Clinical trial NCT02935673
Conditions: Respiratory Syncytial Viruses
Sponsor: Janssen Research & Development, LLC
Start date: 2016-10-25; Completion date: 2018-07-17
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to characterize the Pharmacokinetic and to confirm the popPK model derived from healthy volunteers in hospitalized adults who are infected with respiratory syncytial virus (RSV) and to determine in adults who are hospitalized with respiratory syncytial virus (RSV) infection the dose response relationship of multiple regimens of lumicitabine on antiviral activity based on nasal RSV shedding using quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) assay.

Detailed description:
The study will be conducted in 3 phases: a screening phase, a treatment phase from Day 1 to Day 5/6 (depending on the timing of the loading dose), and a follow-up phase for a total of 28 days post randomization. Participants will have assessments completed at Day 7, Day 10, Day 14, and Day 28. Depending on discharge date, assessments will be completed either while hospitalized or during outpatient visits. The duration of the participant's participation will be approximately 28 days. The study will be performed in 2 parts. Participants will be randomly assigned to one of 2 treatment groups in part 1, and to one of 3 treatment groups in part 2. Treatment groups will be evaluated for PK and safety after a target of approximately 24 participants have been enrolled in part 1 and before initiating part 2 (approximately 90 participants in part 2). An Independent Data Monitoring Committee (IDMC) will be established to monitor the safety of participants and will review data in an unblinded manner on a regular basis to ensure the continuing safety of the participants enrolled in this study and to evaluate whether efficacy objectives are met. The committee will meet periodically to review interim data. Based on the recommendations of the IDMC following interim analyses/reviews, an increase in duration may be implemented.

Arms: arm 1: Participants of part 1 and part 2 will receive a single loading dose (LD) (Dose 1) followed by 9 maintenance doses (MDs) (Doses 2 to 10) of matching placebo, administered twice daily. arm 2: Participants of part 1 and part 2 will receive a single 750 mg LD (Dose 1) followed by nine 250 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily. arm 3: Participants of part 2 will receive a single 1000 mg LD (Dose 1) followed by nine 500 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily.
Interventions: intervention 1: lumicitabine intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration of lumicitabine as tablet. intervention 2: Oral administration of matching placebo.

