227, SMV, and ODV using validated liquid chromatography–tandem mass 
spectrometry methods. In addition, plasma PK samples may be stored for future analysis of the 
protein-binding and/or metabolite profile. 
6.2.1.1 
AL-335 
Details on the collection, processing, storage of AL-335 PK samples are provided in the 
Laboratory Manual. 
Blood samples will be collected to determine the concentration of ALS-022335, ALS-022399, 
ALS-022227 at times specified in the Schedule of Events, Table 6-1 through Table 6-4. 
6.2.1.2 
Odalasvir 
Details on the collection, processing, storage of ODV PK samples are provided in the Laboratory 
Manual. 
Blood samples will be collected to determine the concentration of ODV at times specified in the 
Schedule of Events, Table 6-1 through Table 6-4. 
6.2.1.3 
SMV 
Details on the collection, processing, storage of SMV PK samples are provided in the Laboratory 
Manual.  
Blood samples will be collected to determine the concentration of SMV at times specified in the 
Schedule of Events, Table 6-1 through Table 6-4. 
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For all samples, all efforts will be made to obtain the PK samples at the exact nominal time 
relative to dosing. Deviations will be defined in the study manual. The exact time of sample 
collection will be noted on the source document and the data collection tool.  
PK samples may also be collected on an ad hoc basis as a safety assessment in the event that a 
safety event arises, for which an understanding of drug exposure is clinically important. 
6.2.2 
Laboratory Evaluations 
Laboratory evaluations will be performed both locally, to enable time sensitive safety-driven 
decisions, and centrally, for eligibility determination (screening) and the final data analysis. The 
local laboratory result on Day 1 may be used to confirm continued eligibility.  
The central interpretation of laboratories should also be used for clinical decision making (e.g., 
need for additional workup) unless the local reading is considered sufficiently concerning that it 
is not appropriate to delay decision making until the central reading can be performed.  
In subjects that provide additional informed consent, an optional serum sample will be collected. 
This sample may be utilized as a back-up specimen for safety assessments. This sample may also 
be utilized to explore the impact patient characteristics and potential biomarkers have on 
treatment outcomes.  
6.2.3 
HCV RNA Evaluations 
Blood samples for the determination of HCV RNA levels will be taken at all timepoints, 
processed in real time (centrally) and closely monitored by the Sponsor. The procedures for 
sample collection, processing and storage will be provided in the laboratory manual.  
Plasma HCV RNA levels will be determined using an in vitro nucleic acid amplification test for 
quantification of HCV RNA in human plasma. 
Results will be communicated to the Investigators throughout the study. 
In case HCV RNA is detectable after previous undetectability, the results should be confirmed 
by an HCV RNA retest, which should be scheduled by the investigator as soon as possible 
(preferably within 2 weeks) after the HCV RNA results become available. This might require an 
unscheduled visit. At the time of the retest sample for HCV RNA, a sample for HCV resistance 
evaluation will also be collected. 
Changes in HCV RNA levels will not be reported as AEs or SAEs. 
6.2.4 
HCV Resistance Evaluation 
Sequencing of the HCV NS3/4A, NS5A and NS5B regions will be performed to identify 
pre-existing sequence polymorphisms and characterize emerging HCV viral variants. Blood 
samples for HCV resistance evaluation will be taken at all timepoints to identify pre-existing 
sequence polymorphisms and characterize the potential of emergence of viral resistance to 
AL-335, ODV and SMV. 
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The NS3/4A, NS5A and NS5B regions will be sequenced pre-treatment (from a baseline sample) 
by default in all subjects and post-baseline only in subjects not achieving SVR. Additional 
sequencing of samples may be requested upon review by the Sponsor’s virologist. 
Changes in viral genotype will be evaluated by the Sponsor’s virologist. They will not be 
reported as AEs or SAEs.  
Additional exploratory characterization of the viral genotype and phenotype may be performed. 
No human DNA analysis will be performed on these samples. 
6.2.5 
12-Lead Electrocardiograms  
The investigator will be responsible for evaluating the results and determining if any findings are 
of clinical significance. Throughout the study, triplicate ECGs will be obtained in a semi-
recumbent or recumbent position at the time points specified in Schedule of Events  
(Table 6-1 through Table 6-4). The subject should be at rest and in a (semi)recumbant position 
for at least 5 minutes before ECG recordings and remain resting and in that position during the 
recording. Triplicate ECGs will be performed 1-5 minutes apart and may be repeated at the 
investigator’s discretion to account for erroneous readings. Sequential ECGs will be collected 
until 3 useful recordings are obtained without artifact.  
The average of the 3 readings’ ECG intervals will be used to determine if the subject meets the 
entry criteria or fulfills criteria which would require study drug(s) discontinuation or additional 
workup.  
All ECG recordings must be performed using a standard high-quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements. Each ECG 
will be assessed by a central reader.  
The centrally read screening electrocardiogram results should be used for eligibility 
determination. The local reading of the ECG on Day 1 may be used to confirm continued 
eligibility. The central interpretation of electrocardiograms should also be used for clinical 
decision making (e.g., need for additional workup) unless the local reading is considered 
sufficiently concerning that it is not appropriate to delay decision making until the central 
reading can be performed.  
Digital ECG recording is required. A duplicate for each ECG tracing will be obtained. One copy 
will be sent electronically for assessment by the central reader and the other copy kept at the 
study center. 
For safety monitoring purposes, the investigator must review, sign and date all ECG tracings. 
Paper copies will be kept at the study center with the subject's clinical file as part of the 
permanent record. The ECG intervals (HR, PR, QRS, QT, QTcB, QTcF), information on T- 
(normal or abnormal) and U-waves (absent/normal or abnormal), any clinically significant ECG 
abnormalities, and remarks will be recorded on the CRF. All ECGs will be compared over time 
as an assessment of safety by a central reader.  
6.2.6 
Echocardiograms 
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Echocardiograms will be performed at regular intervals (Section 6.1, Schedule of Events) and 
according to a standard protocol (see Study Manual). There will be a ±3-day visit window for 
these assessments except for screening visit. A variety of echocardiographic parameters, 
including ejection fraction and diastolic parameters will be quantitated and compared over time 
as an assessment of safety by a central reader.  
The centrally read echocardiogram results should be used for eligibility determination. The 
central interpretation of echocardiograms should also be used for clinical decision making (e.g., 
need for additional workup) unless the local reading is considered sufficiently concerning that it 
is not appropriate to delay decision making until the central reading can be performed.  
6.2.7 
Vital Signs 
Vital signs (oral or body temperature, RR, automated supine BP and HR) will be obtained in a 
semi-recumbent or recumbent position after 5 minutes of rest. Blood draws will take precedence 
over vital signs in the event that the 2 procedures need to be conducted at the same time. In this 
case, vital signs should be obtained as close to the scheduled time as possible, after ECG 
assessments and prior to blood collections.  
6.2.8 
Physical Examinations 
Complete Physical Exams, including vital signs (BP, HR, RR, body temperature), are to be done 
at screening, predose on Day 1, early termination, safety follow-up visits. A brief symptom 
directed examination will be conducted at all other timepoints as indicated in the Schedule of 
Events. BMI will be calculated by clinic staff at the Screening visit using the following formula: 
BMI = weight in kg ÷ (height in meters)2 
6.2.9 
Contraception 
Contraception requirements from screening through completion of the study are defined in the 
Inclusion criteria (see Sections 4.2 and 4.3). 
7.0 
SAFETY MONITORING AND REPORTING 
7.1 
Definitions 
7.1.1 
Pretreatment Events 
A pretreatment event is any event that meets the criteria for an AE/SAE and occurs after the 
subject signs the ICF but before receiving the first administration of study drug. 
7.1.2 
Adverse Events 
An AE is any event, side effect, or untoward medical occurrence in a subject enrolled in a 
clinical trial whether or not it is considered to have a causal relationship to the study drug. An 
AE can therefore be any unfavorable and unintended sign, symptom, laboratory finding outside 
of normal range with associated clinical symptoms or suspected latent clinical symptoms in the 
opinion of the investigator, physical examination finding, or disease temporally associated with 
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the use of the study drug, whether or not the event is considered related to the study drug. 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. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the subject was enrolled in the study are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study (e.g., surgery was performed earlier than 
planned). 
7.1.3 
Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose that:  
• Results in death: This includes deaths that appear to be completely unrelated to study 
medication (e.g., a car accident). 
• Is a life-threatening event: An event that places the subject at immediate 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 prolonged hospitalization of an existing 
hospitalization. 
• Results in permanent or prolonged (at least 28 days in duration) disability or incapacity. 
• Is a congenital anomaly or birth defect in the offspring of a study subject. 
• Medically important event: An event that may not be immediately life-threatening, or 
result in death or hospitalization, or require intervention to prevent one of the outcomes 
listed above, but is considered medically significant for other reasons. An opportunistic 
or otherwise unusual infection for the investigator’s practice, such as tuberculosis, will be 
considered medically significant. 
The term severe is used to describe the intensity of a specific event (as in mild, moderate, or 
severe); the event itself, however, may be of minor medical significance (such as severe 
headache). This is not the same as serious, which is based on outcome of the event, as described 
above. Seriousness, not intensity, serves as a guide for defining regulatory reporting obligations. 
7.2 
Documenting and Reporting of AEs (including SAEs) 
Adverse events will be evaluated and documented using the grading scales contained in the 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(November 2014) and shown in Appendix F. 
7.2.1 
Documenting and Reporting Pretreatment Events 
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For enrolled subjects, record all pretreatment AEs that occur after the subject signs the ICF but 
before the first study drug administration on the AE CRF and Clinical Trials SAE Form (if 
applicable). The AE CRF and SAE form will indicate that the event occurred prior to the first 
dose of study drug. 
7.2.2 
Documenting and Reporting AEs 
Record all AEs that occur from Day 1 (from start of study medication administration) to the 
follow-up visit, regardless of the intensity, seriousness, or relationship to study drug, on the AE 
CRF, for all enrolled subject. Subjects who do not enroll (i.e., screen failures), collect AEs until 
the time of screen failure. 
Once an event has resolved, any recurrence will be reported as a new event with a corresponding 
grade. 
Clinically significant changes in objective findings (e.g., laboratory, ECG, physical examination) 
should be considered AEs only if they meet the following criteria: 
• Associated with accompanying symptoms; and/or, 
• Require medical/surgical intervention; and/or, 
• Lead to discontinuation from the study; and/or 
• Lead to significant additional concomitant drug treatment, or other therapy; and/or, 
• Lead to any of the outcomes included in the definition of an SAE.  
Whenever possible, the etiology of the abnormal findings (rather than the abnormal finding(s) 
itself) should be documented as the AE. Repeated additional tests and/or other evaluations 
required to establish the significance and etiology of an abnormal result should be obtained when 
clinically indicated. An AE includes the following: 
• Pre-existing event that increases in frequency or intensity.  
• Condition detected or diagnosed during the study period, even though it may have been 
present, in retrospect, prior to the first dose of study drug. 
• Laboratory abnormalities outside of normal limits and requiring therapeutic intervention.  
• An overdose of the study drug without any signs or symptoms will be considered an AE. 
A calculated dose that exceeds its correct dose by 10% or more and is administered to the 
subject will be considered an overdose and documented as an AE. 
The following events will not be identified as AEs in this study: 
• Progression or exacerbation of the subject’s underlying disease. However, clinical 
sequelae that result from disease progression, such as pleural effusion or small bowel 
obstruction, are reportable as AEs.  
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, etc); however, 
the condition (the “triggering event”) that leads to the procedure may be an AE. 
• Pre-existing conditions present or detected prior to the first dose of study drug that do not 
worsen. 
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7.2.3 
Assigning Attribution of AEs 
The investigator must attempt to determine the cause of each event. To ensure consistency of 
AE/SAE causality assessments, investigators should apply the following guideline: 
Related:  
There is an association between the event and the administration of investigational study drug, a 
plausible mechanism for the event to be related to the investigational study drug and causes other 
than the investigational study drug have been ruled out, and/or the event re-appeared on re-
exposure to the investigational study drug. 
Possibly Related: 
There is an association between the event and the administration of the investigational study drug 
and there is a plausible mechanism for the event to be related to investigational study drug, but 
there may also be alternative etiology, such as characteristics of the subject’s clinical status or 
underlying disease. 
Unlikely Related: 
The event is unlikely to be related to the investigational study drug and likely to be related to 
factors other than investigational study drug. 
Not Related: 
The event is related to an etiology other than the investigational study drug (the alternative 
etiology must be documented in the study subject’s medical record). 
7.2.4 
Classifying Action Taken With Study Drug 
Classification 
Definition 
Dose Not Changed 
Study Drug dose not changed in response to the AE 
Drug Interrupted 
Study drug administration interrupted in response to an AE 
Drug Withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not Applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” should be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt or withdraw treatment is possible. 
7.2.5 
Classifying AE Outcome 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved 
with sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/ 
Not resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” should be used when death is at least possibly 
related to the adverse event. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow up) 
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7.2.6 
Documenting and Reporting Serious Pretreatment Events and SAEs 
All SAEs that occur after obtaining informed consent through the Follow–up visit, regardless of 
causality, must be reported by the investigator to the Sponsor designee for SAE reporting. See 
study manual for reporting specifics. In addition, all SAEs, including those that result in death, 
that occur after the Completion Visit and that are considered related to study drug(s) must be 
reported to Sponsor's designee within 24 hours. 
SAEs will be recorded on the Clinical Trials SAE Form using a recognized medical term or 
diagnosis that accurately reflects the event. SAEs will be assessed by the investigator for 
severity, relationship to the investigational study drug(s) and possible etiologies. On the Clinical 
Trials SAE Form, relationship to study drug(s) will be assessed only as related or not related, and 
severity assessment will not be required. For the purposes of study analysis, if the event has not 
resolved at the end of the study reporting period, it will be documented as ongoing. For purposes 
of regulatory safety monitoring, the investigator is required to follow the event to resolution and 
report to Sponsor’s designee the outcome of the event using the SAE Form. 
The investigator is responsible for notifying the Sponsor within 24 hours of identifying an 
SAE, regardless of the presumed relationship to the investigational study drug. The SAE 
Form should be completed for new/initial events as well as to report follow-up information 
on previously reported events. Investigators are asked to report follow-up information as 
soon as it becomes available, to ensure timely reporting to Health Authorities.  
The SAE Form should be faxed to Sponsor's designee using the fax cover sheet provided. 
Alios BioPharma or its designees, as study Sponsor, is responsible for reporting suspected, 
unexpected, serious adverse reactions (SUSARs) involving the study drug(s) to all regulatory 
authorities, and participating investigators, in accordance with International Conference on 
Harmonisation (ICH) Guidelines, and/or local regulatory requirements, as applicable.  
7.2.7 
Documenting and Reporting of Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 6 months after the last dose of study drug/s. 
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, study treatment must be permanently discontinued immediately. The investigator must 
notify the Sponsor’s Medical Monitor and CRO within 1 business day of the sites’ knowledge of 
the subject’s (or partner’s) pregnancy, by utilizing the Pregnancy Initial Report Form. The 
subject or partner will be followed until end of pregnancy and the infant will be followed for 1 
year after the birth, provided informed consent is obtained. A separate ICF will be provided to 
explain these follow-up activities. Pregnancy itself does not constitute an AE.  
7.3 
Follow-up of AEs and SAEs 
Follow all AEs (serious and non-serious) until resolution or otherwise explained, the subject 
dies, the event stabilizes and is not expected to further resolve, or when alternative therapy is 
instituted, whichever occurs first. If alternative therapy is instituted, it should be documented. 
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Alios BioPharma may request that the investigator perform or arrange for supplemental 
measurements or evaluations to further clarify the nature of the event. 
7.4 
Sponsor’s Review of AEs and SAEs 
Alios BioPharma will maintain an ongoing review of all AEs and SAEs.  
7.5 
Special Safety Considerations 
7.5.1 
Creatine Kinase 
Because nucleosides, as a class, have a known risk of mitochondrial toxicity, which is often 
manifest 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. 
In the event a subject develops clinical signs suggestive of muscle injury (e.g., proximal 
weakness, myalgias), a thorough workup (e.g., assessment of CK, CK-MB fraction (or, 
alternatively, troponin), aldolase, myoglobin, calcium, phosphate, creatinine, and urinalysis) for 
muscle injury should be performed.  
If a study subject’s CK is found to be elevated >3×ULN (without a concomitant proportionate 
CK-MB or troponin elevation), the following stopping criteria for CK elevations should be 
applied (Pasternak et al. 2002): 
In subjects (whether symptomatic or asymptomatic) without a clinical history to suggest etiology 
of CK elevation (e.g., recent exercise or exposure to medication with known risk of myopathy): 
• If CK is ≥20× ULN, immediately re-draw and repeat the test. If the repeat remains 
≥20× ULN, discontinue study medication 
• If CK is ≥3 – <20×ULN: 
o Continue study medication. Assess CK, CK-MB/troponin every ~72 hours 
(follow-up assessments) until the CK has normalized (follow-up assessments) 
o If any follow-up CK assessment is ≥20× ULN, discontinue study medication 
o if the 3rd follow-up CK assessment (i.e., ~9 days after CK elevation was first 
recognized) is ≥ the prior follow-up CK assessment, discontinue study medication  
In subjects with a clinical history suggestive of a non-study drug-related etiology for a CK 
elevation ≥3×ULN (e.g., recent exercise or exposure to medication with known risk of 
myopathy): 
• Study medication may be continued. These patients should immediately discontinue the 
putative cause of their CK elevation and the CK and CK-MB/troponin should be assessed 
every ~72 hours (=follow-up assessment).  
• If initial CK is ≥3- <5× ULN, continue study medication unless follow-up CK 
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assessments are increased to ≥20× ULN  
• If initial CK is ≥5× ULN, continue study drug dosing and assessing follow-up CK and 
CK-MB/troponin every ~72 hours. If the 3rd follow-up CK assessment (i.e., ~9 days after 
CK elevation was first recognized) is ≥ the prior follow-up CK assessment, discontinue 
study medication.  
For any study subject with a treatment-emergent CK >1.5- <3× ULN, consider repeat CK, 
CK-MB/troponin in ~72 hours and continue testing until CK decreases 
If CK-MB/troponin rises commensurately with elevation of CK, an assessment for cardiac 
ischemic injury (e.g., serial EKG, troponin assessments) should be initiated. 
If a subject that experiences CK elevations also demonstrates clinical or laboratory evidence of 
renal insufficiency/damage or other clinically significant muscle signs or symptoms (e.g., 
proximal weakness), study medication should be stopped regardless of the magnitude of the CK 
elevation. 
In all cases where a CK >10× ULN or discontinuation of study drug is planned due to 
suspected muscle injury, the Sponsor Medical Monitor MUST be notified within 24 hours 
so that the clinical case and workup and treatment strategy can be discussed.  
7.5.2 
Cardiotoxicity 
A theoretical risk of nucleosides is mitochondrial toxicity that can manifest as cardiac 
toxicity/congestive heart failure. Surveillance for this theoretical risk will be done in this study 
via assessments of AEs, ECGs and echocardiograms, which will be obtained at specified 
timepoints during the treatment period in this study.  
In order to effectively monitor for potential treatment-related cardiotoxicity during the study, 
subjects presenting at screening must have:  
• ECG PR interval must be <200 msec and there must be no evidence of any conduction 
blocks.  
• echocardiogram ejection fraction (EF) must be ≥55%.  
 
During the treatment period, emergence of or changes in symptoms or clinically significant 
findings in ECG may trigger the following stopping criteria:  
If a first degree AV block is diagnosed and: 
• The PR interval is >200 msec but ≤240 msec, study drugs can be continued. Close 
monitoring with weekly ECG is recommended. 
• The PR interval is >240 msec but ≤300 msec (confirmed by a repeat triplicate analysis at 
least 30 minutes after the initial assessment), an assessment of the subject’s clinical 
status, including symptoms, physical examination and other clinical parameters should be 
made. Based on this assessment, the study drugs may or may not be continued. Close 
monitoring with weekly ECG is recommended. 
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• The PR interval is >300 msec (confirmed by a repeat triplicate analysis at least 
30 minutes after the initial assessment, irrespective of presence or absence of clinical 
symptoms), ODV must be discontinued. The Investigator and Sponsor Medical Monitor 
must determine whether or not continued dosing with AL-335 and SMV is acceptable for 
subjects that discontinue ODV.  
• 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. The Investigator and Sponsor 
Medical Monitor must determine whether or not continued dosing with AL-335 and SMV 
is acceptable for subjects that discontinue ODV.  
 