Protocol documents:
Prot_000.pdf: 
1
Approved, Date: 20 March 2018
Janssen Research & Development*
Clinical Protocol
A Phase 2b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral 
Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally 
Administered ALS-008176 Regimens in Adult Subjects Hospitalized with Respiratory 
Syncytial Virus
Protocol 64041575RSV2003; Phase 2b
AMENDMENT 4
ALS-008176 (JNJ-64041575, lumicitabine)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2016-001653-40
Status:
Approved
Date:
20 March 2018
Prepared by:
Janssen Research & Development, a Division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-120465461, 9.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Protocol History
64041575RSV2003
Document Type and
File Name
Issued Date
Comments
Initial Clinical Protocol
64041575RSV2003_Protocol
12 May 2016
-
Protocol Amendment 1
64041575RSV2003_Protocol_Amend_1
19 July 2016
For details, please refer to Section Amendment 1
Protocol Amendment 2
64041575RSV2003_Protocol_Amend_2
13 January 2017
For details, please refer to Section Amendment 2
Protocol Amendment 3
64041575RSV2003_Protocol_Amend_3
5 September 2017
For details, please refer to Section Amendment 3
Protocol Amendment 4
64041575RSV2003_Protocol_Amend_4
This document
For details, please refer to Section Amendment 4
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Approved, Date: 20 March 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 14
TIME AND EVENTS SCHEDULE .............................................................................................................. 25
ABBREVIATIONS ...................................................................................................................................... 31
DEFINITIONS OF TERMS.......................................................................................................................... 32
1.
INTRODUCTION................................................................................................................................ 33
1.1.
Background .................................................................................................................................... 33
1.2.
Rationale for the Study................................................................................................................... 43
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 43
2.1.
Objectives and Endpoints .............................................................................................................. 43
2.1.1.
Objectives ................................................................................................................................... 43
2.1.2.
Endpoints.................................................................................................................................... 45
2.2.
Hypothesis ..................................................................................................................................... 48
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 48
3.1.
Overview of Study Design.............................................................................................................. 48
3.2.
Study Design Rationale.................................................................................................................. 50
4.
SUBJECT POPULATION.................................................................................................................. 53
4.1.
Inclusion Criteria ............................................................................................................................ 54
4.2.
Exclusion Criteria ........................................................................................................................... 57
4.3.
Prohibitions and Restrictions ......................................................................................................... 59
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 59
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 60
7.
TREATMENT COMPLIANCE............................................................................................................ 61
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 62
9.
STUDY EVALUATIONS .................................................................................................................... 63
9.1.
Study Procedures........................................................................................................................... 63
9.1.1.
Overview..................................................................................................................................... 63
9.1.2.
Screening Phase ........................................................................................................................ 64
9.1.3.
Double-blind Treatment Phase................................................................................................... 65
9.1.4.
Posttreatment Phase (Follow-up)............................................................................................... 67
9.2.
Efficacy Evaluations....................................................................................................................... 67
9.3.
Pharmacokinetics........................................................................................................................... 68
9.3.1.
Evaluations ................................................................................................................................. 68
9.3.2.
Analytical Procedures................................................................................................................. 69
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 69
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 70
9.5.
Biomarkers ..................................................................................................................................... 70
9.6.
Medical Resource Utilization and Health Economics .................................................................... 70
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9.7.
Safety Evaluations ......................................................................................................................... 70
9.7.1.
Specific Toxicities ....................................................................................................................... 73
9.8.
Other Evaluations........................................................................................................................... 74
9.9.
Benefit-risk Evaluations.................................................................................................................. 74
9.9.1.
Known Benefits........................................................................................................................... 74
9.9.2.
Potential Benefits........................................................................................................................ 74
9.9.3.
Known Risks............................................................................................................................... 74
9.9.4.
Potential Risks............................................................................................................................ 75
9.9.5.
Overall Benefit/Risk Assessment ............................................................................................... 76
9.10.
Sample Collection and Handling.................................................................................................... 77
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 78
10.1.
Completion ..................................................................................................................................... 78
10.2.
Discontinuation of Study Treatment/Withdrawal From the Study .................................................. 78
10.3.
Withdrawal From the Use of Research Samples........................................................................... 79
11.
STATISTICAL METHODS................................................................................................................. 79
11.1.
Subject Information ........................................................................................................................ 80
11.2.
Sample Size Determination ........................................................................................................... 80
11.3.
Efficacy Analyses ........................................................................................................................... 81
11.4.
Pharmacokinetic Analyses............................................................................................................. 83
11.5.
Biomarker Analysis ........................................................................................................................ 84
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 84
11.7.
Subject Clinical Outcome Assessments ........................................................................................ 84
11.8.
Katz Activities of Daily Living ......................................................................................................... 84
11.9.
Medical Resource Utilization and Health Economics Analyses..................................................... 84
11.10.
Safety Analyses ............................................................................................................................. 85
11.11.
Interim Analysis.............................................................................................................................. 86
11.12.
Independent Data Monitoring Committee ...................................................................................... 86
12.
ADVERSE EVENT REPORTING ...................................................................................................... 88
12.1.
Definitions ...................................................................................................................................... 88
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 88
12.1.2.
Attribution Definitions.................................................................................................................. 89
12.1.3.
Severity Criteria .......................................................................................................................... 90
12.2.
Special Reporting Situations.......................................................................................................... 90
12.3.
Procedures..................................................................................................................................... 90
12.3.1.
All Adverse Events...................................................................................................................... 90
12.3.2.
Serious Adverse Events ............................................................................................................. 91
12.3.3.
Pregnancy................................................................................................................................... 92
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 93
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 93
13.1.
Procedures..................................................................................................................................... 93
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 93
14.
STUDY DRUG INFORMATION......................................................................................................... 93
14.1.
Physical Description of Study Drug(s) ........................................................................................... 93
14.2.
Packaging ...................................................................................................................................... 93
14.3.
Labeling.......................................................................................................................................... 94
14.4.
Preparation, Handling, and Storage............................................................................................... 94
14.5.
Drug Accountability ........................................................................................................................ 94
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 94
16.
ETHICAL ASPECTS ......................................................................................................................... 95
16.1.
Study-specific Design Considerations ........................................................................................... 95
16.2.
Regulatory Ethics Compliance....................................................................................................... 95
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16.2.1.
Investigator Responsibilities ....................................................................................................... 95
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 95
16.2.3.
Informed Consent ....................................................................................................................... 97
16.2.4.
Privacy of Personal Data ............................................................................................................ 98
16.2.5.
Long-term Retention of Samples for Additional Future Research.............................................. 98
16.2.6.
Country Selection ....................................................................................................................... 99
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 99
17.1.
Protocol Amendments.................................................................................................................... 99
17.2.
Regulatory Documentation ............................................................................................................ 99
17.2.1.
Regulatory Approval/Notification ................................................................................................ 99
17.2.2.
Required Prestudy Documentation........................................................................................... 100
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 100
17.4.
Source Documentation................................................................................................................. 101
17.5.
Case Report Form Completion .................................................................................................... 102
17.5.1.
Katz Activities of Daily Living.................................................................................................... 102
17.6.
Subject Clinical Outcome Assessments ...................................................................................... 103
17.7.
Data Quality Assurance/Quality Control ...................................................................................... 104
17.8.
Record Retention ......................................................................................................................... 104
17.9.
Monitoring .................................................................................................................................... 105
17.10.
Study Completion/Termination..................................................................................................... 105
17.10.1.
Study Completion/End of Study................................................................................................ 105
17.10.2.
Study Termination..................................................................................................................... 105
17.11.
On-site Audits............................................................................................................................... 106
17.12.
Use of Information and Publication.............................................................................................. 106
REFERENCES.......................................................................................................................................... 108
INVESTIGATOR AGREEMENT ............................................................................................................... 130
LIST OF ATTACHMENTS
Attachment 1:
Toxicity Tables ............................................................................................................. 109
Attachment 2:
Respiratory Infection Symptom Questionnaire© .......................................................... 118
Attachment 3:
Additional Questions About Health and Functioning ................................................... 120
Attachment 4:
EuroQol 5-Dimension Questionnaire (EQ-5D)............................................................. 122
Attachment 5:
Katz Activities of Daily Living ....................................................................................... 125
Attachment 6:
Cardiovascular Safety - Abnormalities......................................................................... 126
Attachment 7:
Visit Schedule for Rash Management for Adult Subjects............................................ 127
Attachment 8: 
Details for Pharmacokinetic Sampling and Collection of Food Intake 
Information .............................................................................................................................. 129
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Summary of Efficacy Evaluations ............................................................................................. 21
Table 2: 
Investigational Product and its Metabolites .............................................................................. 33
Table 3:
NOAEL Doses of ALS-008176 and Exposure of ALS-008112 in Adult and Juvenile 
Rats and Dogs After Repeated Dosing of ALS-008176 ........................................................... 35
Table 4:
Pharmacokinetic Parameters of ALS-008112 Following a Single Oral Dose of 
1,000 mg ALS-008176 in Subjects With Different Degrees of Renal Function ........................ 38
Table 5:
Projected Plasma Exposures of ALS-008112 at the Proposed Dose Regimens ..................... 52
Table 6:
Ordinal Scale on Day 5/6 (Depending on the Timing of the LD Administration) ...................... 83
FIGURES
Figure 1:
Schematic Overview of Part 1 of the Study .............................................................................. 50
Figure 2:
Schematic Overview of Part 2 of the Study .............................................................................. 50
Figure 3:
Two Scenarios for the Timing of Collection of Nasal Swabs and Endotracheal 
Samples (if Intubated)............................................................................................................... 66
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ALS-008176 (JNJ-64041575, lumicitabine)  
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Approved, Date: 20 March 2018
PROTOCOL AMENDMENTS
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (This document)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is for Part 2 of the study (1) to 
include additional safety samples for biochemistry, (2) to lift the requirement for triplicate electrocardiograms 
(ECGs) and reduce the ECG timepoints, (3) to prohibit the use of P-glycoprotein (P-gp) inhibitors and inducers, 
and (4) to optimize the pharmacokinetic (PK) sampling scheme.
The table below gives an overview of the rationale for each change and all applicable sections.
Rationale: Based on the observed exposure levels and safety/tolerability data generated in Part 1 of the study, the 
dose regimen for Part 2 of the study will remain unchanged.
SYNOPSIS
3.1 Overview of Study Design
3.2 Study Design Rationale
Rationale: In Part 2 of the study, additional safety samples for biochemistry will be collected on Day 2, 
Days 3-6, and Day 10, to better characterize the clinical observations of isolated, asymptomatic elevations of 
aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (without concomitant elevations of the 
bilirubin levels) observed in Part 1 of the study.
Time and Events Schedule
Rationale: A clinical TQT study (Study 64041575RSV1003) showed that ALS-008176 does not induce QTc 
prolongation of clinical or regulatory concern. Based on this result, the requirement to record triplicate ECGs is 
lifted for Part 2 of the study, and single ECGs will be performed instead. The ECG timepoints were also reduced.
Time and Events Schedule
9.7 Safety Evaluations
Rationale: Based on recent nonclinical data, ALS-008176 has been demonstrated to be a substrate of P-gp. Since 
the effect of P-gp inhibitors and inducers on the PK of ALS-008176 and its metabolites in humans is currently 
unknown, P-gp inhibitors and inducers will be prohibited for 24 hours prior to randomization (14 days for 
inducers) until 24 hours after the last dose of ALS-008176.
1.1 Background
8 PRESTUDY AND CONCOMITANT THERAPY
Rationale: The PK sampling scheme for Part 2 has been optimized, based on the data of Part 1.
SYNOPSIS
Time and Events Schedule
3.1 Overview of Study Design
9.3.3 Pharmacokinetic Parameters
Attachment 8: 
Details for Pharmacokinetic Sampling and Collection of Food Intake Information
Rationale: The protocol is aligned with the lumicitabine Investigator's Brochure Ed9. 
1 INTRODUCTION
9.9 Benefit-risk Evaluations
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ALS-008176 (JNJ-64041575, lumicitabine)  
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Approved, Date: 20 March 2018
Rationale: Minor editorial changes (including alignment with the sponsor’s latest available protocol template 
version), clarifications, and corrections are made, including, but not limited to:
– Clarifying Part 0 of the study.
– Clarify that once all data for Part 1 are collected and the database locked, the sponsor may perform an 
unblinded, secondary analysis on the full dataset of Part 1, to support clinical development.
– Since Part 1 of the study was already completed at the time of the amendment, all references in the Time and 
Events Schedule to Part 1 of the study are grayed-out for convenience of the investigator.
– Assure consistency of the wording "increase in treatment duration to up to 10 days" throughout the document.
– Clarifying that a paper form of the health-related quality of life (HRQoL) questionnaire should be used (as 
required by the vendor) by the subject’s spouse, partner, relative, friend, or the investigator/-site study 
personnel trained on the electronic Clinical Outcome Assessment (eCOA) device if the subject is unable to 
complete the assessment on the device.
– Clarifying the collection of nasal swabs and endotracheal samples (if intubated).
– Correct the statement on the legal age of consent in South Korea.
Throughout the protocol
Amendment 3 (5 September 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment was to remove furosemide, 
ibuprofen, and trimethoprim/sulfametoxazole from the list of prohibited moderate/strong inhibitors of organic 
anion transporter (OAT) 3.
The table below gives an overview of the rationale for each change and all applicable sections.
Rationale: A clinical drug-drug interaction study (Study 64041575RSV1002) between probenecid (strong OAT3 
inhibitor) and ALS-008176 showed that probenecid increased the maximum concentration and area under the 
concentration-time curve from the time of drug administration to the time of the last observation (AUC0-last) of 
ALS-008112 by 1.28-fold and 1.75-fold, respectively. Based on these data, together with pharmacokinetic 
(PK)/pharmacodynamic (PD) modeling data, furosemide, ibuprofen, and trimethoprim/sulfametoxazole were 
removed from the list of prohibited moderate/strong inhibitors of OAT3 as the expected increase on ALS-008112
AUC caused by these drugs was less than 26%, a very mild increase deemed acceptable based on expected 
exposures using popPK modeling and simulation.
1.1 Background
8 PRESTUDY AND CONCOMITANT THERAPY
Rationale: In countries such as Japan and Taiwan, the legal age of consent is 20 years, and in South Korea it is 
19 years. Therefore, the inclusion criterion was adapted to clarify that men or women should have the legal age of 
consent in the jurisdiction in which the study is taking place.
SYNOPSIS
3 STUDY DESIGN AND RATIONALE
4 SUBJECT POPULATION
Rationale: During study conduct, an issue was identified in which the food intake was not documented in 
compliance with the protocol. Currently only the electronic case report form (eCRF) allows the documentation of 
the food intake in relation to the study drug administration in PK forms. No information on food intake can be 
captured in the electronic Clinical Outcome Assessment (eCOA) for discharged subjects for doses 3 to 
10 (maintenance dose [MD] 2 to MD9). Due to the minimal impact of food intake on trough levels (PK sample at 
Day 7), there will be no adjustments made to the eCOA. No food intake information with regard to study drug 
administration will be collected for discharged subjects. Furthermore, it is clarified that the food intake 
information should be recorded in hospitalized subjects only and that the time window should be limited to the 
food ingested within 30 minutes before or after study drug administration.
TIME AND EVENTS SCHEDULE
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Rationale: The protocol is aligned with the sponsor’s latest available protocol template and minor editorial 
changes, clarifications, and corrections were made, including, but not limited to:
-
Addition of the generic name “lumicitabine”.
-
Corrections were made to consistently state in the protocol that the relationship between the PK and PD 
(antiviral activity, clinical outcomes, and selected safety parameters) will be evaluated after single and
repeated oral administration of ALS-008176.
-
Clarifications on SpO2 and ECG assessments in the Time and Events Schedule. 
-
Clarification on details of PK sampling and collection of food intake information in Attachment 8.
-
Language was added to Section 9.1.2 to allow the use of data of subjects that consented for another Janssen 
respiratory study.
-
Correction of a typing eror regarding the relatedness to study drug of the pancytopenia event in the rationale 
table of protocol amendment 2.
Throughout the protocol
Amendment 2 (13 January 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment was to create a new Part 1 of the 
study protocol to characterize the pharmacokinetics (PK), to confirm the population pharmacokinetic (popPK)
model derived from healthy volunteers in hospitalized adults with respiratory syncytial virus (RSV) infection, and 
to more clearly define the study eligibility criteria to ensure subject safety.
Furthermore, changes requested by health authorities were made, women of childbearing potential were allowed 
to participate in the study, the age limit for participants was lowered, the endpoints of the study were updated, 
subjects on extracorporeal membrane oxygenation were excluded, the guidelines concerning corticosteroid use 
were adjusted, clarifications regarding the use of the electronic Clinical Outcome Assessment (eCOA) device 
were added, single electrocardiogram (ECG) measurements were changed to triplicate ECGs, and the dose 
dispensing instructions were deleted. In addition minor editorial changes, clarifications, and corrections were 
made.
The table below gives an overview of the rationale for each change and all applicable sections.
Rationale: Given the report of a probably related serious adverse event (SAE) of reversible pancytopenia in an 
elderly subject found to have ALS-008112 plasma exposures higher than predicted by the popPK model, a new 
Part 1 of the study protocol was created to characterize the PK, to confirm the popPK model derived from healthy 
volunteers in hospitalized adults with RSV infection, and to more clearly define the study eligibility criteria to 
ensure subject safety. To achieve the objective of characterizing the PK and confirming the popPK model, the 
study population was more restricted to recruit subjects with criteria more aligned with those of the Phase 1 
studies and the PK sampling scheme was updated. Pharmacokinetic modeling data suggest that low body weight 
and renal impairment may be associated with increased ALS-008112 plasma exposure so these criteria were 
modified. Furthermore, the plasma exposure of ALS-008112 may also be increased by the concomitant 
administration of medications which are known inhibitors of organic anion transporter 3 (OAT3). Thus, the 
following changes were made to the study protocol:
-
The study design was adapted to include a new Part 1 in the study protocol. In Part 1, the PK will be 
characterized in the low-dose arm of 750 mg loading dose (LD)/250 mg maintenance dose (MD) ALS-008176 
in hospitalized adult subjects infected with RSV. Furthermore, the safety and tolerability of this regimen will 
be investigated before proceeding to Part 2 of the study which will include the high-dose arm of 
1,000 mg LD/500 mg MD ALS-008176. In Part 2, the dose-response relationship of the 750 mg LD/250 mg 
MD and the 1,000 mg LD/500 mg MD ALS-008176 dosing regimens on antiviral activity will be evaluated. 
Stratification factors for both parts have been clarified.
-
The PK sampling scheme was updated to better characterize the PK and to confirm the popPK model.
-
The inclusion criteria were adjusted to only allow subjects with a body weight of at least 50 kg to participate 
in the study.
-
The exclusion criteria were adjusted to disallow subjects who are moderate/severe renally impaired.
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-
Subjects with hematology laboratory abnormalities at screening, as defined in the protocol, will be excluded.
-
List of OAT3 inhibitors which are not allowed during the study and for 24 hours prior to randomization has 
been updated.
Additional stopping rules were provided to ensure that study drug will be discontinued when the subject has an 
estimated glomerular filtration rate ≤30 mL/min/1.73 m² according to the Chronic Kidney Disease Epidemiology 
Collaboration equation and when the subject experiences any of the protocol defined laboratory abnormalities.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1 INTRODUCTION
2 OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
3 STUDY DESIGN AND RATIONALE
4.1 Inclusion Criteria
4.2 Exclusion Criteria
5 TREATMENT ALLOCATION AND BLINDING
6 DOSAGE AND ADMINISTRATION
9.7.1 Specific Toxicities
8 PRESTUDY AND CONCOMITANT THERAPY
9.3 Pharmacokinetics
9.9 Benefit-risk Evaluations
10.2 Discontinuation of Study Treatment/Withdrawal From the Study
11 STATISTICAL METHODS
Rationale: The following changes were made upon health authority request:
- Addition of a mandatory safety sample for hematology and biochemistry on the Day 28 follow-up visit, to 
ensure a comprehensive safety evaluation in all subjects.
- Addition of a follow-up visit 2 days after the last treatment dose for subjects who discontinued treatment early, 
to be consistent with the Day 7 follow-up visit planned for subjects who completed treatment.
- Adjustment of the inclusion criteria, exclusion criteria, and potential risk sections to be consistent with 
recommendations related to contraception and pregnancy testing in clinical trials as described in the Clinical 
Trial Facilitation Group (CTFG) guidance.8
o Extension of the duration of contraception (ie, from 90 to 104 days for men and their female partners of 
childbearing potential, and from 30 to 44 days for heterosexually active women of childbearing potential).
o Adjustment of the duration in which female participants are not allowed to donate eggs (ova, oocytes).
o Clarification of the contraceptive methods recommended for female partners (if of childbearing potential)
of male participants.
- Given that prescription medications such as palivizumab, ribavirin, and intravenous immunoglobulin used to 
prevent or treat RSV infection have a half-life that goes beyond 3 days, they have been included in the list of 
disallowed concomitant medications as prohibited 30 days or 5 half-lives (whichever is longer) before the 
planned first dose of study drug. Furthermore, it was clarified that prescription medications intended to treat the 
symptoms/sequelae of the RSV infection are permitted.
- Adjustment of the definition of the intent-to-treat (ITT) infected population.
- Clarification that the key findings of the popPK and PK/pharmacodynamic (PD) analysis of this study will be 
presented in the final clinical study report.
- Clarification that the interim analysis will be performed upon treatment completion (rather than randomization) 
by 45 subjects to ensure that adequate data is available for interim analysis review.
SYNOPSIS
TIME AND EVENTS SCHEDULE
4.1 Inclusion Criteria
4.2 Exclusion Criteria
8 PRESTUDY AND CONCOMITANT THERAPY
9.1.4 Posttreatment Phase (Follow-up)
9.9.4 Potential Risks
11 STATISTICAL METHODS
11.4 Pharmacokinetic Analyses
11.6 Pharmacokinetic/Pharmacodynamic Analyses
11.11 Interim Analysis
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Approved, Date: 20 March 2018
REFERENCES
Rationale: Based on recent nonclinical toxicology data from embryo-fetal development studies in rats and 
rabbits, and fertility and early embryonic development to implantation studies in rats, the inclusion criteria were 
adjusted to allow women of childbearing potential to participate in the study. Furthermore, serum pregnancy 
testing was replaced by urine pregnancy testing and the definition of women not of childbearing potential was 
clarified. Contraceptive requirements for heterosexually active women of childbearing potential were added and 
details regarding the risk for potential PK drug-drug interaction between ALS-008176 and hormonal 
contraceptives were provided.
TIME AND EVENTS SCHEDULE
1.1 Background
4.1 Inclusion Criteria
9.7 Safety Evaluations
9.9.4 Potential Risks
Rationale: With the availability of the results from embryo-fetal development studies in rats and rabbits, and 
fertility and early embryonic development to implantation studies in rats, the age limit for participants was 
lowered to 18 years. The stratification by age was also adjusted to be in line with the lowered age limit for 
participation in the study.
SYNOPSIS
3 STUDY DESIGN AND RATIONALE
4 SUBJECT POPULATION
5 TREATMENT ALLOCATION AND BLINDING
Rationale: The following changes were made to the endpoints:
-
The determination of the RSV RNA viral load area under the curve (AUC) in subjects assigned to a longer 
dosing duration, if dosing duration is increased by the Independent Data Monitoring Committee (IDMC), was 
moved from the primary to the secondary endpoints.
-
For clarity, the secondary endpoint “Number of hours until peripheral capillary oxygen saturation (SpO2) 
≥93% on room air among subjects who were not on supplemental oxygen prior to current hospitalization” was 
changed to “Number of hours until peripheral capillary oxygen saturation (SpO2) ≥93% on room air among 
subjects who were not on supplemental oxygen prior to the onset of respiratory symptoms”.
-
The exploratory endpoint of disease status and presence of complications with onset after treatment initiation
was adjusted to include respiratory failure and other RSV-related complications to harmonize with the 
electronic case report form (eCRF).
-
Added that if the dosing duration is increased by the IDMC to up to 10 days, supplemental oxygen above 
pre-RSV disease level will be measured from treatment initiation until 1 day after the last dose of study drug.
SYNOPSIS
2.1.2 Endpoints
Rationale: It was clarified that RSV RNA viral load (AUC) will be measured in mid-turbinate nasal swabs of 
non-intubated subjects or in both mid-turbinate nasal swabs and endotracheal samples of intubated subjects. 
Furthermore, it was clarified that mid-turbinate nasal swabs (if non-intubated) or endotracheal samples (if 
intubated) will be collected during screening to confirm RSV infection and to assess for viral and bacterial co-
infection.
SYNOPSIS
TIME AND EVENTS SCHEDULE
2.1.1 Objectives
2.1.2 Endpoints
9.1.2 Screening Phase
9.1.3 Double-blind Treatment Phase
9.2 Efficacy Evaluations
9.8 Other Evaluations
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Rationale: Subjects who are being treated with extracorporeal membrane oxygenation are excluded from 
participation in the study.
4.2 Exclusion Criteria
Rationale: The use of systemic corticosteroids before and during the study was clarified to avoid 
misunderstanding since it is anticipated that a significant proportion of the subjects is expected to suffer from 
chronic obstructive pulmonary disease (COPD) or asthma, wherefore treatment with corticosteriods is considered 
standard of care.
4.2 Exclusion Criteria
8 PRESTUDY AND CONCOMITANT THERAPY
Rationale: The guidelines regarding the use of the eCOA device were adjusted:
- Clarification of the situations in which trained investigator/study-site personnel can complete the eCOA on the 
subject’s behalf.
- Use of the electronic case report form (eCRF) instead of the eCOA device for the Katz Activities of Daily 
Living (ADL) assessment as this is an assessment to be completed by the investigator.
TIME AND EVENTS SCHEDULE
9.1.1 Overview
11.7 Subject Clinical Outcome Assessments
11.8 Katz Activities of Daily Living
17.4 Source Documentation
17.5.1 Katz Activities of Daily Living
17.6 Subject Clinical Outcome Assessments
Rationale: Change from single to triplicate ECG measurements at screening, on Day 1, and on Day 7 to improve 
the precision of the measurements. Additionally triplicate ECGs were added on Day 28.
TIME AND EVENTS SCHEDULE
9.7 Safety Evaluations
Rationale: Deletion of the dose dispensing instructions from the list of study-specific materials. These 
instructions are part of the study-site investigational product and procedures manual and the subject eCOA 
device.
15 STUDY-SPECIFIC MATERIALS
Rationale: Minor editorial changes, clarifications, and corrections were made. 
Throughout the protocol
Amendment 1 (19 July 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to add an inclusion criteria for 
female subjects regarding the donation of eggs and to add a section on rash management. Additionally, the protocol 
is aligned with the sponsor’s latest available protocol template and minor editorial changes, clarifications, and 
corrections are made.
The table below gives an overview of the rationale for each change and all applicable sections.
Rationale: An inclusion criteria was added to assure that woman agree not to donate eggs (ova, oocytes) during the 
study and for at least 90 days after receiving the last dose of study drug.
4.1 Inclusion Criteria
9.9.4 Potential Risks
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Rationale: Rash management was added in the section of “Specific Toxicities” to align with the Phase 2b pediatric 
study protocol. A visit schedule for rash management for adult subjects was added in Attachment 7.
9.7 Safety Evaluations
Attachment 7
Rationale: The following changes were made to align with the sponsor’s latest available protocol template:
- Added a leading phrase to inclusion criteria 9 and 10 indicating that contraceptive use by men or women should be 
consistent with local regulations.
- Revised prohibitions and restrictions criterion 2 to indicate that "all requirements must be met during the study as 
noted in the Inclusion and Exclusion Criteria".
4.1 Inclusion Criteria
4.3 Prohibitions and Restrictions
Rationale: Minor editorial changes, clarifications, and corrections were made, including, but not limited to:
- Correction of the loading dose of regimen C to 1,000 mg.
- Correction of the timing of study drug administration to no later than 4h after randomization.
- Clarification in the protocol that the spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) 
tests will only be performed if available at the study site and the clinical condition of the subject allows testing as 
judged by the investigator.
- Addition of extra blood samples for exploratory biomarker analysis (host RNA).
- Inclusion of the most recent version of the Respiratory Infection Symptom Questionnaire© in Attachment 2.
Throughout the protocol
SYNOPSIS
TIME AND EVENTS SCHEDULE
3 STUDY DESIGN AND RATIONALE
9.1 Study Procedures
9.5 Biomarkers
9.8 Other Evaluations
15 STUDY-SPECIFIC MATERIALS
Attachment 2
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
SYNOPSIS
A Phase 2b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral 
Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered 
ALS-008176 Regimens in Adult Subjects Hospitalized with Respiratory Syncytial Virus
ALS-008176 (also known as JNJ-64041575 or lumicitabine) is a 3’,5’-bisisobutyrate prodrug, which is 
readily metabolized to the cytidine nucleoside analog polymerase inhibitor ALS-008112. Subsequently, 
inside cells, ALS-008112 is efficiently converted to its nucleoside triphosphate (NTP), ALS-008136. This 
NTP is a selective inhibitor of respiratory syncytial virus (RSV) ribonucleic acid (RNA)-dependent RNA 
polymerase activity and works via a classic chain termination mechanism. ALS-008144, the uridine 
analog metabolite of ALS-008112, is the inactive major metabolite noted in systemic circulation.
Investigational Product and its Metabolites
Compound Number
Description
ALS-008176 (JNJ-64041575, 
lumicitabine)
3’,5’-bisisobutyrate prodrug of ALS-008112
ALS-008112 (JNJ-63549109)
parent nucleoside analog, major metabolite of ALS-008176, inactive
ALS-008206 (JNJ-64412309)
3’-isobutyrate monoester of ALS-008112, minor metabolite, inactive
ALS-008207 (JNJ-64412296)
5’-isobutyrate monoester of ALS-008112, minor metabolite, inactive
ALS-008144 (JNJ-64167896)
uridine analog metabolite of ALS-008112, major metabolite, inactive
ALS-008136 (JNJ-65409136)
5’-triphosphate of ALS-008112 (NTP), intracellular metabolite, active
ALS-008137 (JNJ-65409123)
5’-monophosphate of ALS-008112, intracellular metabolite, inactive
Abbreviation: NTP: nucleoside triphosphate.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objectives
For Part 1:
The primary objective is to characterize the pharmacokinetics (PK) and to confirm the population PK 
(popPK) model derived from healthy volunteers in hospitalized adults who are infected with RSV.
For Part 2:
The primary objective is to determine in hospitalized adults who are infected with RSV the dose-response 
relationship of multiple regimens of ALS-008176 on antiviral activity based on nasal RSV shedding using 
quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay.
Secondary Objectives
The secondary objectives for Part 1 and Part 2 are to determine in hospitalized adults who are infected 
with RSV:

The safety and tolerability of ALS-008176.

The impact of ALS-008176 on the clinical course of RSV infection including:

Duration of hospital stay.

Duration of supplemental oxygen.

Evolution of Activities of Daily Living (ADL) as assessed by Katz ADL score.

Time to clinical stability.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018

Improvement on the ordinal scale.

Rate of mortality and complications.

The antiviral activity based on nasal RSV shedding using qRT-PCR assay (secondary for Part 1 
only) and the time to cessation of nasal RSV shedding.

The impact of ALS-008176 on the emergence of resistant strains of RSV.

The PK of ALS-008112 and ALS-008144 (and other metabolites, if applicable) in plasma.

The relationship between the PK and pharmacodynamics (PD; antiviral activity, clinical symptoms, 
and selected safety parameters) after single (loading dose [LD]) and repeated oral dosing 
(maintenance dose [MD]) of ALS-008176.
Exploratory Objectives
The exploratory objectives for Part 1 and Part 2 are to evaluate in hospitalized adults who are infected 
with RSV:

The relationship between viral kinetics and clinical outcome, including the relationship between 
RSV RNA viral load and:

Oxygen supplementation.

Duration of hospitalization.

Katz ADL score.

Clinical stability.

The impact of the baseline viral subtype and genotype on the antiviral activity.

Onset of complications after initiation of treatment.

The impact of ALS-008176 on the clinical course of RSV during and following hospitalization as 
assessed by the subject in the electronic Clinical Outcome Assessment (eCOA) using various scoring 
systems.

The impact of RSV and its treatment on health-related quality of life (HRQoL) as assessed by the 
subject in the eCOA.

The relationship between the Katz ADL score and the subject eCOA responses.

Medical resource utilization to manage subjects.