All study medications must be discontinued: 
• In asymptomatic patients with no clinical evidence of congestive heart failure:  
o If the absolute decline from baseline in EF is >10% AND the post-baseline EF is 
<50%; e.g., 60% 49%) 
 
NOTE: For asymptomatic subjects without clinical evidence of heart failure, but with an 
apparent decline in EF of >10%, an urgent repeat echocardiogram may be performed to 
confirm the finding. If confirmed and <50%, all study drugs should be discontinued as 
described above. If the confirmatory EF is ≤10%, the Investigator and Medical Monitor 
should perform a cardiology assessment (see below) and, based on the subject’s overall 
clinical picture, decide whether or not to discontinue study drug.  
o If the absolute decline from baseline in EF is >5% and ≤10%, an urgent 
unscheduled visit must occur for the assessment of the subject’s clinical status, 
including symptoms, physical exam, and other clinical parameters. This 
assessment should occur before deciding whether to stop or continue study drugs.  
 
• In symptomatic subjects (e.g., dyspnea, orthopnea) or subjects with signs of congestive 
heart failure (e.g., S3 gallop, pedal edema, pulmonary edema): 
o If the absolute decline from baseline in EF is ≥5% (e.g., 61%54%) 
o The Investigator and Sponsor Medical Monitor may also deem it necessary to 
discontinue study drug in symptomatic subjects with an absolute decline from 
baseline in EF of <5%  
 
• In asymptomatic or symptomatic subjects with clinical evidence of heart failure: 
o If absolute decrease in EF from screening is >10%, these subjects must undergo 
mandatory assessment (see below) and have an urgent cardiology referral; the EF 
decrease must be reported to the Medical Monitor within 24 hours so that the 
clinical case and workup and treatment strategy can be discussed. 
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Subjects with an absolute decrease from screening of >5% to ≤10% in LVEF must have an 
urgent unscheduled visit for further assessment as soon as possible. 
The cardiology assessment should include, but is not limited to, the following: 
• Cardiopulmonary review of systems and physical examination, 
• Troponin I assessment - (serial assessments may be indicated) 
• BNP or Pro-BNP (serial assessments may be indicated) 
• 12-lead ECG and 
• Additional echocardiography (at study approved facility) – if clinically indicated, at a 
frequency determined by the Investigator’s judgment.  
 
Echocardiography must be performed at study approved facility on any subject who develops 
symptoms or signs of possible congestive heart failure (e.g., dyspnea, orthopnea, S3 gallop, 
pedal edema) during the study, regardless of the timing of such symptoms, including during the 
Follow-up Period. 
7.5.3 
Prolonged QTc (i.e., >500 msec or change from baseline of >60 msec) 
If a post-baseline QTc is found to be prolonged to >500 msec or if there is a change from 
baseline of >60 msec in repeat ECG assessments (e.g., triplicate ECGs) and this change is 
deemed clinically significant, all study drugs should be discontinued. Additional cardiac workup 
may be performed at the discretion of the Investigator. Any subject with prolonged QTc should 
be advised to discontinue and avoid any medications known to prolong QTc. In addition, serial 
ECGs (approximately weekly) should be assessed until the subject’s QTc has returned to 
baseline.  
7.5.4 
Renal Safety Monitoring 
Renal safety will be monitored by evaluating urine dipstick leukocyte esterase, serum creatinine 
levels, eGFR and serum chemistry results. The investigator should closely monitor for clinically 
relevant changes in serum creatinine and eGFR. In case renal complications develop, subjects 
must be treated as clinically appropriate. Dosing may continue if the renal complication is 
considered not to be related to study drug in the opinion of the investigator. 
For eGFR monitoring, the following guidance should be followed: 
• If the eGFR value is <30 mL/min/1.73m2, the value must be confirmed by repeat testing 
during an unscheduled visit, preferably within 1 week after the results become available 
to the study site.  
• If the eGFR value is confirmed to be <30 mL/min/1.73m2, all study drugs must be 
interrupted and renal function should be followed as clinically appropriate.  
Recommencement of treatment should be discussed with the Sponsor on a case-by-case basis. 
7.6 
Rash (including photosensitivity conditions) 
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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. 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 7-1.  
Discontinuation of SMV should be considered if a photosensitivity reaction occurs and subjects 
should be monitored until the reaction has resolved. If a decision is made to continue SMV in the 
setting of a photosensitivity reaction, expert consultation is advised. 
Table 7-1. 
Guidelines for Subjects Developing Rash Grade 1 to Grade 4 
WHO Grade 
Rash Definition 
Investigator Action 
Grade 1 Rash (with or 
without pruritus) a 
Erythema 
May continue intake of study drugs 
at the investigator’s discretion. 
Grade 2 Rash (with or 
without pruritus) b 
diffuse, maculopapular rash, OR dry 
desquamation 
May continue intake of study drugs 
at the investigator’s discretion. 
Grade 3 Rash 
• 
vesiculation, moist desquamation, or 
ulceration OR 
• 
any cutaneous event with one of the 
following: 
- elevations in AST/ALT >2× baseline value 
- fever >38°C or 100°F 
- eosinophils >1.00 ×103/µL 
Permanently discontinue the intake 
of SMV. 
May continue intake of ODV and 
AL-335 at the investigator’s 
discretion. 
No rechallenge is allowed. 
Grade 4 Rash 
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. 
a In case the rash evolves from a Grade 1 to a higher grade, management of the rash should follow the guidelines 
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indicated for Grade 2 or Grade 3 or 4 rash, respectively 
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. 
c Monotherapy with any of the study drugs is not allowed. 
 
When safety blood samples are drawn as per the rash management guidelines, these should be 
processed by the local laboratory; a separate blood sample should also be sent for central 
laboratory confirmation. The following parameters will need to be tested: AST, ALT, 
sedimentation rate, complete blood cell count (including hemoglobin, hematocrit, red blood cell 
count, white blood cell 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. 
The subject may be treated symptomatically until the rash resolves. Oral antihistamines (e.g., 
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 WHO Toxicity Grading Scale. 
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. 
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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 Grades 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. 
• 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 must be taken. For these and all subsequent local laboratory blood sample assessments, 
the values of the assessments need to be transcribed in the eCRF by the study-site personnel. 
The subject should be advised to contact the investigator immediately if there is any 
worsening of the rash, if any systemic signs or symptoms appear, or if mucosal involvement 
develops. If appropriate, sun protection counseling should be provided. 
In case the rash evolves from a Grade 2 to a Grade 3 to 4 rash, management of the rash should 
follow the guidelines specified for Grade 3 to 4 rash. 
Grade 3 or Grade 4 Rash 
A Grade 3 rash is defined as a rash associated with: 
• vesiculation, moist desquamation, or ulceration OR 
• any cutaneous event with one of the following: 
- 
elevations in AST/ALT >2× baseline value 
- 
fever >38°C or 100°F 
- 
eosinophils >1.00×103/µL 
- 
serum sickness-like reaction 
Subjects will permanently discontinue SMV and may continue ODV and AL-335 (monotherapy 
with any of the study drugs is not allowed). No rechallenge is allowed. 
A Grade 4 rash is defined as: 
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• 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. 
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. 
7.7 
Acute Allergic Reaction 
Oral antihistamines (e.g., 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 7-2. 
Table 7-2. 
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. 
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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. 
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. 
7.8 
Liver Function Tests 
Liver chemistry management criteria have been designed to ensure subject safety. When subjects 
meet the liver chemistry threshold criteria, the subject’s clinical case should be carefully 
reviewed with the medical monitor, additional testing performed, and the subject monitored until 
liver chemistries resolve, stabilize, or return to baseline values.  
In situations requiring additional liver chemistry monitoring, every attempt should be made to 
obtain the following after discussion with the medical monitor: 
Viral hepatitis serology including: 
− Hepatitis A immunoglobulin M (IgM) antibody 
− HBsAg and hepatitis B core antigen IgM antibody 
− HCV RNA 
− Cytomegalovirus IgM antibody 
− Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing) 
− Hepatitis E IgM antibody 
 
• Blood samples for study medication PK analysis. If study treatment is discontinued, 
blood samples should be obtained within 2 days of the last dose of study drug. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of the study 
drug before blood sample draw in the CRF. If the date or time of the last dose is unclear, 
provide the subject’s best approximation. If the date/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period indicated above, do 
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not obtain the PK samples. Instructions for sample handling and shipping are in the 
Laboratory Manual. 
• Serum creatine phosphokinase and lactate dehydrogenase 
• If total bilirubin ≥ 2× ULN, fractionated bilirubin 
• Complete blood count with differential to assess eosinophilia 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the CRF 
• Record use of concomitant medications, acetaminophen, herbal remedies, other OTC 
medications, or putative hepatotoxins, on the CRF 
• Record alcohol use on the liver event alcohol intake page of the CRF 
The following are required for subjects who meet the ALT and bilirubin management criteria but 
are optional for other abnormal liver chemistries and should be discussed with the medical 
monitor: 
• Antinuclear antibody, antismooth muscle antibody, and type 1 anti-liver/kidney 
microsomal antibodies 
• Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution to 
liver injury, detectable by high-performance liquid chromatography assay more than 1 
week following acetaminophen use) (James et al. 2009) 
• Liver imaging (ultrasound, magnetic resonance, or computed tomography) to evaluate 
liver disease 
7.9 
ALT, AST, 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 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 benign 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 direct-acting 
antiviral regimens where SMV is administered without RBV compared to when it is 
administered with RBV.16 
Management of treatment-emergent AST, ALT and/or bilirubin elevations will take into account 
the protocol-defined procedures outlined in Table 7-3, Table 7-4, and Table 7-5. 
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Table 7-3. 
Treatment-Emergent Grade 1 to Grade 4 ALT or AST Elevation and Grade 
1 to Grade 4 Total Bilirubin Elevation 
WHO Toxicity Grade 
AST or ALT, Ranges 
Total Bilirubin, Ranges 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
≥1.25 to ≤2.5× ULN 
>2.5 to ≤5.0× ULN 
>5.0 to ≤10.0 × ULN 
>10.0 × ULN 
≥1.1 to ≤1.5× ULN 
>1.5 to ≤2.5× ULN 
>2.5 to ≤5.0× ULN 
>5.0× 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× 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. 
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 7-4). 
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 (e.g., hereditary 
hyperbilirubinemia [Gilbert’s syndrome] or concomitant medication associated event), subjects 
may continue the study drugs or have SMV discontinued while ODV and AL-335 can be 
continued at the investigator’s discretion (Table 7-5). 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× 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. 
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Table 7-4. 
Guidelines for Subjects Developing ALT and/or AST Elevations 
WHO Toxicity Grade 
Ranges 
Investigator Action 
Grade 1 
≥1.25 to ≤2.5× ULN 
May continue intake of study drugs at the investigator's 
discretion. Monitor for progressive increase in ALT and/or AST 
levels 
Grade 2 
>2.5 to ≤5.0× ULN 
May continue intake of study drugs at the investigator's 
discretion. Monitor for progressive increase in ALT and/or AST 
levels 
Grade 3 
>5.0 to ≤10.0× ULN 
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. 
 
May continue study drugs at the investigator’s discretion (upon 
agreement with the Sponsor) if value is ≤2× 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. 
Grade 4 
>10.0× ULN 
If the Grade 4 ALT and/or AST value is >2× 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  
1) 
ALT of >2x ULN AND >2X the lowest value during the study  
OR 
2) 
any treatment emergent grade 3 ALT elevation (>5 x 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 ab positive 
at screening or baseline). If HBV reactivation is confirmed, then appropriate treatment for HBV 
should be started if clinically appropriate. 
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Table 7-5. 
Guidelines for Subjects Developing Bilirubin Elevations 
WHO Toxicity Grade 
Ranges 
Investigator Action 
Grade 1 
≥1.1 to ≤1.5× ULN 
May continue intake of study drugs at the investigator’s 
discretion. Monitor for progressive increase in bilirubin levels. 
Grade 2 
>1.5 to ≤2.5× ULN 
May continue intake of study drugs at the investigator’s 
discretion. Monitor for progressive increase in bilirubin levels. 
Grade 3 
>2.5 to ≤5.0× ULN 
May continue intake of study drugs at the investigator’s 
discretion. Monitor for progressive increase in bilirubin levels. 
Grade 4 
>5.0× ULN 
A confirmatory measurement should be performed within 
72 hours after receipt of the results. If the value is confirmed and: 
• 
Not considered a sign of worsening liver disease, or if there is 
an identifiable cause a for the confirmed value, subjects may 
continue study drugs or have SMV discontinued while ODV 
and AL-335 can be continued at the investigator’s 
discretion. b 
• 
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. For example, hereditary hyperbilirubinemia (Gilbert’s syndrome) or concomitant medication associated event. 
b. Monotherapy with any of the study drugs is not allowed. 
8.0 
STUDY VARIABLES AND MEASUREMENTS 
8.1 
Safety Variables/Measurements 
Safety evaluation will include AEs and SAEs, vital signs, laboratory tests (including hematology 
and serum chemistries), ECG, echocardiograms, physical examination, urinalysis, and pregnancy 
tests. 
8.1.1 
Adverse Events 
Adverse events, including pretreatment events, will be recorded from the time of consent through 
the SVR24 visit. All AEs/SAEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
8.1.2 
Clinical Laboratory Measurements 
Clinical laboratory variables, including hematology, serum chemistries, urinalysis, and 
pregnancy testing, will be assessed at screening. Hematology, serum chemistries, and pregnancy 
testing will be evaluated periodically during the study as indicated in this protocol. Local labs 
will be used for real time clinical decision making, while central labs will be used for purposes of 
the clinical database.  
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8.1.3 
Prior and Concomitant Medications 
Use of all medications and supportive therapy from within 30 days of the screening visit through 
study completion will be recorded. All concomitant medications will be mapped using the WHO 
Drug Dictionary. 
8.2 
Efficacy Variables/Measurements 
HCV RNA will be measured in all subjects (Section 6.2.3).  
The key efficacy variables include the proportion of subjects who achieve SVR demonstrated by 
sustaining HCV RNA <LLOQ 4, 8, 12, 18 and 24 weeks after the end of treatment (SVR4, 
SVR8, SVR12, SVR18 and SVR24), regardless of whether or not the subject completed the 
assigned treatment regimen. 
The results will be presented by treatment group by means of descriptive statistics.  
The SVR rates will also be presented by subgroups defined by baseline characteristics such as 
HCV genotype, prior HCV treatment, and IL-28B genotype status. 
Additional efficacy variables to be analyzed include: 
• The proportion of subjects who have relapse (i.e., who had <LLOQ HCV RNA at actual 
end of treatment (EOT) followed by ≥LLOQ HCV RNA after planned EOT) 
• The proportion of subjects who achieve undetectable HCV RNA <LLOQ (undetectable) 
at Weeks 2, 4, 6, and 8 after the first dose of study drug 
• Time to achieve HCV RNA <LLOQ and <LLOQ undetectable 
• The proportion of subjects who have on treatment failure 
• The proportion of subjects who achieve SVR12 by IL-28B genotype (CC or non-CC) 
8.2.1 
Virologic Response 
Virologic response is quantitative HCV RNA concentration <LLOQ at any timepoint post-first 
dose of study drug. An SVR is HCV RNA <LLOQ at Weeks 4, 8, 12, 18 or 24 after cessation of 
study treatment. 
8.2.2 
On-Treatment Failure 
Subjects who did not achieve SVR12 and with confirmed HCV RNA ≥LLOQ at the actual end 
of study drug treatment. Includes subjects: 
• With viral breakthrough, defined as a confirmed increase of >1 log10 in HCV RNA from 
nadir, or confirmed HCV RNA of >100 IU/mL in subjects whose HCV RNA had 
previously been <LLOQ while on treatment. 
• With inadequate virologic response, defined as <1 log10 decline from baseline in HCV 
RNA after 4 weeks of treatment 
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• Who do not experience viral breakthrough or inadequate virologic response and have 
confirmed HCV RNA ≥LLOQ at the actual end of study drug treatment (e.g., completed 
study drug treatment, discontinued due to adverse events, withdrawal of consent). 
8.2.3 
Relapse 
Subjects who achieved HCV RNA <LLOQ at the actual end of study drug treatment and 
developed HCV RNA ≥LLOQ during post-treatment follow up. 
8.3 
Viral Resistance 
Blood samples will be collected from subjects to identify pre-existing sequence polymorphisms 
and characterize the potential of emergence of viral resistance to AL-335, ODV and SMV 
(Section 6.2.4).  
8.4 
PK Measurements 
Blood samples will be collected from all subjects at specified times throughout the study for the 
determination of PK parameters for AL-335 and its metabolites, SMV, and ODV (time points 
specified in Table 6-1 through Table 6-4). 
Population PK parameters will be estimated by using non-linear mixed effects modeling. In the 
PK substudy, PK parameters will be estimated using standard non-compartmental methods.  
All calculations will use the actual times recorded on the CRF. AL-335, SMV, and ODV plasma 
concentrations and computed PK parameters will be listed by subject and summarized by 
treatment group (mean, geometric mean, standard deviation, coefficient of variation, minimum, 
maximum, number of observations), as appropriate. Individual and mean (by time) 
concentrations versus time will be plotted by treatment group on both linear and natural 
logarithm scales. 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
General Considerations 
Continuous data will be summarized by descriptive statistics, including number of subjects, 
mean, standard deviation, median, and range. Categorical data will be summarized by the 
number and percentage of subjects. A detailed analysis plan for the analysis of safety data, PK 
data, HCV RNA data, and viral sequencing data will be presented in a statistical/virological 
analysis plan(s) (SAP) before the database is locked for final analysis. An interim data review 
may be conducted which will be documented in the analysis plan. 
9.2 
Study Endpoints 
9.2.1 
Primary Endpoint 
• Safety data including but not limited to tabulation of AEs, physical exam, vital signs, 12-
lead ECGs, echocardiogram, and clinical laboratory results (including chemistry, 
hematology, and urine). 
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9.2.2 
Secondary Endpoints 
• The proportion of subjects who have an SVR (i.e., HCV RNA concentration <LLOQ 
(<15 IU/mL) at 4, 8, 12, 18, 24 weeks after the actual end of study treatment  
• PK parameters for AL-335 (and metabolites), ODV and SMV in plasma. 
• The proportion of subjects who have virologic relapse during follow up 
• The proportion of subjects who have on-treatment failure while receiving study 
medication 
• Viral kinetics, as determined at different timepoints during treatment by the proportion of 
subjects who achieve 
- HCV RNA <LLOQ Undetectable  
- HCV RNA <LLOQ  
• Time to achieve undetectable HCV RNA and <LLOQ HCV RNA 
• The amino acid sequence of the NS5A, NS5B and NS3/4A proteins at baseline and 
post-baseline in subjects who fail treatment.  
• Effect of various baseline and host disease-related characteristics on treatment outcome 
9.3 
Determination of Sample Size 
Up to 320 subjects with GT1, GT2 and GT3 CHC will be enrolled. Since there is no formal 
statistical hypothesis testing, no formal sample size calculation has been performed.  
With a total sample size of 320 subjects, the probability to observe an AE with an incidence of 
1% is 96%. The probability to observe an AE with an incidence of 0.1%, 0.5% and 0.8% is 27%, 
80%, and 92%respectively. 
A sample size of 20 evaluable subjects per arm is considered adequate for estimation of PK 
parameters for each individual compound in the combination regimen. With this sample size, the 
point estimate of the AUC geometric mean is anticipated to fall within 74.2% and 134.8% of the 
true value with 90% confidence, assuming an intersubject standard deviation of 0.77 with respect 
to steady-state log-transformed AUC0-24h. 
Further, with an expected SVR rate of 90%, and 20 subjects per arm, the corresponding 95%, 2-
sided confidence interval (CI) is 68.3% to 98.8%. With 95% SVR, the corresponding 95% CI 
ranges from 75.1% to 99.9%. 
Therefore, a total sample size of up to 320 subjects is considered sufficient to explore the safety, 
pharmacokinetics, and efficacy of the study regimen. 
10.0 
STATISTICAL METHODS 
10.1 
Study Population 
10.1.1 
Subject Disposition 
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An accounting of all subjects over the course of the study will be reported. Enrollment, study 
drug administration, subject completion, premature discontinuation, and major protocol 
violations will be tabulated and summarized. 
10.1.2 
Replacement of Subjects 
There will be no replacement of subjects discontinued prematurely for safety reasons.  
10.1.3 
Procedures for Handling Missing, Unused, or Spurious Data 
Strategies for handling missing, unused, or spurious data will be specified in the SAP. 
10.2 
Analysis Populations 
10.2.1 
Safety and Efficacy Populations 
All subjects enrolled into the study who have received at least one dose of any study drug, 
whether prematurely withdrawn from the study or not, will be included in the safety/ efficacy 
population.  
10.2.2 
Pharmacokinetic Population 
Subjects will be excluded from the PK analysis population if they significantly violate the 
inclusion or exclusion criteria, deviate significantly from the protocol or if data are unavailable 
or incomplete which may influence the PK analysis. Excluded cases will be documented together 
with the reason for exclusion. All decisions on exclusions from the analysis will be made prior to 
database closure. 
10.2.3 
Per Protocol Population 
A per protocol analysis including all subjects enrolled and adherent to the protocol will be 
performed for certain efficacy analyses (see Statistical Analysis Plan).  
10.3 
Demographics and Baseline Characteristics 
Demographic data (age, sex, ethnicity, body weight) and baseline disease characteristics will be 
tabulated and summarized and presented in data listings. 
10.4 
Safety Analysis 
10.4.1 
Adverse Events 
The MedDRA will be used to map the AE/SAE verbatim terms to specific system organ classes 
(SOC) and preferred terms. Adverse events and SAEs will be summarized in summary tables and 
tabulated in by-subject listings by SOC and preferred term by treatment day. Incidence rates will 
be presented. 
10.4.2 
Vital Signs, ECG, Physical Examination, and Laboratory Assessments 
Vital signs will be summarized and tabulated by treatment day. The proportion of subjects with 
abnormal findings based on physical examinations over time will be summarized. Laboratory 
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values will be graded and summarized based on DAIDS, November 2014. Number and 
percentage of subjects with Grades 3 and 4 laboratory abnormalities will be tabulated. 
In the event a safety signal is detected, the PK/pharmacodynamic relationship between study 
drug(s) and various safety parameters including ECG changes, vital signs, and relevant 
laboratory parameters will be evaluated. 
10.4.3 
Concomitant Medications 
All reported concomitant medications will be mapped using the WHO Drug Dictionary. 
Concomitant medications will be tabulated in summary tables and by-subject listings. 
10.5 
Pharmacokinetic Analysis 
Samples at a single timepoint prior to dosing will be obtained at all routine study visits while 
subjects are receiving study medication. In addition, for a subgroup of up to 250 subjects, 
additional samples will be obtained over a 24-hour period at the Week 2 assessment.  
The PK parameters for ALS-022335, ALS-022399, ALS-022227, SMV, and ODV, will be 
determined by standard non-compartmental methods as appropriate. Population PK parameters 
(C0h and AUCtau) will be estimated by using non-linear mixed effects modeling. Separate SAPs 
will be made to describe the population PK methods. 
The calculated values for all PK parameters will be tabulated by subject, by treatment and 
presented as graphs and by-subject listings. Computed PK parameters (primary and secondary) 
will be listed by subject and summarized by treatment group (mean, geometric mean, standard 
deviation, coefficient of variation, median, minimum, maximum, number of observations), as 
appropriate. PK parameters may be explored and the relationship between the measures of 
hepatic function (i.e., Child-Pugh score, albumin, bilirubin, and prothrombin time) and PK 
parameters may be assessed graphically. Additional analyses or summaries may be considered, 
as appropriate. Individual and mean (by time) concentrations versus time will be plotted by 
treatment group on both linear and natural logarithm scales. 
Additional details for statistical consideration for PK analysis will be defined in the SAP. 
10.6 
Pharmacodynamic Analysis 
Efficacy and safety parameters may be subjected to an exploratory PK/pharmacodynamic 
analysis as appropriate. AL-335, ALS-022399, ALS-022227, SMV, and ODV exposure versus 
efficacy and safety parameters may be subjected to an exploratory graphical analysis including 
various transformations in order to get a general overview, as appropriate.  
Special attention will be paid to the plasma concentrations and PK parameters of those subjects 
who have discontinued the study for an AE, or who experienced a severe AE (at least Grade 3), 
or an SAE. 
Additional details for statistical consideration for PK analysis will be defined in the SAP. 
10.7 
Efficacy Analysis 
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Efficacy will be determined by assessing HCV RNA results by time. Where appropriate, data 
will be pooled if identical regimens and patient populations are evaluated in multiple cohorts. 
Efficacy data will be summarized in tables and by subject listings, describing percent 
(un)detectable. Descriptive statistics will be utilized to summarize efficacy analyses.  
Viral sequencing will also be analyzed to look for evidence of emergence of resistance.  Pre-
treatment polymorphisms in the HCV NS3/4A, NS5A and NS5B regions, as applicable, in all 
subjects and relevant changes in the HCV NS3/4A, NS5A and NS5B regions, as applicable, in 
subjects not achieving SVR will be tabulated and described. The effect of pre-treatment NS3/4A, 
NS5A and NS5B polymorphisms, as applicable, 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 sequence and phenotype may be performed and will be reported 
accordingly. 
Please refer to the statistical analysis plan for more details.  
10.8 
Pooled Safety/Efficacy 
To support initiation of a future Phase 3 study, safety, efficacy, and PK data from this study will 
be pooled with data from a separate Phase 2b (Omega-1) study. This will increase the sample 
size for the different 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. 
11.0 
ADMINISTRATIVE CONSIDERATIONS 
The investigator and/or Sponsor, consistent with local regulatory practice, will submit this 
protocol, the informed consent, Investigator’s Brochure, and any other relevant supporting 
information to the competent authority and appropriate IRB/IEC for review and approval prior to 
study initiation. A letter confirming IRB/IEC approval of the protocol and informed consent, a 
statement that the IRB/IEC is organized and operates according to Good Clinical Practice (GCP) 
and the applicable laws and regulations, and financial disclosures (if applicable) must be 
forwarded to Alios BioPharma prior to screening subjects for the study. Amendments to the 
protocol must also be approved by the IRB/IEC and local regulatory agency, as appropriate, prior 
to the implementation of changes in this study. 
11.1 
Study Compliance 
The study will be conducted in compliance with this protocol, principles of ICH GCP, 
Declaration of Helsinki, and all applicable national regulations governing clinical trials.  
11.2 
Informed Consent and Protected Subject Health Information Authorization 
A copy of the IRB/IEC-approved informed consent must be forwarded to Alios BioPharma for 
regulatory purposes. The investigator or designee must explain to each subject the purpose and 
nature of the study, the study procedures, the possible adverse effects, and all other elements of 
consent as defined in § 21CFR Part 50, European Union regulations (for European Union sites), 
and other applicable national and local regulations governing informed consent. Each subject 
must provide a signed and dated informed consent prior to enrollment into this study. Signed 
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consent forms must remain in each subject’s study file and be available for verification by study 
monitors at any time. 
In accordance with individual local and national subject privacy regulations, the investigator or 
designee must explain to each subject prior to screening that for the evaluation of study results, 
the subject’s protected health information obtained during the study may be shared with 
Alios BioPharma and its designees, regulatory agencies, and IECs/IRBs. As the study Sponsor, 
Alios BioPharma will not use the subject’s protected health information or disclose it to a third 
party without applicable subject authorization. It is the investigator’s or designee’s responsibility 
to obtain written permission to use protected health information from each subject, or if 
appropriate, the subject’s legal guardian. If a subject or subject’s legal guardian withdraws 
permission to use protected health information, it is the investigator’s responsibility to obtain the 
withdrawal request in writing from the subject or subject’s legal guardian and to ensure that no 
further data will be collected from the subject. Any data collected on the subject prior to 
withdrawal will be used in the analysis of study results. 
11.3 
Subject Screening Log 
The investigator must keep a record that lists all subjects considered for screening in the study. 
For those subjects subsequently excluded, record the reason(s) for exclusion. 
11.4 
Case Report Forms 
Study site personnel will complete CRFs designed for this study according to the completion 
guidelines that will be provided. Paper CRFs should be completed in black or dark-blue ink. All 
corrections on paper CRFs will be made by drawing a single line through the information to be 
corrected, without obscuring it. All corrections will be initialed and dated (and explained, if 
necessary). Do not use "white-out" or obscuring correction fluid/tape to make changes. An 
electronic CRF (eCRF) may be used for this study. Study site personnel will be trained and 
authorized to use the system in compliance with 21 CFR Part 11 prior to recording data on 
eCRFs. All corrections to eCRFs will be made by authorized users, and the changes will be 
automatically logged in the system. 
The investigator will ensure that the CRFs are accurate, complete, legible, and completed in a 
timely fashion. Separate source records are required to support all CRF entries. The CRF is not 
to be used to document data without prior written or electronic records. Case report forms should 
be completed for every subject enrolled in the study. At the study’s conclusion, a PDF file will 
be created for each site containing their subjects’ data submitted on eCRFs. In the event of an 
audit or regulatory authority inspection, copies of the eCRFs will be printed. 
11.5 
Study Monitoring Requirements 
Representatives of Alios BioPharma or its designee will monitor this study until completion. 
Monitoring will be conducted through personal visits with the investigator and site staff as well 
as any appropriate communications by mail, fax, e-mail, or telephone. The purpose of 
monitoring is to ensure compliance with the protocol and the quality and integrity of the data. 
This study is also subject to Quality Assurance reviews and/or audits under the Alios BioPharma 
Clinical Quality Assurance program. 
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Every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study. However, because of the experimental nature of this treatment, the 
investigator agrees to allow the IRB/IEC, representatives of Alios BioPharma, its designated 
agent, and authorized employees of the appropriate regulatory agencies to inspect the facilities 
used in this study and, for purposes of verification, allow direct access to the hospital or clinic 
records of all subjects enrolled into this study. A statement to this effect will be included in the 
ICF authorizing the use of protected health information. 
11.6 
Retention of Records 
The investigator must retain a copy of all documents relating to this clinical trial for a minimum 
of 5 years after a marketing application is approved for the drug, unless Alios BioPharma notifies 
the investigator in writing that the documents no longer need to be retained because a marketing 
application will not be filed. The investigator must retain the documents for a longer period, 
where so required by other applicable requirements. Essential documents shall be archived in a 
way that ensures that they are readily available, upon request, to the competent authorities and 
appropriate regulatory authorities. The medical files of trial subjects shall be retained in 
accordance with national legislation and the maximum period of time permitted by the hospital, 
institution, or private practice. The investigator is responsible for contacting Alios BioPharma 
before any study-related documents are moved to another location or destroyed, and he or she 
must receive written approval from Alios BioPharma before such relocation or destruction of 
documents proceeds. 
11.7 
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 SMV, ACH3102 
and AL-335, to understand chronic HCV GT1 infection, to understand differential drug 
responders, and to develop tests/assays related to SMV, ACH3102 and AL-335 and chronic 
HCV GT1 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. 
11.8 
Confidentiality and Publication Policy 
By conducting this study, the investigator affirms to Alios BioPharma that all study results and 
information furnished by Alios BioPharma will be maintained in strict confidence. Such 
information will be communicated to the investigator’s IRB/IEC under an appropriate 
understanding of confidentiality. 
A published summary of the results of this study is, however, permissible according to Alios 
BioPharma and is not inconsistent with the preceding affirmation of confidentiality. Any 
publication of data collected as a result of this study will be considered a joint publication by the 
investigator and appropriate Alios BioPharma personnel. Authorship, including order, will be 
determined by Alios BioPharma in consultation with the Principal Investigator. Contribution of 
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the author to the study design, enrollment, data review, and manuscript preparation and review 
will be considered when determining the order of authorship for multicenter studies. Alios 
BioPharma must receive a copy of any presentation, manuscript, or abstract for review at least 
45 days prior to public presentation or submission for publication. Any publication outside of 
this agreement is not permitted. 
11.9 
Conduct of Study and Protection of Human Subjects 
The principal investigator must ensure the following (unless Sponsor is required per local 
regulations): 
1. He or she will personally conduct or supervise the study. 
2. His or her staff and all persons who assist in the conduct of the study clearly 
understand their responsibilities and have their names included in the Study Staff 
Signature and Delegation of Authority log. The investigator will sign the 
authorization log whenever it is updated with new responsibilities or staff 
membership. 
3. The study is conducted according to the protocol and all applicable regulations. 
4. The protection of each subject’s rights and welfare is maintained. 
5. Signed and dated informed consent and permission to use protected health 
information are obtained from each subject prior to conducting study procedures. If a 
subject or subject’s legal guardian withdraws permission to use protected health 
information, the investigator will obtain a written request from the subject or 
subject’s legal guardian and will ensure that no further data be collected from the 
subject. 
6. The consent process is conducted in compliance with all applicable regulations and 
privacy acts. 
7. The IRB/IEC and local competent authority comply with applicable regulations and 
conducts initial and ongoing reviews and approvals of the study. 
8. Any amendment to the protocol is submitted promptly to the competent authority and 
IRB/IEC. 
9. Any significant protocol deviations are reported to Alios BioPharma, the local 
competent authority and the IRB/IEC according to the guidelines at each study site. 
10. All Safety Reports are submitted promptly to the local competent authority and 
IRB/IEC in accordance with the institution’s internal policy. 
11. All SAEs are reported within 24 hours of knowledge of the event, and to the local 
competent authority and the IRB/IEC. 
12.0 
REFERENCES 
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James LP, Letzig L, Simpson PM et al. Pharmacokinetics of acetaminophen-protein adducts in 
adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009; 
37(8):1779–64. 
Janssen Research and Development. Investigator’s Brochure ACH-0143102, Version 7.0. 
December 16, 2016. 
Janssen Research and Development. Investigator’s Brochure AL-335, Version 3.0. December 14, 
2016. 
Janssen Research and Development. Investigator’s Brochure Simeprevir, Version 10. December 
16, 2016. 
Janssen Therapeutics. (2016). Olysio (simeprevir). Prescribing Information. Retrieved from 
http://www.olysio.com/shared/product/olysio/prescribing-information.pdf. 
Lawitz E, et al. Simeprevir plus sofosbuvir with/without ribavirin for treating chronic HCV 
genotype 1 infection in prior null-responders to peginterferon/ribavirin and 
treatment-naïve patients (COSMOS: a randomised study). Lancet 2014:61036-39. 
Pasternak R, et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. JACC. 
2002;40:567–72. 
Perz JF, Armstrong GL, Farrington LA, et al. The contribution of hepatitis B virus and hepatitis 
C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006 
Oct;45(4):529–38. 
Planas R, Balleste B, Alvarez MA, et al. Natural history of decompensated hepatitis C 
virus-related cirrhosis. A study of 200 patients. J Hepatol 2004;40:823–30. 
Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with 
chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. 
Lancet 1997;349:825–32. 
Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for 
the Study of Liver Diseases and the Infectious Diseases Society of America. Accessed 
from http://hcvguidelines.org/full-report-view 
World Health Organization website Global Alert and Response. : 
http://www.who.int/csr/disease/hepatitis/Hepc.pdf Referenced on 5/9/16. 
 
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13.0 
APPENDICES 
 
Appendix A. 
Investigator Signature Page..................................................................... 103 
Appendix B. 
Clinical Laboratory Evaluations ............................................................. 104 
Appendix C. 
Blood Volumes for Week 4 Cohort ........................................................ 105 
Appendix D. 
Blood Volumes for Week 6 Cohort ........................................................ 106 
Appendix E. 
Blood Volumes for Week 8 or 12* Cohort ............................................. 107 
Appendix F. 
Toxicity Tables........................................................................................ 108 
Appendix G. 
Child-Pugh Score .................................................................................... 137 
 
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Appendix B. Clinical Laboratory Evaluations 
Chemistries: 
Albumin 
Bicarbonate 
BUN 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatine Kinase 
Glucose 
 
Lipase 
LDH 
Phosphorus 
Potassium 
 
Sodium 
Total protein 
Triglycerides 
Uric acid 
Liver function tests: 
Alkaline phosphatase 
ALT 
AST 
Total bilirubin 
Direct bilirubin 
HbA1c 
Alpha fetoprotein 
Beta natriuretic peptide (BNP) or NT-pro-BNP  
 
Hematology (CBC): 
Hematocrit 
Hemoglobin 
MCH 
MCHC 
MCV 
MPV 
Platelet count 
RDW 
Red blood cell count 
Reticulocytes 
White blood cell count 
White blood cell differentiation (percentage and ABS) 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Coagulation: 
PT/INR 
PTT 
 
Urinalysis (UA): 
Color and appearance 
pH and SG 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood/hematuria 
Protein 
Urobilinogen 
Microscopic (inc RBSs and WBCs)- reflex test only 
In-house Drug Screen: 
Methadone 
Amphetamines 
Barbiturates 
Cocaine 
Opiates 
Phencyclidine 
Benzodiazepines 
Females only: 
Pregnancy Test 
FSH and estradiol to be collected at Screening only 
Other Tests: 
HAV IgM 
HBsAg 
HBsAb 
HBcAb 
HCVAb 
HIVAb 
HCV RNA 
 
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Appendix C. Blood Volumes for Week 4 Cohort 
Interval 
 
Assessments 
Day 
Week 
Follow-up Week 
Screen 
-50 to -1 
1 
2 
3 
1 
2 
3 
4 
4 
(±1 wk) 
8 
(±1 wk) 
12 
(±2 wk) 
18 
(±2 wk) 
24 (±2 wk) 
Completion 
Drug Screen 
2 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV screen 
(HBsAg, HBsAB, HBcAb, 
HCVAb, HIVAb) 
10 
 
 
 
 
 
 
 
 
 
 
 
 
HCV genotype 
3 
 
 
 
 
 
 
 
 
 
 
 
 
IL28B determination 
 
3 
 
 
 
 
 
 
 
 
 
 
 
PK Samples  
 
6 
 
 
 
60 
12 
12 
2 
2 
2 
2 
2 
Liver Function Tests  
2 
2 
 
 
2 
2 
2 
2 
2 
 
 
 
 
CBC w/diff PT/PTT & INR and 
Urinalysis, Serum Chemistry 
25 
25 
 
 
25 
25 
 
25 
25 
 
 
 
 
HCV RNA concentration 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
Plasma for drug resistance 
monitoring 
 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Pregnancy Test 
2 
2 
 
 
 
 
 
2 
2 
2 
2 
 
2 
Alpha-fetoprotein, glycosylated 
HbA1C 
7 
 
 
 
 
 
 
 
 
 
 
 
 
Stored serum sample 
4 
4 
 
 
4 
4 
4 
4 
4 
 
 
 
 
Totals 
61 
56 
14 
14 
45 
105 
32 
59 
49 
18 
18 
16 
18 
Ab=antibody; CBC=complete blood count; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IL28B=interleukin 28B ; 
INR=International Normalization Ratio; PK=pharmacokinetic; PT=prothrombin time; PTT=partial thromboplastin time. 
Note:  
Estimated total volume is ~ 505 mL. Note that volumes are approximate. There may be some variation in the volumes that are required between laboratories at 
different clinical trial centers 
. 
 