The comparison of the RSV RNA viral loads measured in mid-turbinate nasal swabs and 
endotracheal samples from intubated subjects.

To explore the evolution of diffusing capacity of the lung for carbon monoxide (DLCO) and 
spirometry in subjects hospitalized with RSV infection.
Additionally, the impact of ALS-008176 on the infectious viral load may be evaluated using a 
quantitative culture of RSV (plaque assay) on a selected number of subjects and samples (mid-turbinate 
nasal swabs [if non-intubated] or mid-turbinate nasal swabs and endotracheal samples [if intubated]) at 
the sponsor’s discretion.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Endpoints
Primary Endpoints
For Part 1:
The primary endpoint is the PK of ALS-008112 and ALS-008144 (and other metabolites, if applicable) in 
plasma.
For Part 2:
The primary endpoint is RSV RNA viral load (measured by qRT-PCR in the mid-turbinate nasal swab 
specimens) area under the curve (AUC) from immediately prior to first dose of study drug (baseline) until 
Day 7.
Secondary Endpoints
The secondary endpoints for Part 1 and Part 2 are:

Safety/tolerability including adverse events (AEs), physical examinations, vital signs, 
electrocardiograms (ECGs), and clinical laboratory results.

RSV clinical course endpoints:

Length of hospital stay from admission to discharge and from study treatment initiation to 
discharge.

Length of hospital stay from admission to readiness for discharge and from study treatment
initiation to readiness for discharge, with readiness for discharge defined by the investigator.

Need for and duration of intensive care unit (ICU) stay.

Need for and duration of supplemental oxygen (regardless of method used).

Number of hours until peripheral capillary oxygen saturation (SpO2) ≥93% on room air among 
subjects who were not on supplemental oxygen prior to the onset of respiratory symptoms.

Respiratory rate, SpO2, and body temperature return to pre-RSV disease level.

Need for and duration of noninvasive ventilator support (eg, continuous positive airway 
pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation or 
mechanical ventilation via tracheostomy).

Time to return to pre-RSV functional status (Katz ADL score).

Need for hydration and feeding by intravenous (IV) catheter/nasogastric tube.

Time to clinical stability defined as the time at which the following criteria are all met:
o
normalization of blood oxygen level (return to baseline; by pulse oximetry) without 
requirement of supplemental oxygen beyond baseline level
o
normalization of oral feeding
o
normalization of respiratory rate
o
normalization of heart rate

Improvement on the ordinal scale.

All-cause mortality.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018

RSV RNA viral load as measured by qRT-PCR of the mid-turbinate nasal swab specimens which 
will be used to determine the following:

Viral load over time.

Peak viral load, time to peak viral load, rate of decline of viral load, and time to RSV RNA 
being undetectable.

Proportion of subjects with undetectable viral load at each time point.

The RSV RNA viral load AUC from immediately prior to first dose of study drug (baseline) 
until Day 7 (secondary for Part 1 only).

RSV RNA viral load AUC from immediately prior to first dose of study drug (baseline) until 
Day 10 and until Day 14.

RSV RNA viral load AUC in subjects assigned to a longer dosing duration, if dosing duration is 
increased by the Independent Data Monitoring Committee (IDMC), from baseline until 1 day 
after the last dose of study drug (Part 2 only).

Sequence changes (postbaseline) in the RSV polymerase L-gene and other regions (only if no 
mutations are seen in the L-gene) of the RSV genome compared with baseline sequences.

Population-derived PK parameters of ALS-008112.
Exploratory Endpoints
The exploratory endpoints for Part 1 and Part 2 are:

The amount of:

Supplemental oxygen above pre-RSV disease level (regardless of method used) from study 
treatment initiation to Day 7.
NOTE: If the dosing duration is increased by the IDMC to up to 10 days, supplemental oxygen above 
pre-RSV disease level will be measured from treatment initiation until 1 day after the last dose of study 
drug.

Oxygen delivered by noninvasive ventilator support (eg, continuous positive airway pressure) 
and/or invasive ventilator support (eg, endotracheal-mechanical ventilation or mechanical 
ventilation via tracheostomy).

Subjects (proportion) who started antibiotic use after the first dose of the study drug.

Disease status and presence of complications with onset after treatment initiation:

Bacterial superinfections reported as AEs (eg, pneumonia, acute otitis media, sinusitis, 
bronchitis, bacteremia).

Exacerbations of underlying pulmonary disease (eg, asthma, chronic obstructive pulmonary 
disease).

Cardiovascular and cerebrovascular events (eg, myocardial infarction, congestive heart failure 
exacerbation, arrhythmia, stroke).

Respiratory failure.

Clostridium difficile associated diarrhea.

Other RSV-related complications.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018

Duration and severity of signs and symptoms of RSV infection as assessed by the respiratory 
infection patient-reported outcome (RI-PRO) questionnaire and additional questions about health and 
functioning completed by the subject in the eCOA.

HRQoL assessed by the EuroQoL 5 Dimension 5 level version (EQ-5D-5L) completed by the 
subject in the eCOA.

Hospital readmission for respiratory reasons up to the Day 28 follow-up visit.

Medical resource utilization.

RSV RNA viral load (AUC) as measured by qRT-PCR of mid-turbinate nasal swabs and 
endotracheal samples in intubated subjects.

Lung function measured by the DLCO and spirometry test.

RSV infectious viral load as measured using a quantitative viral culture (plaque assay).
Hypothesis
For Part 1, no formal hypothesis is specified. Part 1 is intended to characterize the PK in the low-dose arm 
of 750 mg LD/250 mg MD ALS-008176 and to confirm the popPK model derived from healthy 
volunteers in hospitalized adult subjects infected with RSV. Furthermore, the safety and tolerability of 
this regimen will be investigated before proceeding to Part 2 of the study which will include the high-dose 
arm of 1,000 mg LD/500 mg MD ALS-008176.
For Part 2, the primary hypothesis is that there is a positive dose-response relationship of active treatment 
on the average RSV RNA viral load AUC with the average AUC on at least 1 of the active treatments 
being lower than the average AUC on placebo.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, dose-finding study of 
ALS-008176 in hospitalized adults of ≥18 years of age (or the legal age of consent in the jurisdiction in 
which the study is taking place) who are infected with RSV. The study will be performed in 2 parts.
Part 1
A target of approximately 24 subjects with a maximum of 36 subjects will be randomized in a 1:2 ratio to 
Regimen A or B:
•
Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10) of matching placebo, 
administered twice daily.
•
Regimen B (low-dose ALS-008176): a single 750 mg LD (Dose 1) followed by nine 250 mg MDs 
(Doses 2 to 10) of ALS-008176, administered twice daily.
The IDMC will review the safety and PK data after approximately 12 subjects have completed treatment
as per the IDMC charter. When approximately 24 subjects have completed the Day 14 follow-up visit, an 
unblinded primary analysis will be performed by the sponsor, for review by the IDMC. Further 
enrollment in this part of the study up to 36 subjects may continue while the data are being analyzed.
Once all data for Part 1 are collected and the database locked, the sponsor may perform an unblinded, 
secondary analysis on the full dataset of Part 1, to support clinical development.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Part 2
A target of approximately 90 subjects will be randomized in a 1:1:1 ratio to Regimen A, B, or C with 
approximately 30 subjects planned per treatment regimen:

Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10) of matching 
placebo, administered twice daily.

Regimen B (low-dose ALS-008176): a single 750 mg LD (Dose 1) followed by nine 250 mg MDs 
(Doses 2 to 10) of ALS-008176, administered twice daily.

Regimen C (high-dose ALS-008176): a single 1,000 mg LD (Dose 1) followed by nine 500 mg MDs 
(Doses 2 to 10) of ALS-008176, administered twice daily.
Each part of the study will be conducted in 3 phases: a screening phase, a treatment phase from Day 1 to 
Day 5/6 (depending on the timing of the LD administration), and a follow-up phase for a total of 28 days 
post randomization. Subjects will have assessments completed during hospitalization and at the Day 7, 
Day 10, Day 14, and Day 28 visits. Depending on discharge date, assessments will be completed either 
while hospitalized or during outpatient visits. For hospitalized subjects additional assessments are done as 
per the Time and Events Schedule. The duration of the subject’s participation will be approximately 
28 days, screening period not included.
Pharmacokinetic assessments will be performed using a popPK model. Intensive PK sampling in Part 1 of 
this study will be used to update and confirm the popPK model that was developed based on the data from 
healthy volunteers. Based on the PK data from hospitalized adult subjects infected with RSV from Part 1 
of this study, the PK sampling for Part 2 was optimized. The popPK model may be further modified or 
adapted as needed.
An unblinded IDMC will be commissioned for this study and a Sponsor Committee will be established. 
For Part 1, the IDMC will review the safety and PK data as described above. In Part 2, based on the 
reviews of PK, efficacy, and safety data, changes to enrollment in the treatment arms, dose regimen 
adjustments, or an increase in dose duration to up to 10 days may be implemented. In Part 2, a maximum 
of 2 formal interim analyses are planned to assess the primary endpoint for early superiority and futility. 
The first formal interim analysis will be performed when at least 45 subjects have completed treatment to 
ensure that adequate data is available for interim analysis review, preferably after the end of a 
hemispheric RSV season. If the study is considered underpowered, a sample size increase may be 
suggested to a maximum of 180 subjects.
SUBJECT POPULATION
Screening for eligible subjects will be performed as soon as possible following admission to the 
emergency room or hospitalization, such that subjects are randomized within 5 days of RSV symptom 
onset. Men or women ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is 
taking place) diagnosed with RSV infection based on a polymerase chain reaction (PCR)-based diagnostic 
assay (with or without co-infection with another respiratory pathogen) who have been (or will be) 
admitted to the hospital and who have signed informed consent will be enrolled. Subjects who were 
admitted to the hospital for another cause but develop an acute respiratory illness while being hospitalized 
are also eligible for screening.
DOSAGE AND ADMINISTRATION
The study drug ALS-008176 will be provided as tablets for oral administration. Study drug administration 
should start as soon as possible, but no later than 4 hours after randomization in order to maximize the 
opportunity for the compound to inhibit viral replication and potentially improve outcomes.
Subjects will be dosed with a single LD followed by 9 MDs twice daily (at least 8 hours apart and 
maximum 16 hours apart, with no more than 2 doses per calendar day) during Day 1 to Day 5/6 
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
(depending on the timing of the LD administration). In Part 1, subjects will be randomized in a 1:2 ratio 
to Regimen A or B. In Part 2, subjects will be randomized in a 1:1:1 ratio to Regimen A, B, or C.
Regimen Aa
Regimen Ba
Regimen Ca
Treatment 
Regimen
Placebo
Low-dose ALS-008176: 
750 mg LD/250 mg MD
High-dose ALS-008176: 
1000 mg LD/500 mg MD
Loading 
Dose
Placebo:
1 intake of 3 tablets
ALS-008176:
1 intake of 3 x 250 mg tablet
ALS-008176:
1 intake of 2 x 500 mg tablet
Placebo:
1 intake of 1 tablet
Maintenance 
Dose
Placebo:
9 intakes of 1 tablet
ALS-008176:
9 intakes of 1 x 250 mg tablet
ALS-008176:
9 intakes of 1 x 500 mg tablet
a
Placebo tablets will be visually identical to their active drug counterparts
Administration of each dose should occur at approximately the same time each day. ALS-008176 can be 
administered without regard to food.
EFFICACY EVALUATIONS
Table 1 describes the efficacy evaluations to be performed.
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Table 1:
Summary of Efficacy Evaluations
Evaluation
Purpose
Viral Load Determination
Evaluation of antiviral activity of ALS-008176; RSV RNA viral load will 
be measured in mid-turbinate nasal swabs (obtained from non-intubated 
subjects) or in mid-turbinate nasal swabs and endotracheal samples
(obtained from intubated subjects or via suction through tracheostomy or 
other sampling methods) using qRT-PCR performed at the central 
laboratory.
RSV infectious viral load may be measured in mid-turbinate nasal swabs
(if non-intubated) or mid-turbinate nasal swabs and endotracheal samples
(if intubated) using a quantitative culture method (plaque assay) in a 
selected number of subjects and samples at the sponsor’s discretion.
Viral Resistance
To identify preexisting sequence polymorphisms and to characterize 
emerging RSV variants: viral resistance will be performed by sequencing 
the polymerase L-gene and other regions (only if no mutations are seen in 
the L-gene) of the RSV genome in samples taken before treatment (at 
baseline), during treatment, and posttreatment.
Clinical Evaluation

Clinical evaluation including, but not limited to:

Oxygen 
requirement 
type 
(eg, 
supplemental 
oxygen, 
noninvasive 
positive 
pressure 
ventilation, 
endotracheal-mechanical ventilation, mechanical ventilation 
by tracheostomy), duration, and amount.

Body weight.

Respiratory rate, heart rate, systolic blood pressure, diastolic 
blood pressure, and body temperature.

SpO2.

Level of hospital care (eg, ICU, transitional care unit, ward 
floor).

Duration of hospitalization.

Need for hydration and feeding by IV catheter/nasogastric 
tube.

Functional status (Katz ADL score).
Subject Evaluation

Evaluation of RSV disease-related signs and symptoms and 
additional questions about health and functioning.

HRQoL (EQ-5D-5L).
Abbreviations: ADL: Activities of Daily Living; EQ-5D-5L: EuroQol 5 Dimension 5 level version; HRQoL: 
health-related quality of life; ICU: intensive care unit; qRT-PCR: quantitative reverse transcriptase-polymerase 
chain reaction; RSV: respiratory syncytial virus; RNA: ribonucleic acid; SpO2: peripheral capillary oxygen 
saturation.
PHARMACOKINETIC EVALUATIONS
Plasma samples will be analyzed to determine concentrations of ALS-008112 and ALS-008144 (and 
other metabolites, if applicable).
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
The relationship between the PK and PD (antiviral activity, clinical outcomes, and selected safety 
parameters) after single and repeated oral administration of ALS-008176 will be evaluated.
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ALS-008176 (JNJ-64041575, lumicitabine)  
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Approved, Date: 20 March 2018
BIOMARKER EVALUATIONS
Blood samples will be collected for exploratory biomarker analyses (host RNA), on the premise that these 
markers may play a role in the treatment response, PK, safety of ALS-008176, or the status and change of 
the RSV-related disease. In addition, leftover mid-turbinate nasal swabs or blood samples collected for 
other testing may be used for biomarker analysis (eg, proteins including cytokines) if available on the 
same premise.
Analyses of biomarkers may be conducted at the sponsor’s discretion and reported separately from this 
study.
No human deoxyribonucleic acid analyses will take place on these samples.
MEDICAL RESOURCE USAGE AND HEALTH ECONOMICS
Collected data may be used to conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected procedures 
(inpatient and outpatient).

Duration of hospitalization (total days length of stay, including duration by wards [eg, ICU]).

Outpatient medical encounters and treatments (including physician or emergency room visits, tests 
and procedures, and medication).