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Appendix D. Blood Volumes for Week 6 Cohort 
Interval 
 
Assessments 
Day 
Week 
Follow-up Week 
Screen 
-50 to -1 
1 
2 
3 
1 
2 
3 
4 
5 
6 
4 
(±1 wk) 
8 
(±1 wk) 
12 
(±2 wk) 
18 
(±2 wk) 
24 (±2wk) 
Completion 
Drug Screen 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV screen 
(HBsAg, HBsAB, HBcAb, 
HCVAb, HIVAb) 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV genotype 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IL28B determination 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Samples  
 
6 
 
 
 
60 
12 
12 
 
12 
2 
2 
2 
2 
2 
Liver Function Tests  
2 
2 
 
 
2 
2 
2 
2 
2 
2 
2 
 
 
 
 
CBC w/diff PT/PTT & INR 
and Urinalysis, Serum 
Chemistry 
25 
25 
 
 
25 
25 
 
25 
 
25 
25 
 
 
 
 
HCV RNA concentration 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
Plasma for drug resistance 
monitoring 
 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Pregnancy Test 
2 
2 
 
 
 
 
 
2 
 
 
2 
2 
2 
 
2 
Alpha-fetoprotein, 
glycosylated HbA1C 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored serum sample 
4 
4 
 
 
4 
4 
4 
4 
4 
4 
4 
 
 
 
 
Totals 
61 
56 
14 
14 
45 
105 
32 
59 
20 
57 
49 
18 
18 
16 
18 
Ab=antibody; CBC=complete blood count; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IL28B=interleukin 28B 
; INR=International Normalization Ratio; PK=pharmacokinetic; PT=prothrombin time; PTT=partial thromboplastin time. 
Note:  
Estimated total volume is ~582 mL. Note that volumes are approximate. There may be some variation in the volumes that are required between laboratories at 
different clinical trial centers. 
 
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Appendix E. Blood Volumes for Week 8 or 12* Cohort 
Interval 
 
Assessments 
Day 
Week 
Follow-up Week 
-50 to -1 
Screen 
1 
2 
3 
1 
2 
3 
4 
5 
6 
7 
8 
4 
(±1 wk) 
8 
(±1 wk) 
12 
(±2 wk) 
18 
(±2 wk) 
24 (±2 wk) 
Completion 
Drug Screen 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV 
screen (HBsAg, 
HBsAB, HBcAb, 
HCVAb, HIVAb) 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV genotype 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IL28B determination 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Samples  
 
6 
 
 
 
60 
12 
12 
 
12 
 
12 
2 
2 
2 
2 
2 
Liver Function Tests  
2 
2 
 
 
2 
2 
2 
2 
2 
2 
2 
2 
2 
 
 
 
 
CBC w/diff PT/PTT & 
INR and Urinalysis, 
Serum Chemistry 
25 
25 
 
 
25 
25 
 
25 
 
25 
 
25 
25 
 
 
 
 
HCV RNA 
concentration 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
6 
Plasma for drug 
resistance monitoring 
 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Pregnancy Test 
2 
2 
 
 
 
 
 
2 
 
 
 
2 
2 
2 
2 
 
2 
Alpha-fetoprotein, 
glycosylated HbA1C 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored serum sample 
4 
4 
 
 
4 
4 
4 
4 
4 
4 
4 
4 
4 
 
 
 
 
Totals 
61 
56 
14 
14 
45 
105 
32 
59 
20 
57 
20 
59 
49 
18 
18 
16 
18 
Ab=antibody; CBC=complete blood count; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IL28B=interleukin 28B ; 
INR=International Normalization Ratio; PK=pharmacokinetic; PT=prothrombin time; PTT=partial thromboplastin time. 
Note: 
Week 8 estimated total volume is ~661 mL. Note that volumes are approximate. There may be some variation in the volumes that are required between 
laboratories at different clinical trial centers. 
* If a 12-week regimen is evaluated, the Week 5, 6, 7, and 8 visits will be repeated at Weeks 9, 10, 11, and 12, respectively. Week 12 estimated total volume is ~817 
mL. Note that volumes are approximate. There may be some variation in the volumes that are required between laboratories at different clinical trial centers 
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Appendix F. Toxicity Tables 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND 
PEDIATRIC ADVERSE EVENTS. PUBLISH DATE: NOVEMBER, 2014 
 
 
 
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Estimating AE severity grade for events not identified in the Grading Table or Laboratory 
Abnormalities which are considered AEs  
AEs not defined by the DAIDs toxicity table and laboratory abnormalities which are considered 
AEs, should be graded according to the following scale, which considers key clinical parameters 
(e.g. symptoms, functional status, need for intervention) and is also defined by the DAIDs scale: 
 
 
 NOTE: Laboratory abnormalities may have their grading defined in the DAIDS table below, 
however, all laboratory abnormalities do not necessarily represent an adverse event.  If a 
laboratory abnormality is considered an AE, the AE need not have the same grade as the 
laboratory abnormality itself.  The AE grade for a laboratory abnormality should be defined by 
the table above. 
 
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….
 
 
 
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Appendix G. Child-Pugh Score 
The score employs 5 clinical measures of liver disease. Each measure is scored 1-3, with 
3 indicating most severe derangement. 
Measure 
1 Point 
2 Points 
3 Points 
Total bilirubin, µmol/L (mg/dL) 
<34 (≤2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L 
>35 
28-35 
<28 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II 
(or suppressed with medication) 
Grade III-IV 
(or refractory) 
 
Chronic liver disease is classified into Child-Pugh class A to C, employing the added score from 
above. 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60 (8):646–9.  
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SAP_001.pdf: 
16.1.9 
Documentation of Statistical Methods 
 
Statistical Analysis Plan (Protocol No: AL-335-604) Version 1.0 dated 17-May-2017 
 
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STATISTICAL ANALYSIS PLAN 
 
 
 
ALIOS BIOPHARMA 
260 E. Grand Ave 
South San Francisco, CA 94080 
 
A Phase 2a, Open-Label Study to Evaluate the Safety, 
Pharmacokinetics and Efficacy of the Combination of AL-335 and 
Odalasvir, with or without Simeprevir, in Treatment-Naïve Subjects 
with Genotype 1, 2 or 3 Chronic Hepatitis C infection with or without 
compensated Child Pugh A Cirrhosis 
Protocol No: AL-335-604 
SAP Version 1.0 
SAP Date: 17 May 2017 
 
 
Prepared by: 
 
inVentiv Health Clinical 
 
This document contains confidential information of Nichi-Iko Pharmaceutical Co., Ltd. Any viewing or 
disclosure of such information that is not authorized in writing by Nichi-Iko Pharmaceutical Co., Ltd., 
is strictly prohibited. Such information may be used solely for the purpose of reviewing or 
performing this study. 
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TABLE OF CONTENTS 
 
1. 
Introduction ..................................................................................................................................... 8 
2. 
Study objectives .............................................................................................................................. 8 
2.1 
Primary objective ............................................................................................................................ 8 
2.2 
Secondary objectives ....................................................................................................................... 8 
3. 
Study methodology ......................................................................................................................... 9 
3.1 
Description of cohorts and groups (based on protocol version 8.1 of the 21st of December 2016) 9 
3.2 
Visit Windows and Phase Definitions ........................................................................................... 10 
4. 
Statistical considerations.............................................................................................................. 15 
5. 
Description of study subjects ....................................................................................................... 17 
5.1 
Definition of analysis sets ............................................................................................................. 17 
5.2 
Subject disposition ........................................................................................................................ 17 
5.3 
Protocol deviations ........................................................................................................................ 18 
5.4 
Definition of subgroups ................................................................................................................. 18 
6. 
Demographic data and baseline characteristics ......................................................................... 18 
6.1 
Demographic data ......................................................................................................................... 18 
6.2 
Other baseline characteristics ........................................................................................................ 18 
6.3 
Medical and surgical history ......................................................................................................... 19 
6.4 
Previous and concomitant medications ......................................................................................... 19 
6.5 
Compliance ................................................................................................................................... 19 
7. 
Pharmacokinetic data ................................................................................................................... 20 
7.1 
Generalities ................................................................................................................................... 20 
7.2 
Plasma pharmacokinetic concentrations and parameters .............................................................. 21 
7.2.1 
Plasma pharmacokinetic parameters ................................................................................. 21 
7.2.2 
Plasma pharmacokinetic analysis ...................................................................................... 22 
8. 
Safety data ..................................................................................................................................... 23 
8.1 
Adverse events .............................................................................................................................. 23 
8.2 
Clinical laboratory data ................................................................................................................. 24 
8.3 
Other safety parameters ................................................................................................................. 27 
8.3.1 
Vital signs data .................................................................................................................. 27 
8.3.2 
Electrocardiogram data ..................................................................................................... 28 
8.3.3 
Other safety parameters ..................................................................................................... 30 
9. 
Efficacy data ................................................................................................................................... 31 
9.1 
Analysis Specifications ................................................................................................................. 31 
9.1.1 
Level of Significance ........................................................................................................ 31 
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9.1.2 
Data Handling Rules ......................................................................................................... 31 
9.2 
Primary Efficacy Endpoint ............................................................................................................ 31 
9.2.1 
Definition .......................................................................................................................... 31 
9.2.2 
Analysis Methods .............................................................................................................. 32 
9.3 
Major Secondary Endpoints .......................................................................................................... 32 
9.3.1 
Definitions ......................................................................................................................... 32 
9.3.2 
Analysis Methods .............................................................................................................. 34 
10. 
Reporting conventions .................................................................................................................. 34 
11. 
Appendices .................................................................................................................................... 36 
11.1 
Appendix 1 - Schedule of assessments of the study .................................................................. 36 
11.2 
Appendix 2 - Criteria for Potentially Clinically Significant Abnormalities (PCSA) ................ 44 
11.3 
Appendix 3 - List of tables, listings and figures included in the clinical study report .............. 45 
11.4 
Appendix 4: Events of special/clinical interest ......................................................................... 60 
11.4.1 
Search terms for Events of Special/Clinical Interest ..................................................... 60 
11.4.2 
RASH – SMQ19.1......................................................................................................... 62 
11.4.3 
CARDIAC EVENTS - SMQ19.1 .................................................................................. 63 
 
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LIST OF ABBREVIATIONS  
 
Abbreviation 
Definition 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Chemical 
AUC 
Area Under the Curve 
AUC0-last 
Area Under the Curve from time zero to last measurable plasma 
concentration 
AUC0-τ 
Area Under the Curve during one dosing interval 
AUC0-inf 
Area Under the Curve from time zero to infinity 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
Clast 
Last measurable plasma concentration 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration 
CI 
Confidence Interval 
CL/F 
Apparent oral clearance 
CRF 
Case Report Form 
CV 
Coefficient of Variation 
ECG 
ElectroCardioGram 
i.e. 
id est 
HCV 
Hepatitis C Virus 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product (synonymous with “study drug”) 
IS 
Included Set 
λz 
Apparent terminal elimination rate constant 
LLN 
Lower Limit of Normal range 
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Abbreviation 
Definition 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
NCA 
Non-Compartmental Analysis 
PCSA 
Potentially Clinically Significant Abnormalities   
PK 
PharmacoKinetics 
PKS 
PharmacoKinetic Set 
PPS 
Per Protocol Set 
PT 
Preferred Term 
QRS 
QRS interval duration 
QT 
Time interval for ventricular depolarisation and repolarisation 
QTc 
Corrected QT interval 
QTcB 
Bazett corrected QT interval 
QTcF 
Fridericia corrected QT interval 
RAV 
Resistance-Associated Variants 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SVR 
Sustained Virologic Response 
t1/2 
Apparent terminal elimination half-life 
TFLs 
Tables, Figures, and Listings 
tlast 
Time corresponding to last measurable plasma concentration 
tmax 
Time to reach maximum plasma concentration 
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Abbreviation 
Definition 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal range 
VL 
Viral load 
Vz/F 
Apparent volume of distribution 
WBC 
White Blood Cell 
WHO 
World Health Organisation 
 
 
 
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1. Introduction 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications, tables, figures and listings. 
It applies to the whole study on final analysis. Viral sequencing (e.g., Resistance-Associated 
Variants (RAV)) analyses will be described in a separate SAP. 
2. Study objectives 
2.1 Primary objective 
The primary objective of this study is as follows:  
• To evaluate the safety and tolerability of AL-335 in combination with ODV with or 
without SMV in subjects with GT1 or GT2 or GT3 CHC infection in treatment-naïve 
subjects with or without compensated Child Pugh A Cirrhosis 
2.2 Secondary objectives 
The secondary objectives of this study are as follows:  
• To evaluate the efficacy of treatment with AL-335 in combination with ODV±SMV in 
subjects with GT1 or GT2 or GT3 CHC infection  
• To evaluate the pharmacokinetics of AL-335 (and metabolites), ODV±SMV in plasma  
• To evaluate the dynamics of HCV RNA in subjects with GT1 or GT2 or GT3 CHC 
infection treated with AL-335 in combination with ODV±SMV  
• To evaluate the effect of baseline host and disease-related characteristics on treatment 
outcome  
• To evaluate the impact of the presence of an (NS) 3 polymorphism (e.g., Q80K; SMV-
containing arms only) and/or NS5A and NS5B polymorphisms at baseline on 
treatment outcome  
• To evaluate the viral resistance profile after ≤12 weeks administration of AL-335 in 
combination with ODV±SMV  
 
 
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3. Study methodology 
3.1 Description of cohorts and groups (based on protocol version 8.1 of the 21st of December 
2016) 
 
Cohort 
# 
Genotype Cirrhosis AL-335 
dose (mg) 
ODV 
dose (mg) 
SMV 
dose (mg) 
Duration 
(weeks) 
Group* 
1 
1 
No 
400 
50 QD 
100 
8 
1 
1b 
1 
No 
800 
50 QOD 
- 
8 
1b+4 
2 
1 
No 
800 
50 QOD 
75 
8 
2 
3 
1 
No 
800 
50 QOD 
75 
6 
3 
4 
1 
No 
800 
50 QOD 
- 
8 (N=5)  
12 (N=8) 
1b+4 
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5 
3 
No 
800 
50 QOD 
75 
8 (N=5)  
12 (N=14) 
5 
6 
1 
Yes 
800 
50 QOD 
75 
8 
6+7+8 
7 
1 
Yes 
800 
25 QD 
75 
8 
6+7+8 
8 
1 
Yes 
800 
25 QD 
75 
8 
6+7+8 
9 
1 
Yes 
800 
25 QD 
75 
12 
9+10 
10 
1 
Yes 
800 
25 QD 
75 
12 
9+10 
11 
2 
Yes 
800 
25 QD 
75 
12 
11 
12 
2 
Yes 
800 
25 QD 
75 
8 
12 
13-15 
To be determined 
*These are combined groups for presentation purpose of all data except pharmacokinetics, 
3.2 Visit Windows and Phase Definitions  
Phases will be constructed as follows:  
Trial phase 
Start date 
End date 
Screening 
(phase 0) 
Minimum of Date of signing 
the 
informed consent and Date of 
the 
first screening visit 
1 day before the first study drug 
intake (AL-335+ODV(±SMV)) 
Treatment 
(phase 1) 
Date of first study drug intake 
(AL-335+ODV(±SMV)) 
Date of last study drug intake: 
MAXIMUM{Date of last study 
drug intake (AL-
335+ODV(±SMV))} + 3 days* 
Follow-up 
(phase 2) 
End date of Treatment phase 
+ 1 
Trial termination date  
*In case the last study drug intake is missing, other dates can be used instead for date of last study 
drug intake: E.g. if the subject discontinued treatment (known from the disposition table): date of the 
withdrawal visit, if the latter is not available: date of first available FU visit minus the number of days 
in follow-up at which this FU visit was scheduled according to the protocol. If those dates are not 
available, date of trial termination. 
The number of days in the treatment phase (ADY) will be defined as: 
 
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ADY = visit date – date of first study drug intake +1 for visits on or after the day of first study 
drug intake 
ADY = visit date – date of first study drug intake for visits before the day of first study drug 
intake 
In case the date of first study drug intake is missing, the date of the baseline visit can be used 
as date of first study drug. 
Actual End of Treatment visit (EOT) is defined as the last visit in the Treatment phase. 
All visits (regardless the investigated parameter) will be allocated within each phase to 
analysis time points based on the number of days in phase (ADY): 
6-Week Cohorts 
Trial phase 
Target 
phase day 
Analysis time 
point 
(numeric 
version) 
Analysis time 
pointb 
Time 
interval 
(days)a 
Screening 
-∞ 
-1 
Screening 
<0 
Treatment 
phase 
1 
0 
Baseline 
≤1 
2 
0.2 
Day 2 
2 
3 
0.3 
Day 3 
[3,5] 
7 
1 
Week 1 
[6,11] 
14 
2 
Week 2 
[12,18] 
21 
3 
Week 3 
[19,25] 
28 
4 
Week 4 
[26,32] 
35 
5 
Week 5 
[33,39] 
42  
6 
Week 6 
[40, + ∞] 
last visit 
while on 
study therapy 
or 3 days 
after the day 
of last dose 
999 
EOT 
 
Follow-up 
phase 
25 
16 
Follow-up Week 
4 
[1,39] 
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53 
20 
Follow-up Week 
8 
[40,67] 
81 
24 
Follow-up Week 
12 
[68,102] 
123 
30 
Follow-up Week 
18 
[103,144] 
165 
36 
Follow-up Week 
24 
[145, +∞] 
 
 
 
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8-Week Cohorts 
Trial phase 
Target 
phase day 
Analysis time 
point 
(numeric 
version) 
Analysis time 
pointb 
Time 
interval 
(days)a 
Screening 
-∞ 
-1 
Screening 
<0 
Treatment 
phase 
1 
0 
Baseline 
≤1 
2 
0.2 
Day 2 
2 
3 
0.3 
Day 3 
[3,5] 
7 
1 
Week 1 
[6,11] 
14 
2 
Week 2 
[12,18] 
21 
3 
Week 3 
[19,25] 
28 
4 
Week 4 
[26,32] 
35 
5 
Week 5 
[33,39] 
42  
6 
Week 6 
[40,46] 
49 
7 
Week 7 
[47,53] 
56  
8 
Week 8 
[54, +∞] 
last visit 
while on 
study therapy 
or 3 days 
after the day 
of last dose 
999 
EOT 
 
Follow-up 
phase 
25 
16 
Follow-up Week 
4 
[1,39] 
53 
20 
Follow-up Week 
8 
[40,67] 
81 
24 
Follow-up Week 
12 
[68,102] 
123 
30 
Follow-up Week 
18 
[103,144] 
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165 
36 
Follow-up Week 
24 
[145, +∞] 
12-Week Cohorts 
Trial phase 
Target 
phase day 
Analysis time 
point 
(numeric 
version) 
Analysis time 
pointb 
Time 
interval 
(days)a 
Screening 
-∞ 
-1 
Screening 
<0 
Treatment 
phase 
1 
0 
Baseline 
≤1 
2 
0.2 
Day 2 
2 
3 
0.3 
Day 3 
[3,5] 
7 
1 
Week 1 
[6,11] 
14 
2 
Week 2 
[12,18] 
21 
3 
Week 3 
[19,25] 
28 
4 
Week 4 
[26,32] 
35 
5 
Week 5 
[33,39] 
42  
6 
Week 6 
[40,46] 
49 
7 
Week 7 
[47,53] 
56  
8 
Week 8 
[54,60] 
84 
12 
Week 12 
[82, +∞] 
last visit 
while on 
study therapy 
or 3 days 
after the day 
of last dose 
999 
EOT 
 
Follow-up 
phase 
25 
16 
Follow-up Week 
4 
[1,39] 
53 
20 
Follow-up Week 
8 
[40,67] 
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81 
24 
Follow-up Week 
12 
[68,102] 
123 
30 
Follow-up Week 
18 
[103,144] 
165 
36 
Follow-up Week 
24 
[145, +∞] 
a The reference day of the Treatment and Screening phase is the day of the first study drug intake (= 
day 1 in Treatment phase).  
b Target day in follow-up phase equals target day in the protocol minus 3 days.  
If two visits fall within the same interval, the last measurement within the interval will be 
used for the descriptive statistics/tabulations per time point and graphics in order to have only 
one evaluation per subject per analysis time point. If there are two measurements on the same 
day and time, then the measurement with the highest sequence number will be used. Listings 
will include all values. 
4. Statistical considerations 
Efficacy and safety data will be analysed using SAS software version 9.4 (SAS institute Inc. 
 USA). 
Pharmacokinetic data from the PK substudy will be analysed using Phoenix WinNonLin 
version 6.4 (Pharsight) and SAS software version 9.4 (SAS Institute Inc. 
 USA) for 
final analysis. 
Descriptive statistics will be supplied according to the nature of the criteria: 
- 
Quantitative variable: sample size, arithmetic mean, standard deviation (SD), standard 
error of the mean (SEM), minimum, median and maximum, and quartiles if necessary 
(with geometric mean, arithmetic and geometric coefficients of variation (CV), and 
quartiles for PK parameters, geometric mean will not be reported in case of value equal to 
0).  
- 
Qualitative variable: sample size, absolute and relative frequencies per class. Percentages 
will be provided with one decimal place. 
Safety data will be organized by cohort. 
All safety and pharmacokinetics listings will be sorted by cohort, subject, and measurement 
time if applicable. 
For all except pharmacokinetics data, cohorts that evaluate the same treatment regimen for the 
same duration (e.g., Cohort 1b and the first 5 subjects in Cohort 4) will be pooled (using 
Label “Cohort 1b+Cohort 4 (8 Weeks).” If multiple treatment durations and/or regimens were 
assessed in a single cohort, the data for that cohort will be presented separately (e.g. Cohort 4 
(12 weeks) will be separate from Cohort 4 (8 weeks), which will be pooled with cohort 1b). 
For cohorts with different clinical characteristics (e.g. HCV genotype, cirrhosis status), 
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treatment regimens or same treatment regimen but with different durations, data will be 
presented separately. 
For pharmacokinetic data, cohorts that evaluate the same treatment regimen (including study 
medications and doses) in the same population (cirrhotic vs non-cirrhotic), whatever the 
duration, or HCV genotype will be pooled, i.e. the presentation of cohorts will be: 
- 
Cohort 1, 
- 
Cohort 1b+4, 
- 
Cohort 2+Cohort 3+Cohort 5, 
- 
Cohort 6. 
- 
Cohort 7+Cohort 8+Cohort 9+Cohort 10+Cohort 11+Cohort 12 
Handling of missing and retest values 
No management of missing data will be done, except for pharmacokinetic values (see section 
7.1) and missing or incomplete start/stop dates (see below). 
Missing start or end dates for events not aligned to a specific visit/week such as adverse 
events, medications reported, etc., will be imputed using the following rules: 
• A completely missing start date of an event will be set to the date of the first dose of 
study medication, unless it is clearly indicated that this is an event happening 
pretreatment. In this case, it will be set to the day before the first dose of study 
medication. 
• A completely missing stop date will not be imputed, but the event will be assumed to 
be ongoing. 
• Partially missing dates where the year is known will be set to 01 January of that year 
or the first dose of study medication date, if the first dose of study medication 
occurred in that year. 
• Partially missing dates where the year and month are known will be set to the first day 
of that month or the first dose of study medication date, if the first dose of study 
medication occurred in that month. 
If, by applying the above rules, the stop date is imputed before the start date, then the stop 
date will be set to be the same as the start date. 
For all parameters and for subjects with retest values, the last reliable value will be used as a 
measurement time before the first investigational medicinal product (IMP) administration 
(provided it was measured before IMP administration) and the first reliable value will be used 
as a measurement time after the first IMP administration. 
Baseline definition 
For all parameters, baseline will be defined as the last available (and reliable if applicable) 
single measurement prior to the first IMP administration unless otherwise specified (e.g. 
ECG). 
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Duration 
Duration (in days, hh:mm) will be calculated as the difference between start and stop date and 
time (e.g. duration of AE (days, hh:mm) = date of AE end date and time – date of AE onset 
date and time). 
Duration (in days) will be calculated as the difference between start and stop date + 1 (e.g. 
duration of a medication (days) = date of medication end date – date of medication onset date 
+ 1). 
Type I error rate 
No significance testing will be performed. However, two-sided Clopper-Pearson 95% CI will 
be constructed around the proportion of subjects with sustained virologic response (SVRx) 
and other virologic response parameters, for each cohort. 
5. Description of study subjects 
5.1 Definition of analysis sets 
The following analysis sets will be defined: 
Included set (IS): all the subjects included in the study. 
Safety/Efficacy/Intent-to-treat population (Safety set): All subjects enrolled into the study 
who have received at least one dose of any study drug, whether prematurely withdrawn from 
the study or not, will be included in the safety/efficacy/Intent-to-treat set. 
Pharmacokinetic set (PKS): Will be comprised of all safety set subjects except those that they 
significantly violate the inclusion or exclusion criteria, deviate significantly from the protocol 
or if data are unavailable or incomplete which may influence the PK analysis. Excluded cases 
will be documented together with the reason for exclusion.  
Per Protocol set (PPS): A per protocol analysis including all subjects enrolled and adherent to 
the protocol may be performed for certain efficacy analyses.  
A subset of major protocol deviations, that may have an impact on the results of the analysis, 
will be identified prior to database lock. If there are a substantial number of subjects with 
such protocol deviations, a per-protocol analysis will be performed on the primary endpoint, 
based on subjects from the Safety set, excluding these subjects. Additional efficacy analysis 
using the PPS may be performed on an ad-hoc basis. 
5.2 Subject disposition 
A summary table with the description of the number of included subjects, the number of 
subjects who completed study and the number of subjects who discontinued classified by 
main reason of withdrawal will be performed by cohort and overall on the subjects included 
in the Included set. Corresponding individual listings will be provided. 
A summary table with the description of the number and percentage of subjects in each 
analysis set (Safety set, and Pharmacokinetic set) will be performed by cohort and overall. A 
specific listing of subjects excluded from safety/efficacy and pharmacokinetic analyses will 
be provided with reason for exclusion. 
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A summary table with the number and percentage of subjects at each visit will be performed 
by cohort and overall on the subjects included in the safety set. 
Listings with end of study status and study visit dates will also be carried out. 
5.3 Protocol deviations 
A summary table by cohort and overall with the number and percentage of subjects presenting 
deviations relating to inclusion/exclusion criteria (all eligibility criteria responses) will be 
prepared on the subjects included in the safety set. A summary table by cohort and overall 
with the number and percentage of subjects presenting other protocol deviations (all 
deviations judged relevant by the sponsor during the data-review meeting) will also be 
prepared. The corresponding listings will be provided with the status of deviation 
(minor/major, as assessed by the sponsor during the data-review meeting). 
5.4 Definition of subgroups 
The following subgroups will be considered to 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 cohort, subgroup categories might be combined. 
• IL28B genotype (CC, CT, TT)   
• HCV genotype/subtype (1a,1b, 1other, 2, 3)  
• Prior treatment status (cirrhosis cohorts only) – prior pegylated interferon + 
ribavirin treatment with relapse   
6. Demographic data and baseline characteristics 
The analyses on demographic and other baseline characteristics will be performed on the 
safety set and PK set. Analyses on medical and surgical history, previous and concomitant 
medication, and compliance will be performed for the safety set. 
Separate ad hoc summary tables of the demographic data and baseline characteristics for all 
subjects in cohorts 1b+4 (N=33) and cohort 5 (N=19) will be generated since, at the time of 
enrolment, all subjects in these two groupings were intended to dose for the same duration. 
6.1 Demographic data 
Subjects’ demographic characteristics (age, sex, race, ethnicity, height, weight and BMI 
recorded at screening and Interleukin 28B genotype) will be summarised by cohort and 
overall, and listed. 
6.2 Other baseline characteristics 
HCV genotype as well as HCV RNA values at baseline (in IU/mL and log10 IU/mL) will be 
summarised by cohort and overall, and listed.  
Serology testing will be listed. 
Positive results of serology will be listed. 
Childbearing status (for female only) and contraception method will be listed. 
Alcohol consumption will be listed. 
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Information related to liver biopsy and fibroscan will be listed as well as Child-Pugh class 
assessment and hepatocellular carcinoma assessment (only for compensated cirrhosis cohort). 
Fibroscan score and Child-Pugh score will be summarised by cohort and overall. 
6.3 Medical and surgical history 
Information on medical and surgical history recorded at the screening visit will be coded 
according to the Medical Dictionary for Regulatory Activities (MedDRA®) Version 19.1. 
A table with the number and percentage of subjects having at least one previous/ongoing 
medical and surgical history (except liver diseases) will be generated by cohort and overall. 
The same table will be provided for liver diseases (SOC: “Hepatobiliary disorders”). 
Previous/ongoing medical and surgical history (except liver diseases) and previous/ongoing 
medical and surgical history related to liver diseases will be listed separately.   
6.4 Previous and concomitant medications 
Information on previous and concomitant medications will be coded according to the WHO 
drug Dictionary (WHO-DD) version of June 2015. 
A previous medication will be defined as a medication stopped prior to the date and time of 
first administration of IMP. A concomitant medication will be defined as a medication which 
is taken by subjects any time during the treatment period (on or after the date and time of first 
IMP administration for each subject).  
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. 
• 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. 
• In case of a partial end date, the therapies are allocated to the phases using the 
available partial information, no imputation is done. If, for instance, for a therapy end 
date only month and year is available and are the same as month and year of the first 
IMP administration, the therapy is considered as concomitant. 
A table with the number and percentage of subjects having at least one previous medication 
will be generated by cohort and overall (overall and by Anatomical Therapeutic Chemical 
(ATC) and by preferred name). A table with the number and percentage of subjects having 
taken at least one concomitant medication will be generated by cohort and overall (overall and 
by Anatomical Therapeutic Chemical (ATC) and by preferred name). Previous and 
concomitant medications will be listed separately.  
6.5 Compliance 
A listing with IMP administration dates and times will be carried out for each study drug. 
Subjects that took additional doses (either extra doses on a dosing day (all drugs) or on 
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additional days other than those planned (for ODV QOD regimens) will be flagged in the 
listing. Time of meals intake will be listed as well.  
7. Pharmacokinetic data  
Two types of PK analysis will be performed for this study: 1) Non-compartmental analysis 
(NCA) for subjects participating in the PK substudy and 2) population PK in all subjects. This 
SAP will only cover the NCA PK analyses done in patients in the PK substudy. The 
population PK analysis will be described in a separate SAP and will have its own report. 
The pharmacokinetic analysis will be performed on the pharmacokinetic set (PKS). 
7.1 Generalities 
The following rules for PK parameters calculation after each administration will be used: 
Actual sampling times will be used for deriving PK parameters. In the case the actual 
sampling time will not be known, the scheduled time will be used, with appropriate 
footnoting. Actual sampling times will be checked for major aberrations. In case a major 
aberration occurs for an actual sampling time (i.e., >20.00% deviation from the scheduled 
time), this plasma concentration will be excluded from descriptive statistics in the plasma 
concentration table and reported in the CSR.  
If an entire concentration-time profile is below the limit of quantification (BLQ), the profile 
will be excluded from the PK analysis. 
All BLQ values will be replaced by “0”. 
All embedded BLQ values (BLQ value between two measurable concentrations) will be 
treated as missing. Details of this exclusion must be documented in the clinical study report. 
For the determination of λz, only those data points judged to describe the terminal log-linear 
decline resulting in an adjusted coefficient of determination value > 0.9 will be used in the 
regression. A minimum of 3 data points will be used in calculating λz (excluding Cmax). The 
number of points and the lower and upper limits of the terminal phase will be identified in the 
study data and in the CSR. 
If there are late positive concentration values following 2 BLQ concentration values in the 
apparent terminal phase, these values will be evaluated. If these values are considered to be 
anomalous or to introduce a substantial bias, they will be set to missing and excluded from the 
PK analysis. 
The following rules for plasma concentration versus time graphic representation will be 
used: 
No graphic representation will be made if all values are BLQ. 
All BLQ values will be replaced by “0”. 
All BLQ values will not be shown on semi-logarithmic plots. 
Profiles and individuals values considered to be outliers should be included in the individual 
plots and excluded in the mean plots. 
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Actual sampling times will be used for individual subjects PK profiles and nominal sampling 
times should be used for mean plots. 
All subjects will be plotted with the same scale and range of values on the x- and y-axes 
The following rules for mean plasma concentration calculation will be used: 
If more than half (>50%) of the values at a single time point are BQL, mean and median 
values will be reported as BQL. Standard deviation and %CV will not be reported; maximum 
and minimum values will be reported as observed (including BQL). 
If more than (or equal) half of values are not BLQ: statistics will be calculated considering 
BLQ values as zero. 
For summary statistics for PK parameters: 
If more than (or equal to) half of values are available: statistics will be calculated considering 
available values. 
If less than half of values are present: mean will not be calculated and presented as missing. 
Min, median and max value on available values will be presented. 
 
All concentrations below the limit of quantification or missing data will be labelled as such in 
the concentration data listings. 
7.2 Plasma pharmacokinetic concentrations and parameters 
7.2.1 Plasma pharmacokinetic parameters  
Blood samples will be drawn for AL-335, SMV and ODV (depending on the cohorts) on: 
- 
On Day 1 at 0 hour, 
- 
On Week 2 at 0, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 hours (For PK substudy only), 
- 
On Week 3 at 0, 2-4 hours, 
- 
On Week 4 at 0, 6-8 hours, 
- 
On Week 6 at 0, 2-4 hours, 
- 
On Week 8 at 0, 6-8 hours (8 or 12 Week Cohorts), 
- 
On Week 10 at 0, 2-4 hours (12 Week Cohorts), 
- 
On Week 12 at 0, 6-8 hours (12 Week Cohorts). 
For subjects in the PK substudy, relevant plasma pharmacokinetic (PK) parameters will be 
calculated for AL-335 and its metabolites (ALS-022399 and ALS-022227), SMV and ODV 
by standard non-compartmental methods for those subjects with sufficient plasma 
concentration data. The rules defined in the previous section 7.1 will be used. 
The different areas under the concentration-time curve (AUC) will be calculated using the 
linear Trapezoidal summation (both ascending and descending phase). 
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The following plasma pharmacokinetic parameters will be calculated for AL-335 and its 
metabolites (ALS-022399 and ALS-022227), SMV and ODV: 
Parameters (unit) 
Definition 
Cmin (unit) 
Minimum observed plasma concentration 
Cmax (unit) 
Maximum observed plasma concentration 
Ctrough (unit) 
Concentration at the end of a dosing interval before the next dose 
administration (Pre-dose or C0h) 
tmax (h) 
Time to reach maximum plasma concentration 
AUC0-last (unit.h) 
Area under the plasma concentration-time curve from time zero to 
last measurable (Non-BLQ) plasma concentration 
In cases where a subject's AUC0-last is estimated over a time interval 
that is very different from that of the other subjects in the group, it is 
recommended that subject's AUC0-last could be excluded from the 
calculation of descriptive statistics. All exclusions must be clearly 
documented in the CSR. 
In cases where more than half of subjects have a different tlast, it may 
not be appropriate for the descriptive statistics for AUC0-last to be 
reported. 
AUC0-24 (unit.h) 
Area under the plasma concentration-time curve from time zero to 24 
hours 
AUC0-48 (unit.h) 
Area under the plasma concentration-time curve from time zero to 48 
hours (only for ODV and QOD cohorts) 
Css,avg 
Average concentration of the drug calculated as follows: 
Css,avg = AUC0- τ / τ  
Clast (unit) 
Last observed plasma concentration 
tlast (h) 
Time to reach last plasma concentration 
 
7.2.2 Plasma pharmacokinetic analysis 
Listings with plasma concentrations of AL-335, ALS-022399 and ALS-022227, SMV and 
ODV (including PK blood sampling dates and times) and PK parameters will be provided by 
cohort, dose, and subject. These listings will be performed on all subjects with an available 
profile (complete or incomplete), including those who are excluded from the PKS. 
A specific listing will be also done focussing on subjects who either discontinue the study for 
an adverse event, experience a severe adverse event or a serious adverse event. 
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Individual plasma concentrations for all subjects and PK parameters of AL-335, ALS-022399 
and ALS-022227, SMV and ODV including descriptive statistics for subjects participating in 
the PK substudy will be presented in tables by cohort and by pooled cohorts.  
Graphs for plasma concentration versus time profiles of AL-335, ALS-022399 and ALS-
022227, SMV and ODV will be generated on linear and log/linear coordinates for arithmetic 
mean (±SD) by cohorts. 
In addition, the plasma concentration versus time profiles of AL-335, ALS-022399 and ALS-
022227 will also be presented on the same graph or as a separate graph on linear and 
log/linear coordinates for arithmetic mean (±SD) by pooled cohort. 
Moreover, the plasma concentration versus time profiles of AL-335, ALS-022399 and ALS-
022227, SMV and ACH-3102 will be presented graphically on linear and log/linear 
coordinates for each subject.  
Pre-dose (“trough”) concentrations of AL-335, ALS-022399 and ALS-022227, SMV and 
ODV for all subjects at all available timepoints will be presented graphically on linear 
coordinates for arithmetic mean (±SD) by cohorts and by pooled cohorts. 
Scatter plots will be generated for the comparison of Ctrough, Cmax, and AUC0-τ parameters of 
AL-335, ALS-022399, ALS-022227, SMV and ODV by cohorts and by pooled cohorts. 
8. Safety data 
The safety analyses will be performed on the safety set. 
8.1 Adverse events 
Adverse events, including pre-treatment events, will be recorded from the time of consent 
through the completion visits, for the treatment and follow-up phase combined. 
Adverse events will be coded according to MedDRA® Version 19.1. 
A treatment-emergent adverse event (TEAE) is an adverse event that occurs after the first 
IMP administration or that was present prior to dosing but exacerbated after the first IMP 
administration. 
Adverse events will be summarised in tables as follows (overall and by System Organ Class 
(SOC) and Preferred Term (PT)): 
- 
Number and percentage of subjects with at least one adverse event and number of 
adverse events for each cohort,  
- 
Number and percentage of subjects with at least one TEAE and number of TEAEs for 
each cohort, 
- 
By intensity, with the number and percentage of subjects with at least one TEAE and 
number of TEAEs for each cohort, 
- 
By causality of each treatment, with the number and percentage of subjects with at 
least one TEAE and number of TEAEs for each cohort. 
Moreover, an overall summary table of all TEAEs will be presented. 
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In addition, summary tables will also be presented for TEAEs, serious TEAEs, TEAEs 
leading to any study drug discontinuation, severe or life threatening (i.e. Grade 3 / 4) TEAEs, 
and TEAEs with fatal outcome by decreasing frequency of PT. 
The incidence and comparable prevalence rate per 2-week time interval for any AEs will be 
summarized and plotted by cohort. 
Note: Repetitions will only be counted once in summary tables. Repetitions are defined as 
follows: if a given subject presents several adverse events with the same preferred term during 
the same phase (treatment and follow-up phase combined), only one event is counted, the 
others are considered repetitions or recurring episodes. The start time of the event will be the 
start time of the first occurrence, the end time will be the end time of the last episode. The 
intensity will be the highest recorded intensity for all episodes. The causality will be the 
highest likelihood recorded for all episodes. 
A summary table of TEAEs of special interest (cardiac events, increased bilirubin 
(hyperbilirubinemia, blood bilirubin increased), rash and photosensitivity) will be also 
presented (see Appendix 4 for detailed list of SMQs). 
The incidence rates for each event of interest by WHO toxicity grades and relationship to 
study drugs will be summarized. Time to the first occurrence of the events of interest will be 
summarized and Kaplan-Meier curves will be plotted.  
The incidence and comparable prevalence rate per 2-week time interval for AEs of special 
interest will be summarized and plotted by cohort. 
Bar graphs of the worst toxicity grade of cardiac events over time by cohort will be plotted. 
All adverse events for subjects who met the Study Stopping Rules(i.e. <1 log decline in HCV 
RNA after 4 weeks of treatment) will be listed.  
All TEAEs reported in the CRF will be listed with the SOC, PT and investigator's verbatim. 
Additional listings will be provided for serious adverse events (SAEs), TEAEs with grade 3 
or grade 4, TEAEs leading to any study drug discontinuation, TEAEs of special interest, and 
TEAEs with fatal outcome. 
In case of rash, all information related to rash assessments will be listed. 
8.2 Clinical laboratory data 
The following clinical laboratory parameters will be measured (see section 12.1): 
- 
At the screening visit,  
- 
On Day 1, Week 1, Week 2, Week 4, Week 6, Week 8 (8 or 12 Week Cohorts), Week 
10 (12 Week Cohorts), Week 12 (12 Week Cohorts), safety follow-up visit. 
Additional measurements are done on Week 3, Week 5 and Week 7 for alanine 
aminotransferase (ALT) and aspartate aminotransferase. 
Haematology parameters will be listed and grouped as follows: 
- Red blood cells: haemoglobin (g/L), haemoglobin A1C (mmol/mol) only at screening, 
hematocrit (fraction of 1), mean corpuscular haemoglobin (MCH) (fmol), mean corpuscular 
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haemoglobin concentration (MCHC) (mmol/L), mean corpuscular volume (MCV) (fL), mean 
platelet volume (MPV) (fl), erythrocyte sedimentation rate (mm/h), red distribution width 
(RDW) (%), reticulocytes (G/L and %) and red blood cell count (RBC) (T/L). 
- White blood cells: basophils (G/L and %), eosinophils (G/L and %), lymphocytes (G/L and 
%), monocytes (G/L and %), neutrophils (G/L and %)) and white blood cell count (WBC) 
(G/L). 
- Platelets (G/L). 
Blood chemistry parameters will be listed and grouped as follows: 
- Liver function: alanine aminotransferase (ALT) (IU/L), alkaline phosphatase (IU/L), 
aspartate aminotransferase (AST) (IU/L), total bilirubin (µmol/L) and direct bilirubin 
(µmol/L).  
- Renal chemistry: creatinine (µmol/L) and blood urea nitrogen (BUN) (mmol/L). 
 - Electrolytes: calcium (mmol/L), chloride (mmol/L), phosphorus (mmol/L), potassium 
(mmol/L), sodium (mmol/L) and bicarbonates (mmol/L). 
- Metabolism parameters: glucose (mmol/L), cholesterol (mmol/L), triglycerides (mmol/L), 
lipase (IU/L), uric acid (µmol/L) and lactate dehydrogenase (LDH) (IU/L). 
- Other parameters: albumin (g/L), creatine kinase (CPK) (IU/L), total protein (g/L), alpha 
fetoprotein (ug/L) only at screening, Alpha-1 Acid Glycoprotein (g/L) only at screening, Beta 
natriuretic peptide (BNP) and NT-pro-BNP. 
 