Need for, and duration of, nursing home or health services from baseline to Day 28.
SAFETY EVALUATIONS
Safety and tolerability will be evaluated throughout the study from signing of the informed consent form 
onwards until the last study-related activity (end of study/early withdrawal).
An IDMC will be established to monitor the safety of subjects and will review data in an unblinded 
manner on a regular basis to ensure the continuing safety of the subjects enrolled in this study and to 
evaluate whether efficacy objectives are met. The committee will meet periodically to review interim 
data. After the review, the IDMC will make recommendations regarding the continuation of the study. 
For Part 1, the IDMC will review the safety and PK data after approximately 12 subjects have completed 
treatment as per the IDMC charter. When approximately 24 subjects have completed the Day 14 
follow-up visit, an unblinded primary analysis will be performed by the sponsor, for review by the IDMC. 
Further enrollment in this part of the study up to 36 subjects may continue while the data are being 
analyzed. Once all data for Part 1 are collected and the database locked, the sponsor may perform an 
unblinded, secondary analysis on the full dataset of Part 1, to support clinical development.
For Part 2, the IDMC will review the safety data, initially after approximately 12 subjects have completed 
treatment and when approximately 12 Japanese subjects have completed treatment to assess that treatment 
may safely continue in each arm.
Any clinically relevant changes occurring during the study must be recorded in the AE section of the 
electronic case report form (eCRF).
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable endpoint is reached.
Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, ECGs, physical examinations, clinical laboratory tests, and other safety evaluations.
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STATISTICAL METHODS
No formal hypothesis is specified for Part 1 of this study. Part 1 is intended to characterize the PK and to 
confirm the popPK model derived from healthy volunteers in hospitalized adult subjects infected with 
RSV. Furthermore the safety and tolerability of the low-dose ALS-008176 treatment regimen will be 
assessed. The number of subjects participating in Part 1 is considered sufficient to achieve the objectives 
of the characterization of the PK in Part 1 and allows for updating the PK model, if deemed necessary, 
based on the results (potential covariates) found in Part 1.
A total sample size of 15 to 16 subjects on active treatment would provide 80% power to achieve a 95% 
confidence interval within 60% and 140% of the geometric mean estimates of clearance and central 
volume of distribution, assuming a between subject variation of 50% (coefficient of variation) as based on 
10,000 simulations of the current popPK model. For the secondary objective of safety assessment the 
probability was calculated to observe an (S)AE that has a true incidence of 1% which would be 15% with 
a total sample size of 16 subjects on active treatment; the probability to observe an (S)AE with a true 
incidence of 0.1%, 0.5% and 0.8% is 2%, 8% and 12%, respectively. Therefore, the current sample size of 
16 subjects on active treatment is deemed adequate for Part 1.
For Part 2, the primary hypothesis of a positive dose-response relationship assumes that dose regimens 
with higher exposure with respect to MD will have at least an equal or better effect on viral load. 
Therefore 2 contrasts will be tested at each of the interim analysis points and final analysis; a contrast 
with no difference between the 2 active regimens tested against placebo and a contrast with a positive 
linear dose-response relationship with respect to active regimens. With respect to multiple contrast 
testing, multiplicity will be controlled at the prespecified (interim) alpha level by calculating adjusted 
p-values from the simulated distribution of the maximum or maximum absolute value of a multivariate 
t random vector (ie, using the correlation between the contrasts to optimally control for alpha). The 
overall (family-wise) type 1 error rate of 2.5% (1-sided) will be adjusted for multiple testing due to formal 
interim analyses using an O’Brien-Fleming alpha spending function with 3 sequential tests (2 interim, 
1 final). As based on 10,000 simulations a sample size of 90 subjects randomized in a 1:1:1 ratio 
(placebo: low-dose ALS-008176: high-dose ALS-008176) will offer approximately 90% power to detect 
a positive dose-response relationship as defined assuming an effect size of 0.77 using Cohen’s d (ie, the 
effect size expressed as the ratio of the standard deviation of the AUC) and approximately 80% power 
assuming an effect size of 0.67 (Cohen’s d). Based on the results of the ALS-008176 RSV human 
challenge study, these effect sizes were considered plausible. The results of Part 1 did not lead to changes 
in the assumptions underlying the sample size determination.
For Part 2, the primary endpoint in this study is RSV RNA log10 viral load (measured by qRT-PCR in the 
mid-turbinate nasal swab specimens) AUC immediately prior to first dose of study drug (baseline) over 
7 days. Mean log10 viral load values over time will be analyzed using a restricted maximum likelihood 
based repeated measures approach. Analyses will include the fixed, categorical effects of treatment, 
strata, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline log10
viral load and baseline log10 viral load by-visit interaction. An unstructured (co)variance structure will be 
used to model the within-subject errors over time. The differences in the AUCs for active versus placebo 
will be derived using appropriate contrasts deriving least square mean differences, including the 95% 
2-sided confidence intervals. For inferential purposes, p-values will be compared with significance levels 
controlling for the (family-wise) type 1 error rate.
Population PK analysis of plasma concentration-time data of ALS-008112 will be performed using 
nonlinear mixed-effects modeling. Data may be combined with those of other selected studies to support a 
relevant structural model. Available baseline subject characteristics (eg, demographics, laboratory 
variables, race) will be tested as potential covariates affecting PK parameters.
Statistical approaches to explore correlations between clinical outcome and biomarkers in blood and 
mid-turbinate nasal swabs vary and depend on the different data types of the applied technology 
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
platforms, as well as on the extent of observed differences among study subjects. Analyses may be 
conducted at the sponsor’s discretion and reported separately from this study.
Efficacy and safety parameters will be subject to PK/PD analysis. ALS-008112 exposures will be 
evaluated as an independent variable, with selected efficacy and selected safety parameters considered as 
dependent variables. Various approaches, including graphical analysis, linear, nonlinear, and logistic 
regression methods may be utilized.
Subject-reported eCOA (RI-PRO, additional questions about health and functioning, and HRQoL 
[EQ-5D-5L]), investigator-reported Katz ADL data, medical resource utilization, and health economics 
assessments will be descriptively summarized by treatment group and compared across treatment groups.
Safety data will be presented descriptively. No statistical testing of safety data is planned. For safety, 
baseline will be defined as the last assessment prior to the first intake of study drug.
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TIME AND EVENTS SCHEDULE
Phase
Screening
Treatment Phase
Follow-up Phasea
Day
0
1
2
3 to 6b
7 
(+2 days)c
8 to 9d
10 
(+2 days)
11 to 13d
14 
(+2 days)
15 to 27
28 
(±2 days) 
EoSe
Study Procedure
Screening/Administrative
Informed consent 
X
Demographics
X
Medical history
X
Inclusion/exclusion criteriaf
X
Urine pregnancy test (all 
female subjects)
X
X
Study Drug Administration
1 LD followed by 9 MDs
MDs may be extended up to 
19 doses over 10 days if 
recommended by the IDMC
Randomization
X
Dispense study drugh
X
X
X
Study drug logi
X
Clinical Efficacy Evaluations
Ordinal scale assessment
Xz
Subject eCOAj
X
Xk
X
X
X
X
X
X
X
X
X
Clinical evaluationl
X
X
X
X
X
X
X
X
X
X
Katz ADLm
X
X
X
X
X
X
X
X
Oxygen saturation (SpO2) n
X (Q4h)
X (Q4h)
X (Q4h)
X (Q4h)
X (Q4h)
X (Q8h)
X (Q8h)
X (Q8h)
X 
X
Medical resource utilization 
and health economics 
assessment
X
X
X
X
DLCO and spirometryo
X
X
X
Clinical Safety Evaluations
Physical examinationp
X
X
X
X
Xg
X
Xg
X
X
Vital signsq
X
bid
bid
bid 
X
Xg
X
Xg
X
X
Part 1: Triplicate 12-lead 
ECGr
X
X
X
Xr
X
Part 2: Single 12-lead ECGr
X
X
X
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Phase
Screening
Treatment Phase
Follow-up Phasea
Day
0
1
2
3 to 6b
7 
(+2 days)c
8 to 9d
10 
(+2 days)
11 to 13d
14 
(+2 days)
15 to 27
28 
(±2 days) 
EoSe
Study Procedure
Nasal Swabs
Mid-turbinate nasal swab (if 
non-intubated) or 
endotracheal sample (if 
intubated): RSV diagnosis 
confirmation, viral and 
bacterial co-infections
X
Mid-turbinate nasal swab (if 
non-intubated) or
mid-turbinate nasal swab 
and endotracheal sample (if 
intubated): RSV RNA viral 
load, viral resistance 
(genome sequencing), 
biomarker and infectious 
virus (plaque assays)s, t
Xu
X
X
X
X
X 
X
Clinical Laboratory Assessments (Performed in Local Laboratory)
Blood sampling for 
hematologyv
X
X
X
X
X
X
X
Part 1: Blood sampling for 
biochemistryv
X
X
X
X
Part 2: Blood sampling for 
biochemistryv
X
X 
X 
X
X 
X
X
Urinalysisv
X
X
X
Pharmacokinetics
Blood sampling for 
pharmacokineticsw
X
X
X
X
X
Biomarkers
Blood sampling for 
biomarkers (host RNA)
X
X
X
X
X
Ongoing Subject Review
Concomitant therapyx
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsy
X
X
X
X
X
X
X
X
X
X
X
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Abbreviations: ADL: Activities of Daily Living; AE: adverse event; bid: twice daily; CPE: complete physical examination; DBP: diastolic blood pressure; 
DLCO: diffusing capacity of the lung for carbon monoxide; DPE: directed physical examination; ECG: electrocardiogram; eCOA: electronic Clinical Outcome 
Assessment; eCRF: electronic case report form; EoS: end of study; EQ-5D-5L: EuroQol 5 Dimension 5 level version; HRQoL: health-related quality of life; ICF: 
informed consent form; IDMC: Independent Data Monitoring Committee; LD: loading dose; MD: maintenance dose; PK: pharmacokinetic(s); Q4h: every 4 hours; Q8h: 
every 8 hours; RI-PRO: respiratory infection patient-reported outcome; RNA: ribonucleic acid; RSV: respiratory syncytial virus; SAE: serious adverse event; SBP: 
systolic blood pressure; SpO2: peripheral capillary oxygen saturation.
Footnotes:
a.
If a subject is discontinued from study drug, a follow-up visit will be scheduled 2 days (+2 days), 5 days (+2 days), 9 days (+2 days), and 23 days (±2 days) after 
the last dose of study drug was administered. Assessments should be performed as indicated in the Time and Events Schedule, respectively for the Day 7, Day 10, 
Day 14, and Day 28 visit.
b.
The subject may be discharged after the Day 2 study procedures. Subjects may also remain hospitalized if deemed appropriate by the investigator. Days 3 to 6 
assessments are to be performed on a daily basis or as indicated only if the subject is still hospitalized with the exception of administration of study drug dose, 
mid-turbinate nasal swabs, and subject eCOA, which are to be continued at home. Hospitalization duration will not be extended solely for study purposes. 
Telephone calls to subjects to facilitate compliance with study procedures between outpatient study visits are permitted.
c.
If dose duration is increased to up to 10 days, then all assessments performed on Day 7 will again be performed 1 day (+2 days) after administration of the last 
MD.
d.
Assessments are to be performed once daily or as indicated only if the subject is still hospitalized.
e.
Day 28 assessments include only the assessments indicated. Other safety assessments need only be collected if deemed clinically necessary based on an assessment 
of the subject’s safety or as follow-up to an earlier AE.
f.
Procedures performed as part of standard of care within approximately 48 hours prior to screening completion (ie, randomization) may be used in determining 
study eligibility.
g.
These assessments are not required per protocol, however, if clinical/safety evaluations are performed as part of routine clinical care while hospitalized, the results 
of these assessments will be collected in the eCRF for viral, safety, and/or clinical evaluation.
h.
Study drug should be given as soon as possible but no later than 4 hours after randomization. Study drug will be given as an LD administered for Dose 1 followed
by 9 MDs, to be given at least 8 hours apart and maximum 16 hours apart, with no more than 2 doses per calendar day, for a total of 10 doses over 5 or 6 days. 
ALS-008176 may be given without regard to food. The date and time of dose administration, the date and time of food intake (limited to the food ingested within 
30 minutes before or after study drug administration), and the type of food will be recorded in the eCRF during hospitalization. The date and time of dose 
administration will be recorded in the electronic device used for eCOA in case the subject is discharged prior to completion of treatment See Attachment 8 for 
details on collection of food intake information.
i.
Upon discharge, subjects will be required to document intake of study drug on the electronic device used for eCOA in a study drug log.
j.
An electronic device will be provided to each subject at screening and the investigator/study-site personnel will provide sufficient information to enable the subject 
to complete the subject eCOA (including RI-PRO, additional questions about health and functioning, and HRQoL [EQ-5D-5L]). The subjects will complete the 
eCOA once daily throughout the study from screening to Day 28 at approximately the same time each day. If the subject is unable to complete the assessment on 
the device, the subject’s spouse, partner, relative, friend or the investigator/study-site personnel trained on the eCOA device can read the questions and responses 
aloud to the subject, and enter the subject’s responses in the eCOA device on the subject’s behalf using the interview administration procedures explained in the 
eCOA completion guide. For Part 2, the questions will be read from the device for RI-PRO and additional questions about health and functioning, and from a paper 
form of the questionnaire provided to the caregiver by the site for HRQoL. If in the investigator’s opinion, the subject (or the subject’s spouse, partner, relative, or 
friend) is unlikely to reliably enter the information in the eCOA device on a daily basis for the duration of the study, the site will retain the eCOA device upon the 
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subject's discharge and arrange for the investigator or trained study-site personnel to interview the subject by phone and record the subject’s responses in the eCOA 
device on the subject's behalf each day post discharge to end of follow-up.
k.
The assessment on Day 1 must be recorded predose, before the LD. If the screening assessment was performed less than 8 hours prior to LD, the predose 
assessment does not need to be performed.
l.
Clinical evaluation includes, but is not limited to, RSV disease symptoms, oxygen requirement (type, duration, and amount), level of hospital care, duration of 
hospitalization, respiratory rate, SpO2, and body temperature.
m.
The Katz ADL questionnaire will be completed by the investigator/study-site personnel after interviewing the subject and the data will be entered into the eCRF by 
the investigator/study-site personnel. The Katz ADL questionnaire will be completed twice at screening to document retrospectively the subject’s pre-RSV 
infection functional status (ie, prior to first signs/symptoms of RSV) and the subject’s current functional status (ie, after the occurrence of RSV signs/symptoms). 
The Katz ADL questionnaire will be completed once daily for the entire duration of hospitalization and on Day 7, Day 10, Day 14, and Day 28 if the subject is 
discharged.
n.
SpO2 will be assessed Q4h (±30 minutes) while the subject is hospitalized through Day 7. Previous time point should be used to calculate the next measurement 
window. In case the last SpO2 assessment on Day 7 was performed after 8 PM, the first SpO2 assessment on Day 8 should be performed within 8 hours from the 
last SpO2 assessment on Day 7. For subjects who remain hospitalized after Day 7, SpO2 assessment should then continue Q8h (±1 hour) until 24 hours after the 
cessation of supplemental oxygen. After discharge, SpO2 will be assessed once on Day 7, Day 10, Day 14, and Day 28.
o.
Only to be performed if the test is available at the study site and the clinical condition of the subject allows testing as judged by the investigator.
p.
A CPE includes all body systems, height (only at screening), and body weight; a DPE includes respiratory system, nose, ear, throat, facial and neck lymph nodes, 
and skin examination. A CPE will be performed at screening and Day 28 and a DPE will be performed on Days 1, 2, 7, 10, and 14. Additionally, physical 
examination findings performed as part of standard of care on Days 8 to 13 will also be collected.
q.
Vital signs are defined as SBP, DBP, temperature, respiratory rate, and heart rate. Symptom-directed vital signs will also be performed when deemed appropriate 
by the investigator or appropriately delegated study team member. Vital signs will be assessed twice daily (preferably at the same times each day, ±30 minutes) for 
the entire duration of hospitalization. After discharge, vital signs will be assessed once on Day 7, Day 10, Day 14, and Day 28. Additionally, vital signs assessed as 
part of standard of care on Days 8 to 13 will be collected.
r.
Part 1: Triplicate 12-lead ECGs (three 10-s recordings at approximately 60-s intervals) will be collected and analyzed by a central laboratory at screening, on 
Day 1, on Day 7, on Day 28, and when clinically indicated. On Day 1, triplicate ECGs will be collected at 2 time points: approximately 30 to 60 minutes and 3 to 
6 hours after the LD. If an ECG is abnormal at Day 7, an additional ECG should be performed at Day 14. Part 2: a single 12-lead ECG will be collected and 
analyzed by a central laboratory at screening, on Day 4 (for subjects who remain hospitalized at this time), on Day 28, and when clinically indicated. If discharged 
earlier than Day 4, the subject needs to have an ECG recorded on the day of discharge. The ECG will be performed 30 minutes to 3 hours after the first dose of 
study drug of that day. If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence:
ECG, followed by vital signs/oxygen saturation, mid-turbinate nasal swabs, then blood draw.
s.
The mid-turbinate nasal swab (if non-intubated) or endotracheal sample (if intubated) taken during screening is placed in 3 mL of transport media and split into 
several aliquots, which are used to confirm RSV infection locally and centrally, and to assess for viral and bacterial co-infection centrally. From Day 1 to Day 7 
and on Day 10, Day 14, and Day 28, 1 mid-turbinate nasal swab (if non-intubated) or 1 mid-turbinate nasal swab and 1 endotracheal sample (if intubated) will be 
taken per day to assess RSV RNA viral load and resistance and in some cases to assess the infectious virus yields using a plaque assay. Should the study drug 
duration be increased to up to 10 days (following review of the data by the IDMC), 1 mid-turbinate nasal swab (if non-intubated) or 1 mid-turbinate nasal swab and 
1 endotracheal sample (if intubated) will be taken every day up to and including 1 day (+2 days) following the last dose of study drug. The timing of the LD will 
determine the nasal swab and/or endotracheal sampling times. If the administration of the LD is in the morning, all nasal swabs and/or endotracheal samples will 
be taken before the morning doses. If the administration of the LD is in the afternoon, all nasal swabs and/or endotracheal samples will be taken before the 
afternoon doses but after the morning doses. In case of nostril bleeding or irritation during the collection of a mid-turbinate nasal swab, all subsequent nasal swabs 
will be performed on the contralateral nostril. In case mid-turbinate nasal swabs are collected at home, this should be documented in the eCOA. Wherever possible, 
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mid-turbinate nasal swabs should be collected by a trained study team member in an inpatient or outpatient (clinic visit) setting. Whenever mid-turbinate nasal 
swabs cannot be taken by a trained study team member, the subject (or the subject’s spouse, partner, relative, or friend) should collect swab specimens after being 
trained by the investigator/study-site personnel.
t.
Leftover mid-turbinate nasal swabs may be used to explore biomarkers (eg proteins including cytokines) at the discretion of the sponsor.
u.
Mid-turbinate nasal swab (if non-intubated) or mid-turbinate nasal swab and endotracheal sample (if intubated) must be taken as close as possible to and before the 
LD on Day 1. If the screening mid-turbinate nasal swab or endotracheal sample was performed less than 8 hours prior to LD, the Day 1 predose sample does not 
need to be collected.
v.
Safety laboratory tests (hematology and biochemistry) will be performed by the local laboratory at screening and during the follow-up phase at Day 7, Day 14, and 
Day 28. Hematology and biochemistry (Part 2 of the study only) tests will be additionally performed during the treatment phase on Day 2, Day 4, and Day 6 while 
hospitalized and during the follow-up phase at Day 10. Urinalysis will be performed at Day 1 and during the follow-up phase at Day 7 and Day 14. A urinalysis 
performed in the context of routine clinical care during the screening period may be used for the baseline urinalysis. If on any other day blood or urine is collected 
during routine clinical care while hospitalized, the results of these assessments will be collected in the eCRF for safety evaluation. Additional safety samples may 
also be collected on an ad hoc basis in the event that a safety event arises, at the discretion of the investigator or at the request of the sponsor. Leftover blood 
samples may be used for exploratory biomarker analyses (eg, proteins including cytokines).
w.
Part 1: PK samples should be collected at: 
Dose 1 (LD): 0.5 to 1 hour postdose, 2 to 3 hours postdose, and 4 to 6 hours postdose
Dose 2: predose, 0.5 to 1.5 hour postdose, and 3 to 6 hours postdose
Dose 3: if patient has not been discharged, predose (preferable), or random sample
Day of discharge if still on study drug: random sample
Dose 10: if patient has not been discharged, predose (preferable) or random sample
Day 7: random sample at visit
Day 10: random sample at visit
If >10 doses are administered upon IDMC recommendation: prior to the last dose (if feasible)
Part 2: PK samples should be collected at: 
Dose 1 (LD): 0.5 to 1 hour postdose, and 2 to 3 hours postdose 
Dose 2: predose, and 3 to 6 hours postdose
Dose 3: if patient has not been discharged, predose (preferable), or random sample
Dose 10: if patient has not been discharged, predose (preferable) or random sample
Day 7: random sample at visit
Day 10: random sample at visit
Day of discharge if still on study drug: random sample
The actual dates and times of sample collection must be recorded in the eCRF. When occurring on the same day, safety and biomarker blood samples may be
collected at the same time as PK sampling to minimize the number of venipunctures. A predose PK sample is defined as one collected within 0.5 hour 
(30 minutes) prior to the next dose. Additional 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, at the discretion of the investigator or at the request of the sponsor.
See Attachment 8 for details on PK sampling and collection of food intake information.
x.
Prestudy therapies administered up to 7 days before the first dose of study drug must be recorded at screening. Concomitant therapies must be recorded throughout 
the study beginning with the start of the first dose of study drug up to the Day 28 visit (±2 days). During hospitalization, concomitant medication will be recorded 
by the site staff in the eCRF. Upon discharge, subjects will be required to document use of concomitant medication in the electronic device in a medication log, 
which will serve as basis for recording the concomitant medication in the eCRF by the site staff.
y.
All AEs and SAEs will be collected continuously from signing of the ICF onwards until the last follow-up visit (EoS visit). Any clinically significant abnormalities 
persisting at the EoS/early withdrawal will be followed by the investigator until resolution or until a clinically stable endpoint is reached.
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ALS-008176 (JNJ-64041575, lumicitabine)  
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Approved, Date: 20 March 2018
z.
The ordinal scale will be assessed on the day of the last dose (Day 5/6 [depending on the timing of the LD administration]). In case the subject is discharged before 
Day 5/6, the subject should be contacted to ask if the subject has returned to usual activities.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
ABBREVIATIONS
ADL
Activities of Daily Living
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-inf
area under the concentration-time curve from time zero extrapolated to infinite time
AUC0-last
area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration
AUC0-xh
area under the concentration-time curve from time 0 to x hours after dosing 
BCRP
breast cancer resistance protein
BFU-E
burst forming unit-erythroid
CFU-GM
colony forming unit-granulocyte monocyte
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
Cmax
maximum observed or predicted concentration
Cmin
minimum observed or predicted concentration
COPD
chronic obstructive pulmonary disease
CV
coefficient of variation
CYP
cytochrome P450
DBP
diastolic blood pressure
DLCO
diffusing capacity of the lung for carbon monoxide
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCOA
electronic Clinical Outcome Assessment
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EQ-5D-5L
EuroQoL 5 Dimension 5 level version
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
IB
Investigator’s Brochure
IC50
concentration resulting in 50% of the maximum inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
ICU
intensive care unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IWRS
interactive web response system
Ki
inhibition constant
LD
loading dose
MD
maintenance dose
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NTP
nucleoside triphosphate
OAT
organic anion transporter
PCR
polymerase chain reaction
PD
pharmacodynamics(s)
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
popPK
population pharmacokinetic(s)
PQC
product quality complaint
PRO
patient-reported outcomes
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qRT-PCR
quantitative reverse transcriptase-polymerase chain reaction
QTc
corrected QT
QTcF
QT corrected according to Fridericia’s formula
RBC
red blood cell
RI-PRO
respiratory infection patient-reported outcome
RNA
ribonucleic acid
RSV
respiratory syncytial virus
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SpO2
peripheral capillary oxygen saturation
SUSAR
suspected unexpected serious adverse reaction
t1/2
elimination half-life
tmax
time to maximum concentration
ULN
upper limit of normal
Vc
central volume of distribution
WBC
white blood cell
DEFINITIONS OF TERMS
Electronic Clinical 
Outcome Assessment 
(eCOA)
Includes patient-reported outcomes (PROs) collected on an electronic device
(eg. respiratory infection PRO [RI-PRO], additional questions about health and 
functioning, and health-related quality of life [HRQoL] EuroQoL 5 Dimension 
[EQ-5D-5L]).
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ALS-008176 (JNJ-64041575, lumicitabine)  
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1.
INTRODUCTION
Respiratory syncytial virus (RSV) is a ribonucleic acid (RNA) virus and a member of the 
Pneumoviridae family, which also includes human and avian metapneumovirus and murine 
pneumonia virus. The RSV season occurs during winter months in regions with temperate 
climates in the Northern and Southern Hemispheres and throughout the year or peaks 
semiannually in tropical regions.5,16
ALS-008176 (also known as JNJ-64041575 or lumicitabine) is an orally administered drug 
intended for the treatment of children and adults infected with RSV. ALS-008176 is a 
3ʹ,5ʹ-bisisobutyrate prodrug of the cytidine nucleoside analog
polymerase inhibitor, 
ALS-008112, and is a replication inhibitor of RSV, which works via a classic chain termination 
mechanism. Once administered, it is rapidly and efficiently converted by esterases to 
ALS-008112, which is subsequently converted intracellularly, to the active nucleoside 
triphosphate (NTP), ALS-008112-5ʹ-triphosphate (ALS-008136). The only major metabolite of 
ALS-008112 is ALS-008144, which is the inactive uridine analog metabolite. The monoester of 
ALS-008176, ALS-008206, is a minor metabolite.
Table 2: 
Investigational Product and its Metabolites
Compound Number
Description
ALS-008176 (JNJ-64041575, 
lumicitabine)
3’,5’-bisisobutyrate prodrug of ALS-008112
ALS-008112 (JNJ-63549109)
parent nucleoside analog, major metabolite of ALS-008176, inactive
ALS-008206 (JNJ-64412309)
3’-isobutyrate monoester of ALS-008112, minor metabolite, inactive
ALS-008207 (JNJ-64412296)
5’-isobutyrate monoester of ALS-008112, minor metabolite, inactive
ALS-008144 (JNJ-64167896)
uridine analog metabolite of ALS-008112, major metabolite, inactive
ALS-008136 (JNJ-65409136)
5’-triphosphate of ALS-008112 (NTP), intracellular metabolite, active
ALS-008137 (JNJ-65409123)
5’-monophosphate of ALS-008112, intracellular metabolite, inactive
Abbreviation: NTP: nucleoside triphosphate.
Data from an RSV human challenge study, Study ALS-8176-502, have demonstrated that 
ALS-008176 doses up to a single 750 mg loading dose (LD) followed by nine 500 mg 
maintenance doses (MDs) resulted in the inhibition of RSV replication with an associated 
reduction in the signs and symptoms of the RSV infection in healthy subjects, and was well
tolerated.9
For the most comprehensive nonclinical and clinical information regarding ALS-008176 refer to 
the latest version of the Investigator’s Brochure (IB) for ALS-008176, and its addenda.2,3,4,5,16
The term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
This study will evaluate the antiviral activity, clinical outcomes, safety, tolerability, and 
pharmacokinetics (PK) of orally administered ALS-008176 regimens in adults hospitalized with 
RSV infection.
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Nonclinical Studies
Pharmacologic Profile
The antiviral activity and selectivity of the parent nucleoside analog ALS-008112 and its 
prodrug, ALS-008176, were evaluated in vitro using a combination of cell-based RSV infectious 
and subgenomic replicon reporter systems, together with cell-extracted replicase and 
recombinant RSV polymerase L-P complex. In vivo, ALS-008176 was evaluated in the African 
Green monkey model of RSV infection.
The major findings as reported in the IB from these studies were:

When incubated with RSV-infected cells, ALS-008112 and ALS-008176 are selective
inhibitors of both RSV laboratory-adapted A and B strains as well as a range of diverse 
clinical isolates.

ALS-008112 and ALS-008176 demonstrate selective inhibition of RSV replication in the 
HeLa cell RSV subgenomic replicon system.

The ALS-008112-5’-triphosphate (ALS-008136), the active metabolite of the compound, is 
a selective inhibitor of RSV RNA-dependent polymerase activity with an inhibition constant 
(Ki) of 0.09 μM.

After nucleotide incorporation using ALS-008136, no subsequent nucleotide was 
incorporated at the 3’OH end of the RNA template indicating that ALS-008136 inhibits the 
RSV polymerase activity by immediate chain termination.

ALS-008136 is formed in high amounts in A549 lung epithelial cells, primary human nasal 
and bronchial epithelial cells, and monkey lung, and demonstrates an intracellular half-life 
(t1/2) of approximately 17.6 hours in cell culture (in normal human bronchial epithelial cells) 
and 29 hours in vivo (in monkey lungs).

ALS-008112 also inhibited the replication of other respiratory viruses such as 
parainfluenza-3 and human metapneumovirus.

Viral resistance to ALS-008112 was mediated by multiple amino acid substitutions 
(M628L/A789V/L795I/I796V) in the RSV polymerase domain of the RSV L-protein.

The effect of prophylactic treatment with ALS-008176 on the replication of RSV A2 in the 
African Green monkey model was studied. At Day 5 postinfection (end of treatment) there 
was a difference of >4 log10 copies/mL between the RSV RNA viral load titers in 
bronchoalveolar lavage samples of the vehicle-treated animals compared with those from the 
ALS-008176-treated animals indicating that ALS-008176 treatment significantly suppressed 
RSV replication in vivo. However, virus relapse was observed in all animals between 
Days +5 and +15, but was not associated with the emergence of viral resistance to 
ALS-8176.

Inhibition of RSV A2 by ALS-008112 was examined in pairwise combination studies with 
palivizumab, the RSV fusion inhibitors, BMS-433771 and GS-5806, the non-nucleoside 
RSV polymerase inhibitors, ALS-028414 and AZ-27, consensus interferon (Infergen®), and 
ribavirin. These ALS-008112 combinations demonstrated strong synergy, synergy or 
additive effects. None of the compound interactions demonstrated antagonistic effects.
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Toxicology Profile
Once administered, ALS-008176 is rapidly and efficiently converted to ALS-008112. Thus, the 
toxicity profile of ALS-008176 is primarily driven by ALS-008112.
The major toxicity findings were:
Repeat-dose Toxicity

Target organ for toxicity in both adult and juvenile rats and dogs was the hematopoietic 
system, next to an effect on body weight (in rats). The no-observed-adverse-effect level 
(NOAEL) doses of ALS-008176 and exposure of ALS-008112 are presented in Table 3.
Table 3:
NOAEL Doses of ALS-008176 and Exposure of ALS-008112 in Adult and Juvenile Rats and 
Dogs After Repeated Dosing of ALS-008176
Target 
Organ
Key Finding
Species/Age Group
Dose
(mg/kg bid)
NOAEL
(ALS-008112 AUC0-24h)
(ng.h/mL)
Hematology
reticulocytes,
red blood cell 
parameters, reversible
Juvenile rat
(PND1-28)a
150
93,900b
Juvenile dog
(PND7-34)
25
108,228
Bone marrow
Cytological changes in 
bone marrow cells, 
myeloid-to-erythroid 
ratios, reversible
Adult rat (14 days)
150
53,600
Adult dog (14 days)
75
192,500
Abbreviations: AUC0-24h: area under the curve from time 0 to 24 hours after dosing; bid: twice daily; NOAEL: 
no-observed-adverse-effect level; PND: postnatal day.
a Effects in rats aged PND21-45 were similar to adult rats.
b Estimated on PND28 predose values.

Following 14 days, 28 days, and 13 weeks of repeated dosing, the hematopoietic changes 
induced by ALS-008112 in adult animals were reversible. 

No effects on early developmental markers, neurobehavior, respiratory function, bone 
geometry, bone densitometry, ophthalmological evaluations, or electrocardiograms (ECGs) 
in juvenile rats (150 mg/kg twice daily; ALS-008112 area under the concentration-time 
curve from time 0 to 24 hours after dosing [AUC0-24h] of 55,450 ng.h/mL) and dogs 
(75 mg/kg twice daily; ALS-008112 at AUC0-24h of 258,862 ng.h/mL). 
Genotoxicity

Non-mutagenic (negative Ames test) and no DNA damage (COMET assay; 
1,750 mg/kg/day, 3 days) potential for ALS-008176 or its metabolites.

Increases in structural chromosomal aberrations in human peripheral blood lymphocytes 
induced by ALS-008112 (≥10 µg/mL). Positive micronucleus test in rats (≥425 mg/kg/day 
ALS-008176, 3 days) at high exposures of ALS-008112 (AUC0-24h ≥107,983 ng.h/mL). The 
no-observed-effect level (NOEL) for in vitro chromosomal aberrations was 5 μg/mL 
ALS-008112 and for in vivo micronucleus induction was a ALS-008112 AUC0-24h of 
57,595 ng.h/mL.
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
The mechanism of clastogenicity is an indirect, threshold-based mechanism of intracellular 
nucleoside triphosphate pool disturbances rather than direct DNA reactivity, as described for 
other nucleoside analog inhibitors in the public domain. 

A maximum average threshold of ALS-008112 exposure in humans has been defined as an 
AUC0-24h of 20,000 ng.h/mL. This threshold provides safety margins that are at least 2.5-fold 
(vs 13-week adult rat study), 2.7-fold (vs 14-day adult rat study), and 4.7-fold (vs 28-day 
juvenile rat study) lower for adults and infants, respectively, than the lowest NOAEL 
exposure obtained in nonclinical studies.
Reproductive Toxicity

The NOAEL for male reproductive toxicity/fertility in rats was 250 mg/kg twice daily 
(ALS-008112 AUC0-24h of 165,000 ng.h/mL). Although a slight decrease in corpora lutea 
and corresponding decrease in implantations and viable embryos was seen at 250 mg/kg 
twice daily in females, it did not have any overall impact on female fertility or in utero 
survival. Therefore, the NOAEL for female reproductive toxicity as well as early embryonic 
toxicity was considered to be 250 mg/kg bid (ALS-008112 AUC0-24h of 193,000 ng.h/mL).

The effects of ALS-008176 on developmental and reproductive parameters were a decrease 
in fetal weight with concomitant skeletal developmental variations in rats at 400 mg/kg 
twice daily and lower litter proportion of viable fetuses due to an increase in post-
implantation losses in rabbits at ≥20 mg/kg twice daily, with no teratogenic effects in fetuses 
in either rats or rabbits. The NOAEL for maternal toxicity and embryo-fetal development in 
rats was 125 mg/kg twice daily (ALS-008112 maximum plasma concentration [Cmax] of 
11,400 ng/mL and AUC0-24h of 87,800 ng.h/mL). The NOAEL for embryo-fetal development 
in rabbits was 10 mg/kg twice daily (ALS-008112 AUC0-24h of 8,220 ng.h/mL) and the 
maternal NOAEL in rabbits was 20 mg/kg twice daily.
Other Toxicity

No measurably cytotoxicity of ALS-008112 (100 µM, 3 days) in the human epithelial type 2 
(HEp-2) and the Huh-7 cell lines. 
Pharmacokinetic and Metabolism Profile
The major nonclinical pharmacokinetic (PK) and metabolism findings were:

The prodrug ALS-008176 was well absorbed after oral administration and rapidly and 
efficiently converted to the parent nucleoside analog ALS-008112 by esterases (mainly 
carboxylesterase 2). Plasma exposures of ALS-008112 were comparable between adult and 
juvenile animals at the same dose levels. The uridine metabolite ALS-008144 was a major 
circulating metabolite (especially in monkeys).

Food slowed down the rate of oral absorption (lowered Cmax values) of ALS-008176, but did 
not change the extent of oral absorption (no change in area under the curve [AUC]) in 
monkeys.

The oral bioavailability, in terms of exposure of the parent nucleoside analog ALS-008112, 
was 44% in dog and monkey.
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
Inside cells ALS-008112 is extensively phosphorylated. In lung, high levels of the 
monophosphate ALS-008137 and especially the active triphosphate ALS-008136 were 
measured.

Cytochrome P (CYP) enzymes play a minor role in ALS-008176 metabolism. No other 
relevant inhibition nor induction of CYP enzymes by ALS-008176, ALS-008112 or other 
metabolites was observed.