Coagulation parameters will be listed and grouped as follows: 
- Coagulation parameters: prothrombin time (PT) (s), activated partial thromboplastin time 
(aPTT) (s) and international normalized ratio (INR). 
Urinalysis parameters will be listed and grouped as follows: 
- Planned urinalysis parameters: dipstick determination of pH, specific gravity, glucose, 
bilirubin, ketones, leukocytes, nitrite, occult blood, protein and urobilinogen. 
- Direct microscopy: in case of abnormal urinalysis parameters (in listing only). 
Hormonology parameters will be listed as follows: FSH (IU/L) and estradiol (pmol/L) 
In case a laboratory test result is censored (no numeric value is available, but only a verbatim 
term), the following rules are applied: 
- 
      x
<
 or 
x
>
 a numeric value will be imputed by a value exceeding the cut-off 
value with one unit. 
- 
x
≤
 or  
x
≥
  imputation by x. 
Laboratory values will be graded based on the following toxicity grading scale: The Division 
of AIDS Table for Grading the Severity of Adult and Pediatric AEs (“DAIDS grading table”, 
version of November 2014), Appendix F - protocol version 8.0 of the 13rd of September 2016. 
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Lab values will also be graded based on WHO grading scale, but summary tables will be 
based on DAIDS grading scale only. 
For haematology, blood chemistry, and coagulation, raw data and changes from baseline (Day 
1) if applicable will be described by measurement time, for each cohort.  
For all lab parameters with toxicity grade, a summary table with the number and percentage 
of subjects with treatment emergent grade 1-4 and 3+4 will be generated for each cohort for 
the worst post-baseline value. The same table will be provided by measurement time. 
For haematology and blood chemistry, graphs of individual subject values (spaghetti plots) 
will be generated for each cohort for the following parameters: ALT, AST, alkaline 
phosphatase, total bilirubin, direct bilirubin, blood urea nitrogen, creatinine, CPK, BNP, 
haemoglobin, platelets and white blood cells.  
A listing of all values of a parameter over time for any parameter with treatment emergent 
Grade 3 or 4 will be generated. A listing of all values of a parameter over time for any 
parameter with treatment emergent abnormal values will be also generated. 
Values will be listed (raw data and change from baseline) and laboratory abnormal values will 
be flagged with their toxicity grades and clinical significance information. 
For urinalysis, raw data will be described by measurement time, for each cohort. 
Urinalysis values will be listed including direct microscopy if any. 
Hormonology parameters will be listed only. 
For applicable lab parameters, cross-tabulation of the worst toxicity grades versus baseline 
will be presented, Plots of mean(SE), mean(SE) of change from baseline by cohort over time 
and Bar graphs of the treatment emergent abnormality by toxicity grade over time for selected 
laboratory parameters will be plotted. 
In determining DAIDS toxicity grades the following rules are applied: 
- 
The worst grades/abnormalities are determined over the whole observational 
period, including all post-reference scheduled and unscheduled measurements. 
- 
The abnormalities “abnormally low” and “abnormally high” are considered 
equally important, i.e. if a subject has an “abnormally low” as well as an 
“abnormally high” post-reference value, 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 CTP will always be used, also for samples obtained under a different condition 
(e.g. samples of withdrawal visits). 
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Definition treatment-emergent: An abnormality (toxicity grade or abnormality based on 
normal ranges) will be considered treatment-emergent in a particular phase if it is worse than 
the reference. If the reference is missing, the abnormality is always considered as treatment-
emergent.  A shift from “abnormally low” at reference to “abnormally high” post reference 
(or vice versa) is also treatment-emergent. 
 
8.3 Other safety parameters 
8.3.1 Vital signs data 
Blood pressures (diastolic [DBP] and systolic [SBP]; mmHg), respiratory rate (breaths/min), 
body temperature (°C) and pulse rate (bpm) will be measured (see section 12.1) for each 
cohort at the screening visit, Day 1, Week 1 and then once a week thereafter. 
Raw data and changes from baseline (Day 1 pre-dose) will be described by measurement 
time, for each cohort.  
A summary table with the number and percentage of subjects with PCSA values (defined in 
section 12.2) will be generated by measurement time, for each cohort. 
A specific listing of all values of a parameter over time for any parameter with PCSA values 
with clinical significance information will be generated. 
Pulse rate, DBP, and SBP are classified in the following abnormality codes: 
 
Pulse (bpm) 
DBP (mmHg) 
SBP (mmHg) 
Abnormally low 
≤ 50 
≤ 50 
≤ 90 
Abnormally high 
≥ 120 
- 
- 
Grade 1 or mild 
- 
> 90 - < 100 
> 140 - < 160 
Grade 2 or moderate 
- 
≥ 100 - < 110 
≥ 160 - < 180 
Grade 3 or severe 
- 
≥ 110 
≥ 180 
A summary table with the number and percentage of subjects with abnormal values (as 
defined above) will be generated for each cohort for the worst post-baseline value. The same 
table will be provided by measurement time. 
A specific listing of all values of a parameter over time for any parameter with abnormal 
values with clinical significance information will be generated. 
Values (raw data and changes from baseline) will be listed and PCSA and abnormal values 
will be flagged with clinical significance information.  
Graph of mean (SE) by cohort over time will be plotted. 
In determining the abnormalities, the following rules are applied: 
- 
Worst grades/abnormalities are determined over the whole observational period, including 
post-baseline scheduled and unscheduled measurements. 
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- 
The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered equally 
important, i.e. if a subject has an ‘abnormally low’ as well as an ‘abnormally high’ or 
graded post-baseline value, both abnormalities are shown in the tables. (This means that 
the sum of the percentages can be more than 100%.) 
Definition treatment-emergent: 
An abnormality will be considered treatment-emergent if it is worse than the baseline. If the 
baseline is missing, the abnormality is always considered as treatment-emergent. A shift from 
‘abnormally low’ at baseline to ‘abnormally high’ or ‘grade 1’ or ‘grade 2’ or ‘grade 3’ post 
baseline (or vice versa) is also treatment-emergent. 
8.3.2 Electrocardiogram data 
Standard 12-lead ECG parameters (including heart rate (bpm), PR interval (ms), QRS 
duration (ms), QT interval (ms), Bazett QTc interval (QTcB; ms) and Fridericia QTc interval 
(QTcF; ms)) from both automatic and centrally read data, information on T- (normal or 
abnormal) and U-waves (normal or abnormal) and ECG abnormality will be measured (see 
section 12.1) for each cohort at the screening visit, Day 1, Week 1 and then once a week 
thereafter. 
The mean of the triplicate ECGs will serve as analysable data for each visit. If one or more 
assessment is missing/not done then the mean will be calculated using the available 
assessments. 
Centrally read data will be used for summary statistics and both locally and centrally read 
data will be listed. 
Raw data and changes from baseline (Day 1 pre-dose) (except for T-and U-wave and ECG 
abnormality) will be described by measurement time, for each cohort.  
A summary table with the number and percentage of subjects with PCSA values (defined in 
section 12.2) will be generated by measurement time, for each cohort. 
Graphs of individual subject values (spaghetti plots) will be generated for each cohort for the 
following parameters: PR, QRS, QTcB, and QTcF. These graphs will include indications for 
the most conservative upper and lower limit of normal. 
A specific listing of all values of a parameter over time for any parameter with PCSA values 
with clinical significance information will be generated. 
A listing of all values over time for subjects with any clinically significantly abnormal ECGs 
will also be generated. 
A listing of subjects with potentially progressive PR prolongation will be generated. 
Potentially progressive PR prolongation is defined as any subject who has a post-baseline 
change of >20 ms from the highest pre-dose value. 
Values (raw data/T- and U-wave/ECG abnormalities and changes from baseline) will be listed 
and data out of PCSA range will be flagged with clinical significance information. 
The following abnormality categories are defined: 
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Abnormality Code 
ECG parameter 
HR 
PR 
QRS 
QTcorrected
* 
Abnormalities on actual values 
Abnormally low 
≤50 bpm 
<120 ms 
NA 
- 
Abnormally high 
≥120 bpm 
]200-240] ms 
>120 ms 
- 
 
]240-300] ms 
 
 
 
>300 ms 
 
 
Borderline: ]450 ms, 480 ms] 
- 
- 
- 
450 ms< QTc ≤480 ms 
Prolonged: ]480 ms, 500 ms] 
Pathologically prolonged: >500 ms 
- 
- 
- 
- 
- 
- 
480 ms< QTc ≤500 ms 
QTc>500 ms 
Abnormalities on increase from 
baseline 
- 
[30; 60] ms 
- 
[30; 60] ms 
- 
>60 ms 
- 
>60 ms 
* QTcB or QTcF 
A summary table with the number and percentage of subjects with abnormal values (as 
defined above) will be generated for each cohort for the worst post-baseline value. The same 
table will be provided by measurement time. 
A specific listing of all values of a parameter over time for any parameter with abnormal 
values with clinical significance information will be generated. 
A specific listing of all overall interpretations over time for any subject with any overall 
interpretation considered to be clinically significantly abnormal will be created. 
In determining the abnormalities, the following rules are applied: 
- 
Worst abnormalities are determined over the whole observational period, 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 post-
baseline, both abnormalities are shown in the tables. (This means that the sum of the 
percentages can be more than 100%). 
Cross-Tabulation of the worst ECG abnormalities in actual value versus the baseline value 
and Cross-Tabulation of the worst QTc increase versus the abnormality on the actual value 
will be presented.  
Graphs of actual mean(SE), mean of change from baseline(SE) by cohort over time will be 
plotted. Spaghetti plots of PR for the patients who had prolonged PR interval or AV block 
(grade>=1) will be plotted. 
Definition treatment-emergent: 
An abnormality will be considered treatment-emergent if it is worse than the baseline. If the 
baseline is missing, the abnormality is always considered as treatment-emergent. A shift from 
‘abnormally low’ at baseline to ‘abnormally high’ or ‘grade 1’ or ‘grade 2’ or ‘grade 3’ post 
baseline (or vice versa) is also treatment-emergent. 
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8.3.3 Other safety parameters 
Echocardiograms will be performed at regular intervals and according to a standard protocol. 
The centrally read echocardiogram results will be used for analysis.   
The maximum decline in mean ejection fraction (EF) from baseline will be summarized in a 
table by cohort with the following cutoffs: decline of >10%, decline of >5-≤10% and decline 
of >0-<=5%.  Moreover, the number of subjects with any mean EF that declines by >10%, 
>5-≤10% or >0-<=5% will be summarized by measurement time and cohort. 
A listing of all mean EFs by time point for subjects with any mean EF that declines by >10% 
or >5-≤10% will be provided. 
Moreover, for the following parameters: diastolic volume, left ventricular ejection fraction 
(LVEF) single plane, LV fractional shortening, LVPW diastolic thickness, systolic volume 
and ventricular septum diastolic thickness, the following analyses will be performed: 
Raw data and changes from baseline (Screening) as well as percent changes from baseline 
will be described by measurement time, for each cohort.  
Graphs of individual subject values (spaghetti plots) will be generated for each parameter and 
each cohort.  
A summary table with the number and percentage of subjects with abnormally low, normal, 
and abnormally high values will be generated by measurement time, for each cohort. 
Overall interpretation of echocardiograms will be listed by time point by cohort.  
Graphs of actual mean(SE), mean of change from baseline(SE) by cohort over time will be 
plotted for mean ejection fraction.  
Weight and BMI will be measured (see section 12.1) for each cohort at the screening visit and 
at the completion visits. 
Raw data and changes from baseline (Day 1) will be described by measurement time, for each 
cohort and listed. 
Complete physical examination will be measured (see section 12.1) for each cohort at the 
screening visit, on Day 1, Week 1 and then once a week after.  
Results from physical examination will be described by measurement time, for each cohort. 
All physical examinations over time for any subject with any clinically significantly abnormal 
physical examinations will be listed as well as all individual data. 
Pregnancy test will be performed (see section 12.1) for each cohort at the screening visit and 
at the completion visits.  
Positive pregnancy test will be listed as well as all individual data. 
Toxicology testing will be listed. 
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9. Efficacy data 
All efficacy analyses will be performed on the Safety set and, if necessary only, on the Per 
Protocol set. 
9.1 Analysis Specifications 
9.1.1 Level of Significance 
No significance testing will be performed. However, a two-sided Clopper-Pearson 95% CI 
will be constructed around the proportion of subjects with SVRx and other virologic response 
parameters, for each cohort. 
9.1.2 Data Handling Rules 
Plasma HCV RNA values will be determined using the Roche Cobas Ampliprep/Cobas 
Taqman v2.0 assay with a lower limit of quantification (LLOQ) of 15 IU/mL and a limit of 
detection (LOD) of 15 IU/mL. 
For the purpose of the analysis HCV RNA results “HCV RNA <15 IU/mL” will be imputed 
by LLOQ-1 IU/mL = 14 IU/mL before log transformation and “HCV RNA not detected” will 
be imputed by LOD-2 IU/mL= 13 IU/mL before log transformation. 
9.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is sustained virologic response 12 weeks after the actual end of 
treatment (SVR12). 
9.2.1 Definition 
SVR12 is classified as success or failure according to the following algorithm based on HCV 
RNA values 12 weeks after the actual end of treatment. 
SVR12 is classified as a success (1) if at the time point of SVR12, HCV RNA value(s) meet 
one of the following: 
 HCV RNA Not detected or 
 < LLOQ detected and 
• the sample is a confirmation* visit 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 and 
• the sample is not from a confirmatory visit* 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 
Otherwise SVR12 is classified as a failure (0). 
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* Confirmed means that the criterion should be fulfilled at 2 or more consecutive time points 
or at the last observed time point. 
 
Time point of SVR12: 
o 12 weeks after the actual EOT (i.e. the last available measurement in the 
SVR12 analysis window) 
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. 
9.2.2 Analysis Methods 
The number and proportion of subjects with SVR12 will be tabulated overall and by cohort, a 
two-sided Clopper-Pearson 95% CI will be constructed. 
9.3 Major Secondary Endpoints 
Secondary efficacy endpoints include: 
• Proportion of subjects with SVR4, SVR18 and SVR24 
• Change from baseline in log10 HCV RNA 
• Actual values of log10 HCV RNA 
• Proportion of subjects with on-treatment virologic response at all timepoints (HCV 
RNA not detected;  HCV RNA < LLOQ detected; HCV RNA not detected or HCV 
RNA < LLOQ detected) 
• Proportion of subjects with failure 
• Proportion of subjects with on-treatment failure 
• Proportion of subjects with viral relapse 
9.3.1 Definitions 
SVR4, SVR18 and SVR24 are defined similarly as SVR12 but with 4 weeks, 18 weeks and 
24 weeks respectively, instead of 12 weeks.  
In addition, for SVR24, the time point of SVR is defined as follows: 
o 24 weeks after actual EOT (i.e. the last available measurement in follow up 
Week 24 analysis window) 
o or, if not available, the first measurement available, after the follow-up Week 
24 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 
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o or, if not available, the last measurement available in the follow up Week 12 
analysis window (on condition that the time point of SVR24 has been reached) 
o or, if not available, the subject is considered as not having SVR24 
For SVR18, the timepoint of SVR is defined as follows: 
o 18 weeks after the actual EOT (i.e. the last available measurement in follow up 
Week 18 analysis window) 
o or, if not available, the subject is considered as not having SVR18 
On-Treatment failure is defined as subjects who did not achieve SVR12 and with confirmed 
HCV RNA ≥LLOQ at the actual end of study drug treatment. Includes subjects:  
• With viral breakthrough, defined as a confirmed increase of >1 log10 in HCV RNA 
from nadir, or confirmed HCV RNA of >100 IU/mL in subjects whose HCV RNA had 
previously been <LLOQ while on treatment.  
• With inadequate virologic response, defined as <1 log10 decline from baseline in 
HCV RNA after 4 weeks of treatment  
• Who do not experience viral breakthrough or inadequate virologic response and have 
confirmed HCV RNA ≥LLOQ at the actual end of study drug treatment (e.g., 
completed study drug treatment, discontinued due to adverse events, withdrawal of 
consent).  
Viral Relapse is defined as follows: 
Subjects who achieved HCV RNA <LLOQ at the actual end of study drug treatment and 
developed HCV RNA ≥LLOQ during post-treatment follow up. 
Failure (No SVR12): Subjects who did not achieve SVR12, including: 
• On-treatment failure (see above) 
• Post-treatment failure, including subjects with: 
- 
Viral relapse (see above)  
- 
Missing HCV RNA at time point of SVR12 
On-treatment virologic response: 
Virologic response is quantitative HCV RNA concentration <LLOQ at any timepoint post-
first dose of study drug. An SVR is HCV RNA <LLOQ at Weeks 4, 8, 12, 18 or 24 after 
cessation of study treatment. 
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 Not Detected or HCV RNA <LLOQ Detected 
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9.3.2 Analysis Methods 
The efficacy analysis will be performed on the Safety set and Per Protocol set, by cohort. 
Descriptive statistics per cohort and per time point for the continuous parameter (actual values 
and changes from baseline in log10 IU/mL HCV RNA) will be calculated. 
Tabulations (numbers and proportions) per cohort and per time point for the categorical 
parameters will be provided. The observed proportion of subjects with SVR4 and SVR24 will 
be analyzed in the same way as the primary endpoint.  
The influence of early virologic response parameters on SVR12 will be explored. 
In addition, the reason for failure will be explored by type of failure (see definition of failure 
above). If more than one type of failure occurs, the order as presented below should be 
respected:  
a) viral relapse 
b) viral breakthrough 
c) confirmed detected at EOT 
d) missing at time point of SVR 
Graphs of individual subject values (spaghetti plots) will be generated for each cohort for the 
viral load (VL) over time. 
Graphs for mean VL change from baseline (+/- SD) over time will be generated for each 
cohort. 
10. Reporting conventions 
All tables, figures and listings are detailed in section 12.3. They will be prepared using SAS 
software as rtf files and the rtf files will be compiled as Word files (one Word file by main 
section). 
The footers will be presented as follows: --- STUDY <study protocol code> / <name of the 
program>.SAS / <name of the output>.RTF / DDMMMYY HH:MM ---. 
Table and Listing Page Set Up Requirements: 
- 
Font Type = Courier New 
- 
Font Size = 8 pt (at a minimum) 
- 
Page Margins: Top=2 cm; Bottom=2 cm; Left=2 cm; Right=2 cm 
- 
Paper Size = A4 (21 cm x 29.7 cm) 
- 
Page Orientation: Landscape 
- 
Graphs: Portable Network Graphics (PNG) format 
 
Summary statistics will be presented as follows.  
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Parameter 
(unit) 
Statistics 
/ Category 
Group X 
(N=xx) 
Quantitative variable* n 
xx 
 
Mean ± SD 
xx.xx ± xx.xx 
 
SEM 
xx.xx 
 
Median 
xx.xx 
 
Min ; Max 
xx.x ; xx.x 
Qualitative variable 
Class 1 (n,%) 
xx ( xx.x) 
 
Class 2 (n,%) 
xx ( xx.x) 
 
… 
… 
* For demographics and Baseline characteristics and for Safety summary tables:  
All statistics, except the minimum and the maximum, will be provided with an additional 
decimal compared to the variable itself.  
For PK summary tables: 
- 
if n=1 or n=2, do not display other statistics than n 
- 
For tmax, only minimum, median, maximum and number of observations will be 
reported. 
- 
For calculated values, PK parameters and descriptive statistics up to, but not including 
100, display to 3 significant figures, for example: 
• 0.35769 is reported 0.358 
• 3.5769 is reported 3.58 
• 35.769 is reported 35.8 
• 357.69 is reported 358 
• For values ≥ 1000, the whole integer is reported (example 3576.9 is reported as 
3577) 
tmax and tlag values are to be reported to 2 decimal places; half-life is to be reported to 1 
decimal place.  
Coefficient of Variation is reported to 1 decimal place. 
Ratios and confidence interval are reported to 2 decimal places. 
Drug concentration data that could not be obtained will be listed as NS (No Sample) in data 
tabulations. 
 
 
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11. Appendices  
11.1 Appendix 1 - Schedule of assessments of the study  
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11.2 Appendix 2 - Criteria for Potentially Clinically Significant Abnormalities (PCSA)   
Vital signs 
PR 
≤ 50 bpm 
≥ 120 bpm 
SBP 
≤ 90 mmHg 
> 140 mmHg 
DBP 
≤ 50 mmHg 
> 90 mmHg 
ECG parameters 
PR 
<120 ms 
> 200 ms  
QRS 
 
> 120 ms 
QTcB or QTcF 
 
> 450 - ≤ 480 ms 
> 480 ms 
> 500 ms 
change from baseline ≥ 30 - ≤ 60 ms 
change from baseline > 60 ms 
 
 
 
 
 
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11.3 Appendix 3 - List of tables, listings and figures included in the clinical study report 
NUMBER 
TITLE 
14 
Tables, figures and graphs referred to but not included in the text 
14.1 
Demographic data 
14.1.1 
Description of study subjects 
14.1.1.1 
Subjects disposition - Included set 
14.1.1.2 
Analysis sets – Included set 
14.1.2 
Protocol deviations 
14.1.2.1 
Deviations relating to inclusion/exclusion criteria - Safety set 
14.1.2.2 
Other deviations - Safety set 
14.1.3 
Demographic data and baseline characteristics 
14.1.3.1.1 
Demographic data - Safety set 
14.1.3.1.2 
Demographic data - PKS 
14.1.3.2 
Other baseline characteristics 
14.1.3.2.1.1 
HCV genotype  – Safety set 
14.1.3.2.1.2 
HCV genotype  – PKS 
14.1.3.2.2.1 
HCV RNA – Safety set 
14.1.3.2.2.2 
HCV RNA – PKS 
14.1.3.2.3.1 
Serology - Safety set 
14.1.3.2.3.2 
Serology - PKS 
14.1.3.2.4 
Listing of positive results of serology - Safety set 
14.1.3.2.5.1 
Cirrhosis status - Safety set 
14.1.3.2.5.2 
Cirrhosis status - PKS set 
14.1.3.2.6.1 
Liver biopsy – Safety set 
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14.1.3.2.6.2 
Liver biopsy – PKS 
14.1.3.2.7.1 
Fibroscan - Safety set 
14.1.3.2.7.2 
Fibroscan - PKS set 
14.1.3.3 
Medical and surgical history  
14.1.3.3.1 
Previous medical and surgical history (except liver diseases) - Safety 
set 
14.1.3.3.2 
Ongoing medical and surgical history (except liver diseases) - Safety 
set 
14.1.3.3.3 
Previous liver diseases - Safety set 
14.1.3.3.4 
Ongoing liver diseases - Safety set 
14.1.3.4 
Previous and concomitant medications 
14.1.3.4.1 
Previous medications - Safety set 
14.1.3.4.2 
Concomitant medications - Safety set 
14.2 
Pharmacokinetic data 
14.2.1 
Plasma concentrations 
14.2.1.1 
AL-335, ALS-022399 and ALS-022227 
14.2.1.1.1 
Plasma concentrations for AL-335, ALS-022399 and ALS-022227 - 
Pharmacokinetic set 
14.2.1.1.2 
Graphs of plasma concentrations means (±SD) over time for AL-335, 
ALS-022399 and ALS-022227 - Pharmacokinetic set 
14.2.1.1.2.1 
Graphs of plasma concentrations means (±SD) over time for AL-335, 
ALS-022399 and ALS-022227 by analyte 
14.2.1.1.2.2 
Graphs of plasma concentrations means (±SD) over time for AL-335, 
ALS-022399 and ALS-022227 by cohort 
14.2.1.1.3 
Graphs of trough plasma concentrations means (±SD) over time for 
AL-335, ALS-022399 and ALS-022227 - Pharmacokinetic set 
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14.2.1.2 
Simeprevir 
14.2.1.2.1 
Plasma concentrations for simeprevir - Pharmacokinetic set 
14.2.1.2.2 
Graphs of plasma concentrations means (±SD) over time for 
simeprevir - Pharmacokinetic set 
14.2.1.2.3 
Graphs of trough plasma concentrations means (±SD) over time for 
simeprevir - Pharmacokinetic set 
14.2.1.3 
Odalasvir 
14.2.1.3.1 
Plasma concentrations for odalasvir - Pharmacokinetic set 
14.2.1.3.2 
Graphs of plasma concentrations means (±SD) over time for 
odalasvir - Pharmacokinetic set 
14.2.1.3.3 
Graphs of trough plasma concentrations means (±SD) over time for 
odalasvir - Pharmacokinetic set 
14.2.2 
PK parameters in plasma 
14.2.2.1 
AL-335, ALS-022399 and ALS-022227 
14.2.2.1.1 
PK parameters in plasma for AL-335, ALS-022399 and ALS-022227 - 
Pharmacokinetic set 
14.2.2.1.2 
Scatter plots of Cmax and AUC0-τ for AL-335, ALS-022399 and ALS-
022227 by cohort - Pharmacokinetic set 
14.2.2.1.3 
Box whisker plots of Cmax and AUC0-τ for AL-335, ALS-022399 and 
ALS-022227 by cohort - Pharmacokinetic set 
14.2.2.2 
Simeprevir 
14.2.2.2.1 
PK parameters in plasma for simeprevir - Pharmacokinetic set 
14.2.2.2.2 
Scatter plots of Cmax and AUC0-τ for simeprevir by cohort - 
Pharmacokinetic set 
14.2.2.2.3 
Box whisker plots of Cmax and AUC0-τ for simeprevir by cohort - 
Pharmacokinetic set 
14.2.2.3 
 Odalasvir 
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14.2.2.3.1 
PK parameters in plasma for odalasvir - Pharmacokinetic set 
14.2.2.3.2 
Scatter plots of Cmax and AUC0-τ for odalasvir by cohort -
Pharmacokinetic set 
14.2.2.3.3 
Box whisker plots of Cmax and AUC0-τ for odalasvir by cohort - 
Pharmacokinetic set 
14.3 
Safety data 
14.3.1 
Adverse events 
14.3.1.1 
Adverse events - Safety set 
14.3.1.2 
Treatment emergent adverse events 
14.3.1.2.1 
Treatment emergent adverse events summary table - Safety set 
14.3.1.2.2 
Treatment emergent adverse events - Safety set 
14.3.1.2.3 
Treatment emergent adverse events by preferred term - Safety set 
14.3.1.2.4 
Treatment emergent adverse events by intensity - Safety set 
14.3.1.2.5 
Treatment emergent adverse events by causality - Safety set 
14.3.1.2.6 
Treatment emergent serious adverse events by preferred term - 
Safety set 
14.3.1.2.7 
Treatment emergent adverse events leading to any study drug 
discontinuation by preferred term - Safety set 
14.3.1.2.8 
Treatment emergent adverse events of special interest - Safety set 
14.3.1.2.9 
Adverse Events with fatal outcome – Included set 
14.3.1.2.10 
The incidence and comparable prevalence rate per 2-week time 
interval for any AEs 
14.3.1.2.11 
The incidence rates for adverse events of special interest by WHO 
toxicity grade 
14.3.1.2.12 
The incidence rates for adverse events of special interest by 
relationship to study drugs 
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14.3.1.2.13 
The incidence rates for serious adverse events of special interest by 
relationship to study drugs 
14.3.1.2.14 
Time to the first occurrence of adverse events of special interest 
14.3.1.2.15 
The incidence and comparable prevalence rate per 2-week time 
interval for adverse events of special interest 
14.3.1.3.1 
Graph of incidence and comparable prevalence rate for any AE over 
time 
14.3.1.3.2 
Kaplan Meier Curve for the Time to Onset of adverse events of 
special interest 
14.3.1.3.3 
Graph of incidence and comparable prevalence rate for adverse 
event of special interest over time 
14.3.1.3.4 
Bar chart of the worst toxicity grade of cardiac events over time 
14.3.2.1 
Listing of deaths, SAEs and TEAEs leading to study drug 
discontinuation - Safety set 
14.3.2.2 
Listing of TEAEs with grade 3 or grade 4 - Safety set 
14.3.2.3 
Glossary of adverse events 
14.3.2.4 
Listing of adverse events for subjects who met the study stopping 
rules 
14.3.3 
Clinical laboratory data 
14.3.3.1 
Haematology 
14.3.3.1.1 
Haematology parameters - Safety set 
14.3.3.1.2 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – Worst post-baseline value - Safety set 
14.3.3.1.3 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – By measurement time - Safety set 
14.3.3.1.4 
Listing of all values for subjects presenting any treatment emergent 
value that is grade 3 and 4 (toxicity grading scale) - Safety set 
14.3.3.1.5 
Listing of subjects with treatment emergent abnormal values - 
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Safety set 
14.3.3.1.6 
Graphs of individual subject values (spaghetti plots) – Safety Set 
14.3.3.1.7 
Cross-tabulation of the worst toxicity grades versus baseline 
14.3.3.1.8 
Plot of mean(SE) by cohort over time 
14.3.3.1.9 
Plot of mean(SE) change from baseline by cohort over time 
14.3.3.1.10 
Bar chart of the treatment emergent abnormality by toxicity grade 
over time 
14.3.3.2 
Blood chemistry 
14.3.3.2.1 
Blood chemistry parameters - Safety set 
14.3.3.2.2 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – Worst post-baseline value - Safety set 
14.3.3.2.3 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – By measurement time - Safety set 
14.3.3.2.4 
Listing of all values for subjects presenting any treatment emergent 
values that are grade 3 and 4 (toxicity grading scale) - Safety set 
14.3.3.2.5 
Listing of subjects with treatment emergent abnormal values - 
Safety set 
14.3.3.2.6 
Graphs of individual subject values (spaghetti plots) – Safety Set 
14.3.3.2.7 
Cross-tabulation of the worst toxicity grades versus baseline 
14.3.3.2.8 
Plot of mean(SE) by cohort over time 
14.3.3.2.9 
Plot of mean(SE) change from baseline by cohort over time 
14.3.3.2.10 
Bar chart of the treatment emergent abnormality by toxicity grade 
over time 
14.3.3.3 
Coagulation - Safety set 
14.3.3.3.1 
Coagulation parameters - Safety set 
14.3.3.3.2 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – Worst post-baseline value - Safety set 
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14.3.3.3.3 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – By measurement time - Safety set 
14.3.3.3.4 
Listing of all values for subjects presenting any treatment emergent 
values that are grade 3 and 4 (toxicity grading scale) - Safety set 
14.3.3.3.5 
Listing of subjects with treatment emergent abnormal values - 
Safety set 
14.3.3.3.6 
Cross-tabulation of the worst toxicity grades versus baseline 
14.3.3.3.7 
Plot of mean(SE) by cohort over time 
14.3.3.3.8 
Plot of mean(SE) change from baseline by cohort over time 
14.3.3.3.9 
Bar chart of the treatment emergent abnormality by toxicity grade 
over time 
14.3.3.4 
Urinalysis - Safety set 
14.3.3.4.1 
Urinalysis parameters - Safety set 
14.3.3.4.2 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – Worst post-baseline value - Safety set 
14.3.3.4.3 
Number and percentage of subjects by treatment emergent toxicity 
grade (Grade 1,2,3,4,3+4) – By measurement time - Safety set 
14.3.3.4.4 
Listing of all values for subjects presenting any treatment emergent 
values that are grade 3 and 4 (toxicity grading scale) - Safety set 
14.3.3.4.5 
Listing of subjects with treatment emergent abnormal values - 
Safety set 
14.3.4 
Other safety parameters 
14.3.4.1 
Vital signs data 
14.3.4.1.1 
Vital signs parameters - Safety set 
14.3.4.1.2 
Number and percentage of subjects presenting PCSA values - Safety 
set 
14.3.4.1.3 
Listing of subjects presenting PCSA values - Safety set 
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14.3.4.1.4 
Number and percentage of subjects presenting abnormal values – 
Worst post-baseline value - Safety set 
14.3.4.1.5 
Number and percentage of subjects presenting abnormal values – 
By measurement time - Safety set 
14.3.4.1.6 
Listing of subjects presenting abnormal values - Safety set 
14.3.4.1.7 
Plots of mean (SE) by cohort over time 
14.3.4.2 
Electrocardiogram data 
14.3.4.2.1 
ECG parameters – Safety set 
14.3.4.2.2 
Number and percentage of subjects with PCSA values - Safety set 
14.3.4.2.3 
Listing of subjects presenting PCSA values - Safety set 
14.3.4.2.4 
Listing of All ECG Parameters over time for Subjects with Any Post-
baseline Overall Statement of Potentially Clinically Significant 
Abnormal ECG 
14.3.4.2.5 
Listing of Subjects with Potentially Progressive PR Prolongation 
14.3.4.2.6 
Number and percentage of subjects presenting abnormal values – 
Worst post-baseline value - Safety set 
14.3.4.2.7 
Number and percentage of subjects presenting abnormal values – 
By measurement time - Safety set 
14.3.4.2.8 
Listing of subjects presenting abnormal values - Safety set 
14.3.4.2.9 
Graphs of individual subject values (spaghetti plots) – Safety Set 
14.3.4.2.10 
Cross-Tabulation of the worst ECG abnormalities in actual value 
versus the baseline value 
14.3.4.2.11 
Cross-Tabulation of the worst QTc increase versus the abnormality 
on the actual value 
14.3.4.2.12 
Plots of actual mean(SE) by cohort over time 
14.3.4.2.13 
Plots of mean change from baseline(SE) by cohort over time 
14.3.4.2.14 
Spaghetti plot of PR for the patients who had prolonged PR interval 
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or AV block (grade>=1) 
14.3.4.3 
Echocardiogram data 
14.3.4.3.1 
Summary Table of Maximum Decrease from baseline in Mean 
Ejection Fraction – Safety set 
14.3.4.3.2 
Number and Percentage of subjects who have a decrease greater 
than 5% or ≤10% and >10% compared to baseline – Safety set 
14.3.4.3.3 
Listing of all EF values for Subjects with any >5%-≤10 Decrease from 
baseline in Mean Ejection Fraction – Safety set 
14.3.4.3.4 
Listing of all EF values for Subjects with any More Than 10% 
Decrease from baseline in Mean Ejection Fraction – Safety set 
14.3.4.3.5 
Listing of Ejection Fraction Data and Overall Comment – Safety set 
14.3.4.3.6 
Echocardiogram parameters – Safety set 
14.3.4.3.7 
Number and percentage of subjects with abnormal values - Safety 
set 
14.3.4.3.8 
Graphs of individual subject values (spaghetti plots) – Safety set 
14.3.4.3.9 
Plots of actual mean(SE) by cohort over time 
14.3.4.3.10 
Plots of mean change from baseline(SE) by cohort over time 
14.3.4.4 
Weight and BMI – Safety set 
14.3.4.5 
Physical examination  
14.3.4.5.1 
Physical examination - Safety set 
14.3.4.5.2 
Abnormal physical examination - Safety set 
14.3.4.6 
Positive pregnancy test - Safety set 
14.4 
Efficacy data 
14.4.1 
HCV RNA – Safety set 
14.4.2 
Number and percentage of subjects who are HCV RNA not detected 
or below the limit of quantification – Safety set 
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14.4.3 
Sustained virologic response 
14.4.3.1 
Number and percentage of subjects with sustained virologic 
response 12 weeks after end of treatment – Safety set 
14.4.3.2 
Number and percentage of subjects with sustained virologic 
response 4 weeks after end of treatment – Safety set 
14.4.3.3 
Number and percentage of subjects with sustained virologic 
response 24 weeks after end of treatment – Safety set 
14.4.4 
Number and percentage of subjects with virologic failure – Safety 
set 
14.4.5.1 
Graphs of individual subject values of viral load (spaghetti plots) – 
Safety set 
14.4.5.2 
Graphs of mean viral load change from baseline – Safety set 
16.2 
SUBJECT DATA LISTINGS 
16.2.1 
Subjects disposition 
16.2.1.1 
Discontinued subjects - Included set 
16.2.1.2 
Subjects disposition and analysis sets - Included set 
16.2.1.3 
End of study status - Included set 
16.2.1.4 
Subject visit dates - Included set 
16.2.2 
Protocol deviations 
16.2.2.1 
Deviations relating to inclusion/exclusion criteria - Safety set 
16.2.2.2 
Other deviations – Safety set 
16.2.3 
Subjects excluded from analysis sets - Included set 
16.2.4 
Demographic data and baseline characteristics 
16.2.4.1 
Demographic data and baseline characteristics - Safety set 
16.2.4.2 
Other baseline characteristics 
16.2.4.2.1 
HCV genotype  – Safety set 
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16.2.4.2.2 
HCV RNA – Safety set 
16.2.4.2.3 
Serology - Safety set 
16.2.4.2.4 
Childbearing status – Safety set 
16.2.4.2.5 
Contraception method – Safety set 
16.2.4.2.6 
Alcohol consumption – Safety set 
16.2.4.2.7 
Cirrhosis status – Safety set 
16.2.4.2.8 
Liver biopsy – Safety set 
16.2.4.2.9 
Fibroscan – Safety set 
16.2.4.2.10 
Child-Pugh class assessment (only for compensated cirrhosis cohort) 
– Safety set 
16.2.4.2.11 
Hepatocellular carcinoma assessment (only for compensated 
cirrhosis cohorts) – Safety set 
16.2.4.3 
Medical and surgical history  
16.2.4.3.1 
Medical and surgical history (except liver diseases) – Safety set 
16.2.4.3.2 
Liver diseases – Safety set 
16.2.4.4 
Previous and concomitant medications 
16.2.4.4.1 
Previous medications - Safety set 
16.2.4.4.2 
Concomitant medications - Safety set 
16.2.5 
Compliance and/or drug concentration data 
16.2.5.1 
Compliance and dosing data 
16.2.5.1.1 
IMP administration – Safety set 
16.2.5.1.2 
Meals intake – Safety set 
16.2.5.2 
Pharmacokinetic data 
16.2.5.2.1 
Plasma pharmacokinetic concentrations and parameters 
16.2.5.2.1.1 
AL-335, ALS-022399 and ALS-022227 
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16.2.5.2.1.1.1 
Plasma concentrations for AL-335, ALS-022399 and ALS-022227 - 
Pharmacokinetic set 
16.2.5.2.1.1.2 
Plasma concentrations for AL-335, ALS-022399 and ALS-022227 – 
Subgroup of subjects who discontinue the study for an adverse 
event, experience a severe adverse event or a serious adverse event 
- Pharmacokinetic set 
16.2.5.2.1.1.3 
Individual plasma concentration time curves for AL-335, ALS-022399 
and ALS-022227- Pharmacokinetic set 
16.2.5.2.1.1.4 
PK parameters in plasma for AL-335, ALS-022399 and ALS-022227 - 
Pharmacokinetic set 
16.2.5.2.1.1.5 
PK parameters in plasma for AL-335, ALS-022399 and ALS-022227 – 
Subgroup of subjects who discontinue the study for an adverse 
event, experience a severe adverse event or a serious adverse event 
– Pharmacokinetic set 
16.2.5.2.1.2 
Simeprevir 
16.2.5.2.1.2.1 
Plasma concentrations for Simeprevir - Pharmacokinetic set 
16.2.5.2.1.2.2 
Plasma concentrations for Simeprevir – Subgroup of subjects who 
discontinue the study for an adverse event, experience a severe 
adverse event or a serious adverse event - Pharmacokinetic set 
16.2.5.2.1.2.3 
Individual plasma concentration time curves for Simeprevir - 
Pharmacokinetic set 
16.2.5.2.1.2.4 
PK parameters in plasma for Simeprevir - Pharmacokinetic set 
16.2.5.2.1.2.5 
PK parameters in plasma for Simeprevir – Subgroup of subjects who 
discontinue the study for an adverse event, experience a severe 
adverse event or a serious adverse event - Pharmacokinetic set 
16.2.5.2.1.3 
Odalasvir 
16.2.5.2.1.3.1 
Plasma concentrations for Odalasvir - Pharmacokinetic set 
16.2.5.2.1.3.2 
Plasma concentrations for Odalasvir – Subgroup of subjects who 
discontinue the study for an adverse event, experience a severe 
adverse event or a serious adverse event - Pharmacokinetic set 
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16.2.5.2.1.3.3 
Individual plasma concentration time curves for Odalasvir - 
Pharmacokinetic set 
16.2.5.2.1.3.4 
PK parameters in plasma for Odalasvir - Pharmacokinetic set 
16.2.5.2.1.3.5 
PK parameters in plasma for Odalasvir – Subgroup of subjects who 
discontinue the study for an adverse event, experience a severe 
adverse event or a serious adverse event - Pharmacokinetic set 
16.2.6 
Efficacy data 
16.2.6.1 
HCV RNA – Safety set 
16.2.6.2 
HCV RNA for subjects with virologic failures– Safety set 
16.2.7 
Adverse event listings 
16.2.7.1 
All adverse events – Included set 
16.2.7.2 
Treatment emergent adverse events - Safety set 
16.2.7.3 
Serious adverse events – Included set 
16.2.7.4 
Treatment emergent adverse events leading to study drug 
discontinuation – Safety set 
16.2.7.5 
Treatment emergent adverse events of special interest - Safety set 
16.2.7.6 
Adverse events with fatal outcome – Included set 
16.2.7.7 
Rash assessments 
16.2.7.7.1 
Photosensitivity – Safety set 
16.2.7.7.2 
Rash assessments – Safety set 
16.2.7.7.3 
Associated rash or cutaneous event – Safety set 
16.2.7.7.4 
Rash or cutaneous event follow-up – Safety set 
16.2.7.7.5 
Final rash, cutaneous event or photosensitivity evaluation – Safety 
set 
16.2.7.7.6 
Primary lesions of rash or cutaneous event – Safety set 
16.2.7.7.7 
Secondary lesions of rash or cutaneous event – Safety set 
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16.2.7.7.8 
Rash questionnaire – Safety set 
16.2.7.7.9 
Rash event grading – Safety set 
16.2.8 
Clinical laboratory data  
16.2.8.1 
Haematology 
16.2.8.1.1 
Normal ranges for SI units and local units 
16.2.8.1.2 
All haematology values (SI unit) - Safety set 
16.2.8.2 
Blood chemistry 
16.2.8.2.1 
Normal ranges for SI units and local units 
16.2.8.2.2 
All blood chemistry values (SI unit) - Safety set 
16.2.8.3 
Coagulation 
16.2.8.3.1 
Normal ranges for SI units and local units 
16.2.8.3.2 
All coagulation values (SI unit) - Safety set 
16.2.8.4 
Urinalysis  
16.2.8.4.1 
Normal ranges for SI units and local units 
16.2.8.4.2 
All urinalysis values (SI unit) - Safety set 
16.2.8.5 
Hormonology – Safety set 
16.2.9 
Other safety parameters 
16.2.9.1 
Vital signs data 
16.2.9.1.1 
PCSA ranges 
16.2.9.1.2 
Vital signs parameters - Safety set 
16.2.9.2 
Electrocardiogram data 
16.2.9.2.1 
PCSA ranges 
16.2.9.2.2.1 
Standard 12-lead ECG parameters (centrally read data) - Safety set 
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16.2.9.3 
Echocardiogram data – Safety set 
16.2.9.4 
Weight and BMI – Safety set 
16.2.9.5 
Physical examination – Safety set 
16.2.9.6 
Pregnancy test - Safety set 
16.2.9.7 
Toxicology – Safety set 
 