ALS-008176 is a substrate of P-glycoprotein (P-gp) at 0.5 μM and higher, with no P-gp 
saturation measured up to 150 μM. ALS-008176 is not an inhibitor of P-gp. ALS-008112
appears to be a P-gp substrate at 2 μM, but not at 50 μM and higher concentrations, and it is 
not an inhibitor of P-gp. ALS-008144 is neither a substrate nor inhibitor of P-gp. 
ALS-008176, but not ALS-008112 and ALS-008144, might be weak inhibitors of organic 
anion-transporting polypeptide (OATP) 1B1/1B3, but none of them are substrates of these 
OATP1B transporters. Data indicated that ALS-008112 and ALS-008144 are neither 
substrates nor inhibitors of organic cation transporter (OCT) 2, organic anion transporter 
(OAT) 1, and bile salt export pump (BSEP). There is no clear indication that ALS-008176 
and ALS-008112 are substrates of breast cancer resistance protein (BCRP). ALS-008144 is 
no BCRP substrate. None of them are inhibitors of BCRP. ALS-008112 is a substrate but 
not an inhibitor of OAT3 (Ki >258 μM). ALS-008144 is not a substrate or inhibitor of 
OAT3

Based on the in vitro data, ALS-008176 and its major metabolites are predicted to have a 
low potential for CYP- and transporter-mediated drug-drug interactions, with the exception 
of OAT3 inhibitors and potential exception of P-gp inhibitors and inducers.
Clinical Studies
Human Pharmacokinetics
Single-dose PK in healthy adult subjects was characterized for single doses of ALS-008176
ranging from 40 to 750 mg in a suspension formulation (Study ALS-8176-501) and for single 
doses of 1,500 and 3,000 mg in a tablet formulation (Study 64041575RSV1003) administered 
orally to healthy adult subjects in the fasted state. ALS-008176 was rapidly converted to 
ALS-008112. The only other major metabolite measurable in plasma was ALS-008144, the 
inactive uridine metabolite of ALS-008112. The majority of the plasma concentrations of 
ALS-008112 generally decreased to low levels within 6 to 12 hours postdose, indicating rapid 
and extensive distribution of this metabolite. With increasing doses of ALS-008176 (40 to 
3,000 mg), the Cmax of ALS-008112 increased in a less than dose proportional manner, while the 
Cmax of ALS-008144 and the AUCs of both metabolites increased close to dose proportionally. 
The plasma PK profile of the metabolite, ALS-008144, was similar to that of ALS-008112 and 
exposure (area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration [AUC0-last]) was approximately 20% to 54% of that of ALS-008112. 
Food effect was assessed for several ALS-008176 suspension and tablet formulations 
(Study ALS-8176-501: suspension at 250-mg dose, Study ALS-8176-509: 500-mg tablet, and 
Study 64041575RSV1005: suspension at 240-mg dose and 250-mg tablet). Intake of a single 
240-mg oral dose of the ALS-008176 suspension used in Study 64041575RSV2004 with a high 
fat, high calorie meal lowered ALS-008112 Cmax by 57% as compared with the fasted state, 
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without affecting the ALS-008112 area under the concentration-time curve (Treatment B and C 
in Study 64041575RSV1005). Administration of ALS-008176 500-mg tablet used in Study 
64041575RSV2003 with a high fat, high calorie meal had a minor effect on ALS-008112 area 
under the concentration-time curve and Cmax, as compared to the fasted state (Formulation A in 
Study ALS-8176-509).
Study ALS-8176-504 determined the absolute bioavailability of ALS-008112 and mass balance 
of ALS-008176 in healthy adult subjects. Following oral administration of a 375 mg 
14C-ALS-008176 solution, 84% of the total administered radioactive dose was recovered in the 
urine and feces during the 312-hour collection period. Approximately half of the administered 
dose was recovered within the first 24 hours. Approximately two-thirds of the total radioactivity 
was recovered in the urine suggesting renal elimination is the major route of elimination for the 
prodrug and its metabolites. Metabolite profiling and identification confirmed that ALS-008112
and ALS-008144 are the 2 major metabolites in plasma, urine, and/or feces. The absolute oral 
bioavailability of an oral dose of 500-mg of ALS-008176, measured by the formation of the 
parent nucleoside analog, ALS-008112 (AUC0-last), was determined to be approximately 60%.
Study 64041575RSV1006 investigated the PK of ALS-008176 after a single oral dose of 
1,000 mg in adult subjects with various degrees of impaired renal function. Overall, based on the 
geometric mean ratios, Cmax of ALS-008112 was similar in subjects with impaired renal function 
compared to subjects with normal renal function, and AUC0-last and area under the concentration-
time curve from time zero extrapolated to infinite time (AUC0-inf) increased with a decrease in 
renal function (Table 4).
Table 4:
Pharmacokinetic Parameters of ALS-008112 Following a Single Oral Dose of 1,000 mg 
ALS-008176 in Subjects With Different Degrees of Renal Function 
Pharmacokinetic 
Parameter of
ALS-008112
Normal renal 
function
Mild impaired 
renal function
Moderate 
impaired renal 
function
Severe 
impaired renal 
function
End-stage 
renal disease
na
14
6a
6
6b
6a
Cmax (ng/mL)
3,258
2,800
4,108
3,721
3,682
AUC0-last (ng.h/mL)
11,659
12,905
18,260
19,105
25,335
AUC0-inf (ng.h/mL)
12,438
14,455
19,550
21,086
30,410
Abbreviations: AUC0-last: area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration; AUC0-inf: area under the concentration-time curve from time zero extrapolated to 
infinite time; Cmax: maximum plasma concentration; eGFR: estimated glomerular filtration rate. 
Normal renal function: eGFR ≥90 mL/min; Mild renal impairment: eGFR ≥60 to <90 mL/min; Moderate renal 
impairment: eGFR ≥30 to <60 mL/min; Severe renal impairment: eGFR ≥15 to <30 mL/min; End-stage renal 
disease: eGFR <15 mL/min if not on hemodialysis or requiring hemodialysis treatment for ≥3 months before 
screening if on hemodialysis
a n=5 for AUC0-inf
b n=5 for AUC0-last and AUC0-inf
Multiple dose PK was characterized in healthy adult subjects in Study ALS-8176-501, in healthy 
adult subjects challenged with RSV in Study ALS-8176-502, and in hospitalized adult subjects 
with RSV infection in Part 1 of Study 64041575RSV2003. Following multiple oral doses of 
ALS-008176 in healthy adult subjects in Study ALS-8176-501, including 2 loading doses (LDs) 
up to 750 mg on Day 1 followed by administration of maintenance doses (MDs) up to 500 mg up 
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to 13 days every 12 hours (Q12h), the plasma profiles of ALS-008112 and ALS-008144 were 
similar to those obtained following single doses of ALS-008176. Accumulation of either 
ALS-008112 or ALS-008144 was insignificant after 5 days of dosing. Steady-state minimum 
observed analyte concentration (Cmin) of ALS-008112 was reached by the second dose and 
minimal changes in Cmin concentrations were noted between Days 1 and 5 or 14. In general, the 
plasma profiles for ALS-008112 following the PM dose were lower than following the AM dose. 
Study ALS-8176-502 was an RSV challenge study in healthy adult subjects. Subjects received 
5-day dosing regimens of ALS-008176 as an oral suspension. The 3 dose regimens were: 375 mg 
Q12h (n=11), 750 mg LD/500 mg MD Q12h (n=14), and 750 mg LD/150 mg MD Q12h (n=19). 
Intensive PK samples were evaluated on Days 1 and 5 of the study and the highest mean plasma 
AUC0-24h for ALS-008112 was 10,794 ng.h/mL on Day 5 for the 750 mg LD/500 mg MD group. 
There was no difference between the average exposures after oral dosing of ALS-008176 in 
healthy adult subjects in Study ALS-8176-501 as compared with healthy adult subjects 
challenged with RSV in Study ALS-8176-502. The primary objective of Part 1 of Study 
64041575RSV2003 was to characterize the PK and to confirm the population pharmacokinetic 
(popPK) model derived from healthy subjects in hospitalized adults who are infected with RSV. 
The PK data used in the analysis for Part 1 of this study were obtained from 15 subjects dosed 
with 750 mg LD/250 mg MD ALS-008176. Individual concentrations and clearance, Cmax, Ctrough
and AUC0-24h were reliably estimated. The mean model AUC0-24h was 9,872 ng.h/mL on Day 1 
and 7,551 ng.h/mL on Day 5, well below the average limit of exposure set at AUC0-24h of 
20,000 ng.h/mL. 
Multiple dose PK was also characterized in hospitalized pediatric subjects with RSV infection in 
Study ALS-8176-503. In the multiple ascending dose (MAD) part, RSV-infected infants 
received a LD (up to 60 mg/kg) followed by 5-day MDs (twice daily) of ALS-008176 (up to 
40 mg/kg). The mean plasma ALS-008112 AUC0-24h increased slightly less than dose 
proportionally on Day 1 from 1,210 ng.h/mL for the 4.1 mg/kg LD/1.37 mg/kg MD regimen to 
15,420 ng.h/mL for the 60 mg/kg LD/40 mg/kg MD regimen.
Based on an integrated popPK approach, race (ie, Caucasian versus Asian, including Japanese) 
does not affect exposures to ALS-008112, and body weight and creatinine clearance are 
important covariates on the clearance of ALS-008112. Additionally, lumicitabine formulation as 
a suspension or tablet, and intake of food are important covariates on the absorption and its 
between-subject variability.
Study 64041575RSV1002 investigated the potential PK effect of probenecid (chosen as a 
clinically relevant and strong OAT3 inhibitor) on ALS-008112. Based on the LSmeans ratios, 
the ALS-008112 Cmax and AUC0-last were 1.28-fold and 1.75-fold higher, respectively, after 
coadministration of probenecid with ALS-008176
compared to the administration of 
ALS-008176 alone.
Efficacy/Safety Studies
ALS-008176 demonstrated similar in vitro antiviral activity against the closely related 
Pneumoviridae virus family members hMPV and RSV.16 Currently, no studies evaluating the 
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efficacy of ALS-008176 for the treatment of hMPV infection in hospitalized adult subject are 
available. Information from RSV-related studies is therefore reported. Based on the in vitro 
results, the safety profile of ALS-008176 is expected to be similar in hospitalized adult subjects
infected with RSV and in those infected with hMPV.
The efficacy of ALS-008176 in naturally RSV-infected subjects has not yet been demonstrated; 
however, it has been assessed in healthy adult subjects infected with RSV in a human challenge 
model (Study ALS-8176-502). In this study, 62 subjects were administered a nasal inoculation of 
RSV-A Memphis 37b virus on Study Day 0 and then monitored from Study Day 2 to 5 for the 
presence of RSV infection using a qualitative polymerase chain reaction (PCR) assay in nasal 
washes collected twice daily. Twelve hours after RSV detection by qualitative PCR, or at Day 6 
for subjects who did not have an RSV positive result by qualitative PCR by the evening of Study 
Day 5, subjects were randomized and administered the first dose of study drug. Subjects were 
randomized to receive 5 days treatment with placebo or with 1 of the 3 lumicitabine dosing 
regimens: 750 mg LD/500 mg MD Q12h, 750 mg LD/150 mg MD Q12h, or 375 mg Q12h. 
Respiratory syncytial virus viral load was measured using a quantitative reverse transcriptase-
polymerase chain reaction (qRT-PCR) assay in nasal washes collected twice daily from Study 
Day 2 through 12 and once daily on Study Day 16 and 28. Data from this study demonstrate that 
MDs of 150 and 500 mg of ALS-008176, following a 750 mg LD, resulted in rapid, substantial 
declines in RSV viral load with an accompanying comparable improvement in signs and 
symptoms of RSV infection compared with placebo-treated subjects. There was a statistically 
significant difference in RSV AUC in subjects treated with 375 mg Q12h compared with placebo 
but the effect was more pronounced when the regimens included a LD.
For Study ALS-8176-503 in hospitalized pediatric subjects with RSV infection, RSV viral load 
data are available from a snapshot analysis for the 40 mg/kg LD/20 mg/kg MD cohort (N=12 
lumicitabine and N=5 placebo) and the 60 mg/kg LD/40 mg/kg MD cohort (N=5 lumicitabine 
and N=0 placebo). A steeper slope of RSV RNA decline is observed in both active treatment 
arms compared to the placebo arm during the first 3 days of treatment, with at Day 3 a mean 
change from baseline in RSV RNA of -2.6 log10 PFUe/mL in both the active treatment arms 
compared to -1.2 log10 PFUe/mL in the placebo arm. In the 60 mg/kg LD/40 mg/kg MD 
treatment arm the mean viral load appeared to increase again at Day 4 and 5; however, the 
number of subjects with RSV RNA data available in this analysis is limited, hence conclusions 
cannot be made. 
Safety and Tolerability
Healthy Adult Subjects
Data from 8 Phase 1/2a studies (ALS-8176-501, ALS-8176-502, ALS-8176-504, ALS-8176-509, 
64041575RSV1001 
[ALS-8176-511], 
64041575RSV1002, 
64041575RSV1003, 
and 
64041575RSV1005), in healthy adult subjects (N=300, for 447 exposures to ALS-008176), 
indicate that ALS-008176 was well tolerated and that no safety concerns were identified, after 
receiving ALS-008176 as single doses up to 3,000 mg or as multiple doses up to 750 mg twice 
daily on Day 1 followed by up to 500 mg Q12h MDs for up to 13 days. No deaths, serious 
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adverse events (SAEs) or adverse events (AEs) leading to study drug discontinuation considered 
to be at least possibly related to ALS-008176 reported. All AEs were mild or moderate in 
severity, except for 3 events, all of which were severe. Two of these severe events were 
asymptomatic laboratory abnormalities (increased alanine aminotransferase [ALT] and increased 
blood creatine phosphokinase) and occurred in Study ALS-8176-502; neither event was 
considered related to ALS-008176. The third severe AE (increased cholesterol) occurred in 
Study 64041575RSV1001 (ALS-8176-511; single ascending dose [SAD] study in healthy 
Japanese adult subjects) on Day 14 after the subject received a single oral dose of ALS-008176
(750 mg) on Day 1 and was considered possibly related to ALS-008176. Among healthy adult 
subjects receiving multiple doses of ALS-008176, the most commonly reported AEs (ie, ≥2% of 
subjects in any of the treatment groups) that occurred more often in ALS-008176-treated versus 
placebo-treated subjects were: epistaxis, ALT increased, headache, oropharyngeal pain, platelet 
count decreased, and upper respiratory tract infection. No clinically concerning findings for any 
laboratory parameter were reported.
No prolongation of the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF) of clinical or regulatory concern was noted in Study 64041575RSV1003.
Hospitalized Adult Subjects with RSV Infection
Data is available from 2 Phase 2a/b studies (ALS-8176-510 and 64041575RSV2003) in 
hospitalized adult subjects with RSV infection. 
A total of 9 subjects were enrolled in Study ALS-8176-510, of which 6 subjects received 
ALS-008176 as a single 750 mg LD followed by 500 mg MDs twice daily for 5 days. All AEs 
were mild or moderate in severity, apart from one non-serious Grade 4 hematologic AE 
(neutropenia, laboratory Grade 4) reported in an adult hospitalized subject with RSV infection. 
The subject had a relevant past medical history including anxiety disorder, chronic obstructive 
pulmonary disease, depression, and past infections including cellulitis, pneumonia, and urinary 
tract infection. Some of the subject’s concomitant medications could be associated with 
neutropenia, including acetylsalicylic acid, augmentin, and metoprolol. The event started 
approximately 23 days after the last dose of ALS-008176 (750 mg LD/500 mg MD twice daily) 
and was considered possibly related to ALS-008176 by the investigator. One subject in the 
ALS-008176 group had an SAE of abdominal pain that was considered not related to the study 
drug. Enrollment in this study was stopped, as it was decided to perform a Phase 2b dose-finding 
study (64041575RSV2003) instead of a study with a single dose level of ALS-008176.
The Phase 2b Study 64041575RSV2003 was initially designed as a 1-part study to investigate 
the dose-response relationship of a ALS-008176 dose regimen of 750 mg LD/250 mg MD twice 
daily and 1,000 mg LD/500 mg MD bid. A Grade 3 SAE of pancytopenia (laboratory Grade 4) 
that started 2 days after the last dose of ALS-008176 (1,000 mg LD/500 mg MD twice daily) was 
reported in an adult subject with a medical history of pneumonia, bronchiectasis, anemia, 
emaciation, and non-tuberculous mycobacteriosis. The event was considered probably related to 
ALS-008176 by the investigator. This subject had a decreased renal function and concomitant 
medications that could decrease the renal clearance of lumicitabine, and was found to have 
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ALS-008112 plasma exposures (Day 1 AUC0-24h=37,400 ng.h/mL) higher than predicted by the 
initial popPK model. Consequently, the study was temporarily halted (with N=2, 1 subject on 
ALS-008176 and 1 subject on placebo, further defined as Part 0), and adapted into a 2-part study. 
Part 1 of Study 64041575RSV2003 was created to characterize the PK in the low-dose arm of 
750 mg LD/250 mg MD ALS-008176, to confirm the popPK model derived from healthy 
volunteers in hospitalized adults with RSV infection, and to more clearly define the study 
eligibility criteria to ensure subject safety. Furthermore, the safety and tolerability of this 
regimen was investigated before proceeding to Part 2 of the study which includes the high-dose 
arm of 1,000 mg LD/500 mg MD ALS-008176.
As of 02 January 2018, 24 subjects had been randomized in Part 1 of Study 64041575RSV2003 
(15 on ALS-008176 750 mg LD/250 mg MD twice daily and 9 on placebo). Safety analysis was 
performed on data collected from these subjects up to 16 January 2018, including the subject on 
placebo from Part 0 of the study, resulting in a safety set of 25 subjects. The subject treated with 
ALS-008176 in Part 0 was not included in the analysis due to the different dose and the different 
inclusion criteria used in Part 1. All AEs were considered mild to moderate. Adverse events 
reported in at least 12% of subjects in any group were chest pain (muscular), myalgia, rash, 
headache, ALT increased, hepatic function abnormal, and insomnia. Two subjects in the ALS-
008176
group discontinued treatment due to an AE (rash [1 subject] and alanine 
aminotransferase increased [Grade 3 elevated ALT, 1 subject, concomitant to a Grade 1 
elevation in aspartate aminotransferase (AST)]), which were considered mild in nature in both 
cases. The elevations in ALT and AST were isolated, reversible, asymptomatic, and not 
associated with concomitant elevations in bilirubin. All AEs resolved during the study period and 
no severe grade AEs or fatal events were reported. No AEs with regards to neutrophils or other 
laboratory hematologic parameters, and no cases of graded neutropenia were observed. One 
subject in both treatment groups had an SAE in the follow-up period, considered not related to 
study medications (chronic obstructive pulmonary disease [COPD]) for the subject on 
ALS-008176, and thermal burn and cardiac failure for the subject on placebo).
Hospitalized Pediatric Subjects with RSV Infection
Data is available from 1 Phase 1b first-in-infant study (ALS-8176-503) and 1 Phase 2b study 
(64041575RSV2004) in hospitalized pediatric subjects with RSV infection. The clinical phase of 
Study ALS-8176-503 has been completed, but the database has not yet been locked.
Seventy pediatric subjects were treated in the SAD part of Study ALS-8176-503. Fifty-
three subjects received single doses of ALS-008176 up to 25 mg/kg and 17 subjects received 
placebo. All AEs were of mild or moderate severity, except for 1 ≥Grade 3 SAE of bacterial 
pneumonia which was considered unrelated to the study drug.
In the MAD part of Study ALS-8176-503, 111 pediatric subjects were treated, of which 
78 received multiple doses of ALS-008176 up to a 60 mg/kg LD followed by 40 mg/kg MDs 
twice daily, and 33 subjects received placebo twice daily. All AEs were of mild or moderate 
severity, except for 6 Grade ≥3 AEs of neutropenia (N=2 Grade 3 and N=4 Grade 4), 1 Grade 3 
AE of respiratory failure, and 1 Grade 3 AE of anemia. Four SAEs were reported: lymphadenitis, 
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neutropenia, bronchiolitis, and respiratory failure. Only the Grade 4 SAE of neutropenia 
(laboratory Grade 4) reported within 17 hours after the first dose of ALS-008176 (40 mg/kg 
LD/20 mg/kg MD twice daily) was considered possibly related to the study drug, and resulted in 
premature discontinuation of the study drug after the second MD. The subject experiencing a 
Grade 3 SAE of respiratory failure presented also a Grade 2 bacterial pneumonia, and was 
discontinued from the study on Day 2. 
In Study 64041575RSV2004, a Grade 4 SAE of febrile neutropenia (laboratory Grade 4) that 
started 1 day after the last dose of study treatment was reported in a pediatric subject. The event 
was considered possibly related to the study drug by the investigator.
1.2.
Rationale for the Study
RSV is associated with considerable morbidity and mortality, particularly at the extremes of age
(ie, infants and elderly). In the United States alone, among patients >65 years of age, 
177,000 hospitalizations and approximately 14,000 deaths per year are attributable to RSV 
infection.7 In other countries, the 60-day mortality rate for adults hospitalized with RSV 
infection has been observed to be as high as 13.8%.14 There are currently no approved treatments 
or vaccines to prevent RSV infection in adults. As such, there is a significant unmet medical 
need for an RSV therapeutic.
This study is designed to determine the antiviral activity, clinical outcomes, safety, tolerability, 
and PK of multiple ALS-008176 dosing regimens in a population of hospitalized adults naturally 
infected with RSV. The study will be performed in 2 parts. In Part 1, the PK will be 
characterized in the low-dose arm of 750 mg LD/250 mg MD ALS-008176. Furthermore, the 
safety and tolerability of this regimen will be investigated before proceeding to Part 2 of the 
study which will include the high-dose arm of 1,000 mg LD/500 mg MD ALS-008176. In Part 2, 
the dose-response relationship of the 750 mg LD/250 mg MD and the 1,000 mg LD/500 mg MD 
ALS-008176 dosing regimens on antiviral activity will be evaluated. The results of this study 
will assist in determining the design for subsequent studies in a similar RSV-infected adult
population.
Note that, as per Amendment 2, the study will be performed in 2 parts. The 2 subjects (1 on 
ALS-008176 and 1 on placebo) that were enrolled before the study was temporarily halted, are 
defined as Part 0. For details, refer to Section 1.1 Background, page 42.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objectives
For Part 1:
The primary objective is to characterize the PK and to confirm the popPK model derived from 
healthy volunteers in hospitalized adults who are infected with RSV.
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For Part 2:
The primary objective is to determine in hospitalized adults who are infected with RSV the 
dose-response relationship of multiple regimens of ALS-008176 on antiviral activity based on 
nasal RSV shedding using qRT-PCR assay.
Secondary Objectives
The secondary objectives for Part 1 and Part 2 are to determine in hospitalized adults who are 
infected with RSV:

The safety and tolerability of ALS-008176.

The impact of ALS-008176 on the clinical course of RSV infection including:

Duration of hospital stay.

Duration of supplemental oxygen.

Evolution of Activities of Daily Living (ADL) as assessed by Katz ADL score.

Time to clinical stability.

Improvement on the ordinal scale.

Rate of mortality and complications.

The antiviral activity based on nasal RSV shedding using qRT-PCR assay (secondary for 
Part 1 only) and the time to cessation of nasal RSV shedding.

The impact of ALS-008176 on the emergence of resistant strains of RSV.

The PK of ALS-008112 and ALS-008144 (and other metabolites, if applicable) in plasma.

The relationship between the PK and pharmacodynamics (PD; antiviral activity, clinical 
symptoms, and selected safety parameters) after single (LD) and repeated oral dosing (MD) 
of ALS-008176.
Exploratory Objectives
The exploratory objectives for Part 1 and Part 2 are to evaluate in hospitalized adults who are 
infected with RSV:

The relationship between viral kinetics and clinical outcome, including the relationship 
between RSV RNA viral load and:

Oxygen supplementation.

Duration of hospitalization.

Katz ADL score.

Clinical stability.

The impact of the baseline viral subtype and genotype on the antiviral activity.

Onset of complications after initiation of treatment.
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
The impact of ALS-008176 on the clinical course of RSV during and following 
hospitalization as assessed by the subject in the electronic Clinical Outcome Assessment 
(eCOA) using various scoring systems.

The impact of RSV and its treatment on health-related quality of life (HRQoL) as assessed 
by the subject in the eCOA.

The relationship between the Katz ADL score and the subject eCOA responses.

Medical resource utilization to manage subjects.

The comparison of the RSV RNA viral loads measured in mid-turbinate nasal swabs and 
endotracheal samples from intubated subjects.

To explore the evolution of diffusing capacity of the lung for carbon monoxide (DLCO) and 
spirometry in subjects hospitalized with RSV infection.
Additionally, the impact of ALS-008176 on the infectious viral load may be evaluated using a 
quantitative culture of RSV (plaque assay) on a selected number of subjects and samples
(mid-turbinate nasal swabs [if non-intubated] or mid-turbinate nasal swabs and endotracheal 
samples [if intubated]) at the sponsor’s discretion.
2.1.2.
Endpoints
Primary Endpoints
For Part 1:
The primary endpoint is the PK of ALS-008112 and ALS-008144 (and other metabolites, if 
applicable) in plasma.
For Part 2:
The primary endpoint is RSV RNA viral load (measured by qRT-PCR in the mid-turbinate nasal 
swab specimens) AUC from immediately prior to first dose of study drug (baseline) until Day 7.
Secondary Endpoints
The secondary endpoints for Part 1 and Part 2 are:

Safety/tolerability including AEs, physical examinations, vital signs, ECGs, and clinical 
laboratory results

RSV clinical course endpoints:

Length of hospital stay from admission to discharge and from study treatment initiation 
to discharge.

Length of hospital stay from admission to readiness for discharge and from study 
treatment initiation to readiness for discharge, with readiness for discharge defined by 
the investigator.

Need for and duration of intensive care unit (ICU) stay.

Need for and duration of supplemental oxygen (regardless of method used).
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
Number of hours until peripheral capillary oxygen saturation (SpO2) ≥93% on room air 
among subjects who were not on supplemental oxygen prior to the onset of respiratory 
symptoms.

Respiratory rate, SpO2, and body temperature return to pre-RSV disease level.

Need for and duration of noninvasive ventilator support (eg, continuous positive airway 
pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation or 
mechanical ventilation via tracheostomy).

Time to return to pre-RSV functional status (Katz ADL score).

Need for hydration and feeding by IV catheter/nasogastric tube.

Time to clinical stability defined as the time at which the following criteria are all met:
o
normalization of blood oxygen level (return to baseline; by pulse oximetry) without 
requirement of supplemental oxygen beyond baseline level
o
normalization of oral feeding
o
normalization of respiratory rate
o
normalization of heart rate

Improvement on the ordinal scale.

All-cause mortality.

RSV RNA viral load as measured by qRT-PCR of the mid-turbinate nasal swab specimens 
which will be used to determine the following:

Viral load over time.

Peak viral load, time to peak viral load, rate of decline of viral load, and time to RSV 
RNA being undetectable.

Proportion of subjects with undetectable viral load at each time point.

The RSV RNA viral load AUC from immediately prior to first dose of study drug 
(baseline) until Day 7 (secondary for Part 1 only).

RSV RNA viral load AUC from immediately prior to first dose of study drug (baseline) 
until Day 10 and until Day 14.

RSV RNA viral load AUC in subjects assigned to a longer dosing duration, if dosing 
duration is increased by the IDMC, from baseline until 1 day after the last dose of study 
drug (Part 2 only).

Sequence changes (postbaseline) in the RSV polymerase L-gene and other regions (only if 
no mutations are seen in the L-gene) of the RSV genome compared with baseline sequences.

Population-derived PK parameters of ALS-008112.
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Exploratory Endpoints
The exploratory endpoints for Part 1 and Part 2 are:

The amount of:

Supplemental oxygen above pre-RSV disease level (regardless of method used) from 
study treatment initiation to Day 7.
NOTE: If the dosing duration is increased by the IDMC to up to 10 days, supplemental 
oxygen above pre-RSV disease level will be measured from treatment initiation until 
1 day after the last dose of study drug.

Oxygen delivered by noninvasive ventilator support (eg, continuous positive airway 
pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation or 
mechanical ventilation via tracheostomy).

Subjects (proportion) who started antibiotic use after the first dose of the study drug.

Disease status and presence of complications with onset after treatment initiation:

Bacterial superinfections reported as AEs (eg, pneumonia, acute otitis media, sinusitis, 
bronchitis, bacteremia).

Exacerbations of underlying pulmonary disease (eg, asthma, chronic obstructive 
pulmonary disease).

Cardiovascular and cerebrovascular events (eg, myocardial infarction, congestive heart 
failure exacerbation, arrhythmia, stroke).

Respiratory failure.

Clostridium difficile associated diarrhea.

Other RSV-related complications.

Duration and severity of signs and symptoms of RSV infection as assessed by the 
respiratory infection patient-reported outcome (RI-PRO) questionnaire and additional 
questions about health and functioning completed by the subject in the eCOA.

HRQoL assessed by the EuroQoL 5 Dimension 5 level version (EQ-5D-5L) completed by 
the subject in the eCOA.

Hospital readmission for respiratory reasons up to the Day 28 follow-up visit.

Medical resource utilization.

RSV RNA viral load (AUC) as measured by qRT-PCR of mid-turbinate nasal swabs and
endotracheal samples in intubated subjects.

Lung function measured by the DLCO and spirometry test.

RSV infectious viral load as measured using a quantitative viral culture (plaque assay).
Refer to Section 9 for evaluations related to endpoints.
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2.2.
Hypothesis
For Part 1, no formal hypothesis is specified. Part 1 is intended to characterize the PK in the 
low-dose arm of 750 mg LD/250 mg MD ALS-008176 and to confirm the popPK model derived 
from healthy volunteers in hospitalized adult subjects infected with RSV. Furthermore, the safety 
and tolerability of this regimen will be investigated before proceeding to Part 2 of the study 
which will include the high-dose arm of 1,000 mg LD/500 mg MD ALS-008176.
For Part 2, the primary hypothesis is that there is a positive dose-response relationship of active 
treatment on the average RSV RNA viral load AUC with the average AUC on at least 1 of the 
active treatments being lower than the average AUC on placebo.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, dose-finding
study of ALS-008176 in hospitalized adults of ≥18 years of age (or the legal age of consent in 
the jurisdiction in which the study is taking place) who are infected with RSV. The study will be 
performed in 2 parts.a
Part 1
A target of approximately 24 subjects with a maximum of 36 subjects will be randomized in a 
1:2 ratio to Regimen A or B:
•
Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10) of matching 
placebo, administered twice daily.
•
Regimen B (low-dose ALS-008176): a single 750 mg LD (Dose 1) followed by nine 250 mg 
MDs (Doses 2 to 10) of ALS-008176, administered twice daily.
The IDMC will review the safety and PK data after approximately 12 subjects have completed 
treatment as per the IDMC charter. When approximately 24 subjects have completed the Day 14 
follow-up visit, an unblinded primary analysis will be performed by the sponsor, for review by 
the IDMC. Further enrollment in this part of the study up to 36 subjects may continue while the 
data are being analyzed. Once all data for Part 1 are collected and the database locked, the 
sponsor may perform an unblinded, secondary analysis on the full dataset of Part 1, to support 
clinical development.
                                                
a
Note that, as per Amendment 2, the study will be performed in 2 parts. The 2 subjects (1 on ALS-008176 and 
1 on placebo) that were enrolled before the study was temporarily halted, are defined as Part 0. For details, refer 
to Section 1.1 Background, page 41.
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Part 2
A target of approximately 90 subjects will be randomized in a 1:1:1 ratio to Regimen A, B, or C
with approximately 30 subjects planned per treatment regimen:

Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10) of matching
placebo, administered twice daily.

Regimen B (low-dose ALS-008176): a single 750 mg LD (Dose 1) followed by nine 250 mg 
MDs (Doses 2 to 10) of ALS-008176, administered twice daily.