 
 
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11.4 Appendix 4: Events of special/clinical interest 
11.4.1 Search terms for Events of Special/Clinical Interest 
 
 
MedrDRA 
Term Level 
Searching Terms 
Events of special interest 
 
 
Cardiac Events 
SMQ 
Cardiac arrhythmias (SMQ) [Arrhythmia related 
investigations, signs and symptoms (SMQ); 
Cardiac arrhythmia terms (incl bradyarrhythmias 
and tachyarrhythmias) (SMQ)]; 
Cardiac failure (SMQ); 
Cardiomyopathy (SMQ); 
Ischaemic heart disease (SMQ)[ Myocardial 
infarction (SMQ)]; 
Shock (SMQ)[ Shock-associated circulatory or 
cardiac conditions (excl torsade de pointes) 
(SMQ)]; 
Torsade de pointes/QT prolongation (SMQ); 
 
Please see Appendix 3 
 Increased Bilirubin 
MedDRA PTs 
Bilirubin conjugated abnormal  
Bilirubin conjugated increased  
Bilirubin excretion disorder  
Bilirubinuria  
Blood bilirubin abnormal  
Blood bilirubin increased  
Blood bilirubin unconjugated increased  
Hyperbilirubinaemia  
Icterus index increased 
Jaundice  
Jaundice cholestatic  
Jaundice extrahepatic obstructive  
Jaundice hepatocellular  
Ocular icterus  
Urine bilirubin increased  
Yellow skin 
Events of clinical interest 
 
 
Rash (all type) 
MedDRA 
HLTs, PTs 
Erythemas - HLT 
Papulosquamous conditions - HLT 
Rashes, eruptions and exanthems NEC - HLT 
PT:  
Photodermatosis 
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Photosensitivity reaction 
Polymorphic light eruption 
Solar dermatitis 
Sunburn 
SMQ 
SMQ-Severe cutaneous adverse reaction: All 
narrow terms and selected broad terms (refer 
APPENDIX 2B below) 
Pruritus 
MedDRA HLT 
Pruritus NEC 
Photosensitivity conditions 
MedDRA PTs 
Photodermatosis 
Photosensitivity reaction 
Polymorphic light eruption 
Solar dermatitis 
Sunburn  
 
 
 
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11.4.2 RASH – SMQ19.1 
SMQ 19.1: “Severe cutaneous adverse reaction” : all narrow and selected broad terms 
SCOPE 
Preferred Term 
NARROW 
CUTANEOUS VASCULITIS 
NARROW 
DERMATITIS BULLOUS 
NARROW 
DERMATITIS EXFOLIATIVE 
NARROW 
DERMATITIS EXFOLIATIVE GENERALISED 
NARROW 
ERYTHEMA MULTIFORME 
NARROW 
OCULOMUCOCUTANEOUS SYNDROME 
NARROW 
SKIN NECROSIS 
NARROW 
STEVENS-JOHNSON SYNDROME 
NARROW 
TOXIC EPIDERMAL NECROLYSIS 
NARROW 
ACUTE GENERALISED EXANTHEMATOUS PUSTULOSIS 
NARROW 
TOXIC SKIN ERUPTION 
NARROW 
EPIDERMAL NECROSIS 
NARROW 
EXFOLIATIVE RASH 
NARROW 
DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS 
BROAD 
BLISTER 
BROAD 
BULLOUS IMPETIGO 
BROAD 
DRUG ERUPTION 
BROAD 
EPIDERMOLYSIS BULLOSA 
BROAD 
MUCOCUTANEOUS ULCERATION 
BROAD 
NIKOLSKY'S SIGN 
BROAD 
PEMPHIGOID 
BROAD 
PEMPHIGUS 
BROAD 
SKIN EROSION 
BROAD 
SKIN EXFOLIATION 
BROAD 
EPIDERMOLYSIS 
BROAD 
ACQUIRED EPIDERMOLYSIS BULLOSA 
 
 
 
 
 
 
 
 
 
63 of 76
NCT02569710


11.4.3 CARDIAC EVENTS - SMQ19.1 
Narrow/Broad 
PT Term 
Cardiac arrhythmias (SMQ) 
Arrhythmia related investigations, signs and symptoms (SMQ) 
Narrow 
Chronotropic incompetence 
Narrow 
Electrocardiogram repolarisation abnormality 
Narrow 
Electrocardiogram RR interval prolonged 
Narrow 
Electrocardiogram U-wave abnormality 
Narrow 
Sudden cardiac death 
Broad 
Bezold-Jarisch reflex 
Broad 
Bradycardia 
Broad 
Cardiac arrest 
Broad 
Cardiac death 
Broad 
Cardiac telemetry abnormal 
Broad 
Cardio-respiratory arrest 
Broad 
Central bradycardia 
Broad 
Electrocardiogram abnormal 
Broad 
Electrocardiogram ambulatory abnormal 
Broad 
Electrocardiogram change 
Broad 
Heart rate abnormal 
Broad 
Heart rate decreased 
Broad 
Heart rate increased 
Broad 
Loss of consciousness 
Broad 
Palpitations 
Broad 
Rebound tachycardia 
Broad 
Sudden death 
Broad 
Syncope 
Broad 
Tachycardia 
Broad 
Tachycardia paroxysmal 
Cardiac arrhythmia terms (incl bradyarrhythmias and tachyarrhythmias) 
(SMQ) 
Bradyarrhythmias (incl conduction defects and disorders of sinus node 
function) (SMQ) 
Bradyarrhythmia terms, nonspecific (SMQ) 
Narrow 
Bradyarrhythmia 
Narrow 
Ventricular asystole 
Conduction defects (SMQ) 
Narrow 
Accessory cardiac pathway 
Narrow 
Adams-Stokes syndrome 
Narrow 
Agonal rhythm 
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NCT02569710


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 
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 
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NCT02569710


Narrow 
Heart alternation 
Narrow 
Heart rate irregular 
Narrow 
Pacemaker generated arrhythmia 
Narrow 
Pacemaker syndrome 
Narrow 
Paroxysmal arrhythmia 
Narrow 
Pulseless electrical activity 
Narrow 
Reperfusion arrhythmia 
Narrow 
Withdrawal arrhythmia 
Tachyarrhythmias (incl supraventricular and ventricular 
tachyarrhythmias) (SMQ) 
Supraventricular tachyarrhythmias (SMQ) 
Narrow 
Arrhythmia supraventricular 
Narrow 
Atrial fibrillation 
Narrow 
Atrial flutter 
Narrow 
Atrial parasystole 
Narrow 
Atrial tachycardia 
Narrow 
Junctional ectopic tachycardia 
Narrow 
Sinus tachycardia 
Narrow 
Supraventricular extrasystoles 
Narrow 
Supraventricular tachyarrhythmia 
Narrow 
Supraventricular tachycardia 
Broad 
ECG P wave inverted 
Broad 
Electrocardiogram P wave abnormal 
Broad 
Retrograde p-waves 
Tachyarrhythmia terms, nonspecific (SMQ) 
Narrow 
Anomalous atrioventricular excitation 
Narrow 
Cardiac fibrillation 
Narrow 
Cardiac flutter 
Narrow 
Extrasystoles 
Narrow 
Tachyarrhythmia 
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 
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NCT02569710


Narrow 
Ventricular parasystole 
Narrow 
Ventricular pre-excitation 
Narrow 
Ventricular tachyarrhythmia 
Narrow 
Ventricular tachycardia 
Cardiac failure (SMQ) 
Narrow 
Acute left ventricular failure 
Narrow 
Acute pulmonary oedema 
Narrow 
Acute right ventricular failure 
Narrow 
Cardiac asthma 
Narrow 
Cardiac failure 
Narrow 
Cardiac failure acute 
Narrow 
Cardiac failure chronic 
Narrow 
Cardiac failure congestive 
Narrow 
Cardiac failure high output 
Narrow 
Cardiogenic shock 
Narrow 
Cardiopulmonary failure 
Narrow 
Cardiorenal syndrome 
Narrow 
Chronic left ventricular failure 
Narrow 
Chronic right ventricular failure 
Narrow 
Cor pulmonale 
Narrow 
Cor pulmonale acute 
Narrow 
Cor pulmonale chronic 
Narrow 
Ejection fraction decreased 
Narrow 
Hepatic congestion 
Narrow 
Hepatojugular reflux 
Narrow 
Left ventricular failure 
Narrow 
Low cardiac output syndrome 
Narrow 
Neonatal cardiac failure 
Narrow 
Obstructive shock 
Narrow 
Pulmonary oedema 
Narrow 
Pulmonary oedema neonatal 
Narrow 
Radiation associated cardiac failure 
Narrow 
Right ventricular ejection fraction decreased 
Narrow 
Right ventricular failure 
Narrow 
Ventricular failure 
Broad 
Artificial heart implant 
Broad 
Atrial natriuretic peptide abnormal 
Broad 
Atrial natriuretic peptide increased 
Broad 
Bendopnoea 
Broad 
Brain natriuretic peptide abnormal 
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NCT02569710


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 
Broad 
Post cardiac arrest syndrome 
Broad 
Prohormone brain natriuretic peptide abnormal 
Broad 
Prohormone brain natriuretic peptide increased 
Broad 
Pulmonary congestion 
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NCT02569710


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 
Narrow 
Myocardial haemorrhage 
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NCT02569710


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 
70 of 76
NCT02569710


Broad 
Cardiac imaging procedure abnormal 
Broad 
Cardiac index abnormal 
Broad 
Cardiac index decreased 
Broad 
Cardiac index increased 
Broad 
Cardiac monitoring abnormal 
Broad 
Cardiac operation 
Broad 
Cardiac output decreased 
Broad 
Cardiac pseudoaneurysm 
Broad 
Cardiac resynchronisation therapy 
Broad 
Cardiac ventricular scarring 
Broad 
Cardiac ventriculogram abnormal 
Broad 
Cardiac ventriculogram left abnormal 
Broad 
Cardiac ventriculogram right abnormal 
Broad 
Cardiomegaly 
Broad 
Cardiothoracic ratio increased 
Broad 
Cardiovascular disorder 
Broad 
Cardiovascular function test abnormal 
Broad 
Chest pain 
Broad 
Chest X-ray abnormal 
Broad 
Computerised tomogram thorax abnormal 
Broad 
Coxsackie carditis 
Broad 
Coxsackie myocarditis 
Broad 
Cytomegalovirus myocarditis 
Broad 
Decreased ventricular preload 
Broad 
Diastolic dysfunction 
Broad 
Dilatation atrial 
Broad 
Dilatation ventricular 
Broad 
Directional Doppler flow tests abnormal 
Broad 
Dyspnoea 
Broad 
ECG signs of ventricular hypertrophy 
Broad 
Echocardiogram abnormal 
Broad 
Electrocardiogram abnormal 
Broad 
Electrocardiogram change 
Broad 
Endocardial fibroelastosis 
Broad 
External counterpulsation 
Broad 
Gonococcal heart disease 
Broad 
Heart and lung transplant 
Broad 
Heart transplant 
Broad 
Hepatomegaly 
Broad 
Hyperdynamic left ventricle 
71 of 76
NCT02569710


Broad 
Increased ventricular preload 
Broad 
Irregular breathing 
Broad 
Labile blood pressure 
Broad 
Left atrial dilatation 
Broad 
Left atrial enlargement 
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 
72 of 76
NCT02569710


Broad 
Right atrial enlargement 
Broad 
Right atrial pressure increased 
Broad 
Right ventricle outflow tract obstruction 
Broad 
Right ventricular dilatation 
Broad 
Right ventricular enlargement 
Broad 
Right ventricular heave 
Broad 
Right ventricular systolic pressure decreased 
Broad 
Scan myocardial perfusion abnormal 
Broad 
Sudden cardiac death 
Broad 
Sudden death 
Broad 
Surgical ventricular restoration 
Broad 
Syncope 
Broad 
Systolic anterior motion of mitral valve 
Broad 
Systolic dysfunction 
Broad 
Ultrasound Doppler abnormal 
Broad 
Vascular resistance pulmonary increased 
Broad 
Ventricular arrhythmia 
Broad 
Ventricular assist device insertion 
Broad 
Ventricular dysfunction 
Broad 
Ventricular dyskinesia 
Broad 
Ventricular dyssynchrony 
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 
73 of 76
NCT02569710


Narrow 
Myocardial infarction 
Narrow 
Myocardial necrosis 
Narrow 
Myocardial reperfusion injury 
Narrow 
Myocardial stunning 
Narrow 
Papillary muscle infarction 
Narrow 
Post procedural myocardial infarction 
Narrow 
Postinfarction angina 
Narrow 
Silent myocardial infarction 
Narrow 
Troponin I increased 
Narrow 
Troponin increased 
Narrow 
Troponin T increased 
Broad 
Blood creatine phosphokinase abnormal 
Broad 
Blood creatine phosphokinase increased 
Broad 
Cardiac ventricular scarring 
Broad 
ECG electrically inactive area 
Broad 
ECG signs of myocardial infarction 
Broad 
Electrocardiogram Q wave abnormal 
Broad 
Electrocardiogram ST segment abnormal 
Broad 
Electrocardiogram ST segment elevation 
Broad 
Electrocardiogram ST-T segment elevation 
Broad 
Infarction 
Broad 
Myocardial necrosis marker increased 
Broad 
Scan myocardial perfusion abnormal 
Broad 
Vascular graft occlusion 
Broad 
Vascular stent occlusion 
Broad 
Vascular stent thrombosis 
Shock (SMQ) 
Shock-associated circulatory or cardiac conditions (excl torsade de pointes) 
(SMQ) 
Narrow 
Acute left ventricular failure 
Narrow 
Adams-Stokes syndrome 
Narrow 
Atrial parasystole 
Narrow 
Cardiac arrest 
Narrow 
Cardiac arrest neonatal 
Narrow 
Cardiac death 
Narrow 
Cardiac fibrillation 
Narrow 
Cardiac flutter 
Narrow 
Cardiogenic shock 
Narrow 
Cardio-respiratory arrest 
Narrow 
Cardio-respiratory arrest neonatal 
74 of 76
NCT02569710


Narrow 
Cardiovascular insufficiency 
Narrow 
Circulatory collapse 
Narrow 
Obstructive shock 
Narrow 
Pulse absent 
Narrow 
Pulseless electrical activity 
Narrow 
Shock 
Narrow 
Shock symptom 
Narrow 
Sudden cardiac death 
Narrow 
Ventricular asystole 
Narrow 
Ventricular fibrillation 
Narrow 
Ventricular flutter 
Narrow 
Ventricular parasystole 
Broad 
Acute kidney injury 
Broad 
Acute prerenal failure 
Broad 
Acute respiratory failure 
Broad 
Anuria 
Broad 
Blood pressure immeasurable 
Broad 
Cerebral hypoperfusion 
Broad 
Grey syndrome neonatal 
Broad 
Hepatic congestion 
Broad 
Hepatojugular reflux 
Broad 
Hepatorenal failure 
Broad 
Hypoperfusion 
Broad 
Jugular vein distension 
Broad 
Myocardial depression 
Broad 
Neonatal anuria 
Broad 
Neonatal multi-organ failure 
Broad 
Neonatal respiratory failure 
Broad 
Organ failure 
Broad 
Prerenal failure 
Broad 
Propofol infusion syndrome 
Broad 
Renal failure 
Broad 
Renal failure neonatal 
Broad 
Respiratory failure 
Torsade de pointes/QT prolongation (SMQ) 
Narrow 
Electrocardiogram QT interval abnormal 
Narrow 
Electrocardiogram QT prolonged 
Narrow 
Long QT syndrome 
Narrow 
Long QT syndrome congenital 
Narrow 
Torsade de pointes 
75 of 76
NCT02569710


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 
 
 
76 of 76
NCT02569710