Regimen C (high-dose ALS-008176): a single 1,000 mg LD (Dose 1) followed by nine 
500 mg MDs (Doses 2 to 10) of ALS-008176, administered twice daily.
Each part of the study will be conducted in 3 phases: a screening phase, a treatment phase from 
Day 1 to Day 5/6 (depending on the timing of the LD administration), and a follow-up phase for 
a total of 28 days post randomization. Subjects will have assessments completed during 
hospitalization and at the Day 7, Day 10, Day 14, and Day 28 visits. Depending on discharge 
date, assessments will be completed either while hospitalized or during outpatient visits. For 
hospitalized subjects additional assessments are done as per the Time and Events Schedule. The 
duration of the subject’s participation will be approximately 28 days, screening period not 
included.
Assessments during the study will include the antiviral activity, measured by RSV RNA viral 
load using a qRT-PCR assay as well as an evaluation of the clinical course of RSV infection as 
assessed by the clinician and an evaluation of RSV disease-related signs and symptoms and 
HRQoL as assessed by the subject. Safety and tolerability, including AEs, laboratory
assessments, ECGs, physical examination, and vital signs will be assessed throughout the study 
from signing of the informed consent form (ICF) until the subject’s last study-related activity.
Pharmacokinetic assessments will be performed using a popPK model. Intensive PK sampling in 
Part 1 of this study will be used to update and confirm the popPK model that was developed 
based on the data from healthy volunteers. Based on the PK data from hospitalized adult subjects 
infected with RSV from Part 1 of this study, the PK sampling for Part 2 was optimized. The 
popPK model may be further modified or adapted as needed.
Viral sequencing analysis will be performed to identify preexisting sequence polymorphisms, to 
characterize RSV variants of the L-gene and other regions of the RSV genome if warranted, and 
to evaluate emergence of any resistance-associated mutations. Additionally, exploratory 
biomarkers may be assessed to determine the effects of ALS-008176 on markers of RSV disease.
An unblinded IDMC will be commissioned for this study and a Sponsor Committee will be 
established, refer to Section 11.12 for details. For Part 1, the IDMC will review the safety and 
PK data as described above. In Part 2, based on the reviews of PK, efficacy, and safety data, 
changes to enrollment in the treatment arms, dose regimen adjustments, or an increase in dose 
duration to up to 10 days may be implemented. In Part 2, a maximum of 2 formal interim 
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analyses are planned to assess the primary endpoint for early superiority and futility (see 
Section 11.11).
Diagrams of the study design for Part 1 and Part 2 are provided in Figure 1 and Figure 2, 
respectively.
Figure 1:
Schematic Overview of Part 1 of the Study
Abbreviations: bid: twice daily; ER: emergency room; LD: loading dose; MD: maintenance dose; 
Rand: randomization
Figure 2:
Schematic Overview of Part 2 of the Study
Abbreviations: bid: twice daily; ER: emergency room; LD: loading dose; MD: maintenance dose; 
Rand: randomization.
3.2.
Study Design Rationale
Blinding, Control, Stratification, and Treatment Regimens
There is no approved treatment routinely used for the treatment of RSV infection. A placebo 
control will be used for both parts of the study to establish the frequency and magnitude of 
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changes in virologic and clinical endpoints that may occur in the absence of active treatment. 
The use of a placebo control will allow for any AEs or laboratory abnormalities observed during 
the course of the study to be evaluated properly, ie, to be able to differentiate between events 
potentially related to the use of ALS-008176 versus those related to the underlying disease.
Randomization will be used to minimize bias in the assignment of subjects to treatment 
regimens, to increase the likelihood that known and unknown subject attributes (eg, demographic 
and baseline characteristics) are evenly balanced across treatment regimens, and to enhance the 
validity of statistical comparisons across treatment regimens. In Part 1, subjects will be 
randomized in a 1:2 ratio to receive placebo or the low-dose ALS-008176 dosing regimen. In 
Part 2, subjects will be randomized in a 1:1:1 ratio to receive 1 of the ALS-008176 regimens or 
matching placebo. For Part 1, randomization will be stratified by region (Japan versus 
non-Japan). For Part 2, randomization will be stratified by region (Japan versus non-Japan) and 
age (≥18 to <65 years and ≥65 years). Blinded treatment will be used to reduce potential bias 
during data collection and evaluation of clinical endpoints.
The number of subjects exposed as part of the study has been limited to the absolute minimum to 
reach the objectives of the study. For Part 2, the IDMC will be empowered such that if early 
superiority on the primary endpoint is established, the randomization ratio to placebo may be 
altered, thereby avoiding unnecessary risk and discomfort to placebo-treated subjects.
Doses Selected
The doses selected for this study are based on PK/PD modeling, which was developed to 
characterize the in vivo antiviral activity of ALS-008176, based on the data from the RSV 
challenge study in healthy volunteers (Study ALS-8176-502). The model was used to 
characterize the exposure-response relationships of ALS-008112. To characterize the 
exposure-response relationships, a semimechanistic model was utilized to describe the 
conversion of plasma ALS-008112 to the active NTP in lung tissue. The model was fit 
simultaneously to the PK and viral kinetic data for both placebo- and ALS-008176-receiving 
subjects from Study ALS-8176-502. A sigmoid maximum efficacy relationship described the 
NTP inhibition of RSV production. The model estimated the NTP 50% effective concentration 
and 90% effective concentration to be 1.79 μM and 2.64 μM, respectively, which is generally 
consistent with the reported in vitro half maximal inhibitory concentration (0.23 μM) and 90% 
inhibitory concentration (3 μM) against a different strain of RSV. The proposed dose regimens 
are projected to rapidly (within 1 to 2 hours following dosing) achieve and maintain lung tissue 
concentrations at least 3 times the 90% effective concentration throughout the duration of 
treatment in the majority of the subjects.
Because RSV is an acute infection, achieving therapeutic concentrations rapidly is an important 
consideration for treatment. Therefore, LD regimens were evaluated, considering not only 
achievement of the above targets, but also time to achieve these targets. To account for popPK 
variability, the probability of target attainment across the population was also considered. The 
assessment of twice daily dose regimens in the study is supported by the long in vitro 
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intracellular t1/2 of the NTP (17.6 hours in normal human bronchial epithelial cells) and the 
observed sustained levels of the NTP in monkey lungs (estimated t1/2 of approximately 29 hours).
Overall, based on the data available at the time of initial protocol writing, it is anticipated that the 
proposed doses are expected to be in the therapeutic range to optimize antiviral activity of 
ALS-008176 in adult subjects, which includes a single 750 mg LD followed by a MD regimen of 
250 mg twice daily or a single 1,000 mg LD followed by an MD regimen of 500 mg twice daily. 
At the proposed high dose of 1,000 mg LD/500 mg MD, plasma ALS-008112 exposures in 
adults are projected to be at or slightly above levels observed in healthy volunteers in the RSV 
challenge study where potent antiviral activity against RSV was noted (AUC0-24h approximately
10,000 ng.h/mL, ALS-8176-502). At the 750 mg LD/250 mg MD regimen, the projected average 
ALS-008112 plasma exposure is expected to be slightly more than 2-fold lower than the high 
dose at Day 5, which will aid in dose-response evaluation.
Simulations of the typical lung NTP exposure showed that both dose regimens rapidly achieved 
concentrations above EC90 (the highest concentration required to achieve 90% inhibition of virus 
replication across all RSV strains tested in vitro). Based on simulations, both a LD of 750 mg 
and a LD of 1,000 mg are expected to rapidly achieve the target of 3 x EC90.
In Table 5, the simulations of the projected plasma exposures for the 2 regimens are shown. The 
simulations are based upon the popPK model that was updated with additional data of Part 1 of 
Study 64041575RSV2003. 
Table 5:
Projected Plasma Exposures of ALS-008112 at the Proposed Dose Regimens
Dose (mg)
Average Plasma AUC0-24h ALS-008112 
(ng.h/mL)
Average Plasma Cmax ALS-008112 
(ng/mL)
LD
MD
Day 1 
Day 5 
Day 1 
Day 5 
750
250
9,273
6,854
1,555
657
1,000
500
13,215
12,100
2,027
1,221
Abbreviations: AUC0-24h: area under the curve from time 0 to 24 hours after dosing; Cmax: maximum plasma 
concentration.
Based on data derived from the primary analysis of Part 1 of the study, the doses to be used in 
Part 2 were confirmed to remain as planned.
Given the active nature of the ongoing development program, the IDMC may recommend that 
one of the dose regimens be removed or one or both of the dose regimens be adjusted based on 
safety and/or antiviral activity considerations from ongoing studies. Irrespective of the dose, the 
average projected ALS-008112 plasma exposure (Table 5) will not exceed a projected average 
AUC0-24h of 20,000 ng.h/mL, a limit that is 2.5-fold lower than the lowest systemic NOAEL 
observed in nonclinical toxicity studies.
Treatment Duration
Treatment will last for 5 days as this was the duration of treatment assessed in healthy adult 
subjects infected with RSV in a human challenge model (Study ALS-8176-502), which 
demonstrated substantial declines in RSV RNA viral load and improvement in RSV signs and 
symptoms. The long terminal t1/2 of the NTP is anticipated to provide therapeutic levels of the 
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active NTP beyond the 5-day dose duration. The treatment duration may be extended to up to 
10 days if recommended by the IDMC, based on emerging data from the present and other 
ongoing clinical studies with ALS-008176.
Clinical Outcomes of RSV Treatment
Treatment with ALS-008176 may reduce the severity and duration of RSV signs and symptoms 
and their impact on functioning, reduce the need for and duration of supportive care (eg, oxygen 
supplementation, IV fluids, days of hospitalization) and accelerate the subjects’ return to 
pre-RSV health status and HRQoL. The study will compare treatment regimens to evaluate the 
impact of treatment with ALS-008176 on the clinical course of RSV disease.
Biomarker Collection
Blood samples will be collected for exploratory biomarker analyses (host RNA), on the premise 
that these markers may play a role in the treatment response, PK, safety of ALS-008176, or the 
status and change of the RSV-related disease. In addition, leftover mid-turbinate nasal swabs or 
blood samples collected for other testing may be used for biomarker analysis (eg, proteins 
including cytokines) if available on the same premise. They may help to explain interindividual 
variability in clinical outcomes or to identify population subgroups that respond differently to the
drug.
Biomarker samples may be used to help address emerging issues and to enable the development 
of safer, more effective, and ultimately individualized therapies.
Biomarker analyses may be performed upon the discretion of the sponsor and will be reported 
separately from this study.
Medical Resource Utilization and Health Economics Data Collection
Treatment with ALS-008176 may result in lower utilization of hospital or outpatient healthcare 
services; therefore comparison will be done across treatment regimens.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed as soon as possible following admission to the 
emergency room or hospitalization, such that subjects are randomized within 5 days of RSV
symptom onset. Men or women ≥18 years of age (or the legal age of consent in the jurisdiction 
in which the study is taking place) diagnosed with RSV infection based on a PCR-based 
diagnostic assay (with or without co-infection with another respiratory pathogen) who have been 
(or will be) admitted to the hospital and who have signed informed consent will be enrolled.
Subjects who were admitted to the hospital for another cause but develop an acute respiratory 
illness while being hospitalized are also eligible for screening.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
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For a discussion of the statistical considerations of subject selection, refer to Section 11.2.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Criterion modified per Amendment 2:
1.1.
Criterion modified per Amendment 3:
1.2
Men or women ≥18 years of age (or the legal age of consent in the jurisdiction in 
which the study is taking place), defined at the time of randomization.
2.
Hospitalized (or in emergency room prior to hospitalization) at the time of 
randomization and unlikely to be discharged for the first 24 hours after randomization.
3.
Criterion modified per Amendment 2:
3.1.
Diagnosed with RSV infection based on PCR-based assay with or without 
co-infection 
with 
another 
respiratory 
pathogen 
(eg, influenza, 
human 
metapneumovirus, or bacteria).
NOTE: in cases where commercial PCR-based assays are not available at the 
site, the sponsor should be consulted for agreement on the assay to be used.
4.
Criterion modified per Amendment 2:
4.1.
Has an acute respiratory illness with signs and symptoms consistent with a viral 
infection (eg, fever, cough, nasal congestion, runny nose, sore throat, myalgia, 
lethargy, shortness of breath, or wheezing) with onset ≤5 days from the 
anticipated time of randomization.
NOTE: The viral infection may present in any way as long as the underlying 
precipitant of the illness is considered by the investigator to be due to RSV 
infection. Examples of such an illness include:

An upper or lower viral respiratory tract infection (eg, “flu-like illness”)

Pneumonia

Respiratory distress

Asthma exacerbation

Chronic obstructive pulmonary disease (COPD) exacerbation
5.
Criterion modified per Amendment 2:
5.1.
With the exception of the RSV disease, medically stable on the basis of medical 
history, physical examination, vital signs, and 12-lead ECG performed at 
screening. If there are abnormalities, they must be consistent with the underlying 
illness in the study population and/or the RSV infection. This determination must 
be recorded in the subject’s source documents and initialed by the investigator.
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6.
Medically stable on the basis of clinical laboratory tests performed at screening. If the
results of the serum chemistry, hematology, or urinalysis are outside the normal 
reference ranges, the subject may be included only if the investigator judges the 
abnormalities or deviations from normal do not pose an unacceptable risk to the subject, 
are not clinically significant, or are appropriate and reasonable for the population under 
study. This determination must be recorded in the subject’s source documents and 
initialed by the investigator. A single repeat laboratory evaluation is allowed for 
eligibility determination.
7.
Must sign an ICF (or their legally acceptable representative must sign) indicating that he 
or she understands the purpose of, and procedures required for, the study and is willing 
to participate in the study.
8.
Criterion modified per Amendment 2:
8.1.
A woman must have a negative urine -human chorionic gonadotropin at 
screening.
9.
Criterion modified per Amendment 2:
9.1.
Contraceptive use by women should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical 
studies.
Before randomization, a woman must be either:
a. Not of childbearing potential defined as:
o
Postmenopausal: a postmenopausal state is defined as >45 years and no 
menses for 12 consecutive months without an alternative medical cause, 
OR
o
Permanently 
sterile: 
permanent 
sterilization 
methods 
include 
hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation 
procedures (without reversal operation), and bilateral oophorectomy.
b. Of childbearing potential and, if heterosexually active,
o
Practicing a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly)
Examples of highly effective contraceptives include
- User-independent methods:
implantable progestogen-only hormone contraception associated with 
inhibition 
of 
ovulation; 
intrauterine 
device; 
intrauterine 
hormone-releasing system; vasectomized partner; sexual abstinence 
(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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- User-dependent methods:
combined 
(estrogen-
and 
progestogen-containing) 
hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, 
and 
transdermal; 
progestogen-only 
hormone 
contraception associated with inhibition of ovulation: oral and 
injectable
Typical use failure rates may differ from those when used consistently 
and correctly.
o
Agrees to remain on a highly effective method throughout the study and 
for at least 44 days after the last dose of study drug.
Note: If the childbearing potential changes after start of the study or the risk of 
pregnancy changes (eg, a woman who is not heterosexually active becomes 
active) a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
10.
Criterion modified per Amendment 2:
10.1.
Contraceptive use by men should be consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical studies.
During the study and until the end of relevant systemic exposure, plus a 
minimum of 1 spermatogenesis cycle (ie, 104 days in total) after receiving the 
last dose of study drug, a man:

Who is sexually active with a woman of childbearing potential must agree 
to use a barrier method of contraception (eg, condom with spermicidal 
foam/gel/film/cream/suppository)

Who is sexually active with a pregnant woman must use a condom

Must agree not to donate sperm
11.
Criterion modified per Amendment 2:
11.1.
Female partners of men must either be surgically sterilized, postmenopausal 
(amenorrhea for a minimum of 1 year) or, if of childbearing potential, must 
agree to practice a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly) during the study and for 104 days 
following the last dose of study drug.
12.
Criterion modified per Amendment 2:
12.1.
A woman must agree not to donate eggs (ova, oocytes) during the study and for 
at least 44 days after receiving the last dose of study drug.
13.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
14.
Subject must have a body weight 50.0 kg, at screening.
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4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Subjects who are not expected to survive for more than 48 hours.
2.
Subjects who have had major thoracic or abdominal surgery in the 6 weeks prior to 
randomization.
3.
Criterion modified per Amendment 2:
3.1.
Subjects who are considered by the investigator to be immunocompromised 
within the past 12 months, whether due to underlying medical condition (eg, 
malignancy or genetic disorder) or medical therapy (eg, medications other than 
corticosteroids for the treatment of COPD or asthma exacerbations, 
chemotherapy, radiation, stem cell or solid organ transplant).
4.
Subjects with a known history of human immunodeficiency virus (HIV) or chronic viral 
hepatitis.
5.
Subjects with ALT ≥3 times the upper limit of normal (ULN) AND bilirubin ≥2×ULN 
(direct >35%) OR ALT ≥5×ULN at screening.
6.
Criterion modified per Amendment 2:
6.1.
Subjects undergoing peritoneal dialysis, hemodialysis, or hemofiltration or with 
an estimated glomerular filtration rate (GFR, determined by Chronic Kidney 
Disease 
Epidemiology 
Collaboration 
[CKD-EPI] 
equation15)
of 
<60 mL/min/1.73m2.
 = 141 ∗ 

 , 1

∗  

 , 1
.
∗ 0.993!"# ∗ $% ∗
&'%Legend:
Min
minimum of Scr/κ or 1
max
maximum of Scr/κ or 1
Scr
serum creatinine measured in mg/dL
κ
0.7 for women, 0.9 for men
α
-0.329 for women, -0.411 for men
Age
measured in years
Sex
1.018 for women, 1 for men
Race
1.159 for black, 1 for white and other
NOTE: The IDMC may recommend to lower the exclusionary GFR limit to 
<30 or <15 mL/min/1.73m2 if any available emerging PK data in subjects with 
GFR ≥60 mL/min/1.73m2 suggest that ALS-008112 exposure in the setting of 
moderate (ie, GFR ≥30 to <60 mL/min/1.73m2) or severe (ie, GFR ≥15 to 
<30 mL/min/1.73m2) renal impairment are projected to remain within an 
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acceptable range.
In the event a local site is unable to perform a CKD-EPI determination, an 
alternative methodology for determining GFR is permissible if discussed with 
and approved by the sponsor.
7.
Known allergies, hypersensitivity, or intolerance to ALS-008176 or its excipients (refer 
to the IB).16
8.
Criterion deleted per Amendment 2
9.
Subjects unwilling to undergo mid-turbinate nasal swab procedures or with any physical 
abnormality which limits the ability to collect regular nasal specimens.
10.
Subjects unable to take medications enterally or with a known gastrointestinal-related 
condition that is considered by the sponsor or investigator to be likely to interfere with 
study drug absorption.
11.
Women who are pregnant or breastfeeding.
12.
Criterion modified per Amendment 2:
12.1.
Men who plan to father a child while enrolled in this study or within 104 days 
after the last dose of study drug.
13.
Subjects taking any disallowed therapies as noted in Section 8 before the planned first 
dose of study drug.
14.
Criterion modified per Amendment 2:
14.1.
Subjects who received prescription medications intended to prevent or treat the 
RSV infection itself (eg, ribavirin, IV immunoglobulin, palivizumab), an 
investigational drug, an investigational vaccine,
or used an invasive 
investigational medical device within 30 days or 5 half-lives (whichever is 
longer) before the planned first dose of study drug or is currently enrolled in an 
investigational study.
15.
Subjects with any condition for which, in the opinion of the investigator, participation 
would not be in the best interest of the subject (eg, compromise the well-being) or that 
could prevent, limit, or confound the protocol-specified assessments.
16.
Subjects who have used systemic corticosteroids for >7 consecutive days immediately 
prior to randomization at doses higher than 20 mg/day of prednisone or equivalent.
17.
Subject is being treated with extracorporeal membrane oxygenation.
18.
Subjects with 1 or more of the following laboratory abnormalities at screening as 
defined by the Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table (see Attachment 1):

Hemoglobin <9.5 g/dL
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
Platelet count <75,000/mm3

White blood cell count <1,000/mm³

Absolute neutrophil count <1,000/mm³
Note: Retesting of abnormal laboratory values that may lead to exclusion will be 
allowed once without asking prior approval from the sponsor. Retesting will be 
performed once within the screening window. Subjects with a normal value at retest 
may be included.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject’s clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 9.1.2 describes options for retesting. Section 17.4 describes the 
required documentation to support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Section 8 for details regarding prohibited and restricted therapy during the 
study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
inclusion and exclusion criteria (eg, contraceptive requirements).
3.
Concurrent administration of medications/use of licensed devices is allowed as 
supportive therapy per local standard of care, as long as the medication/licensed device 
will not affect the subject’s participation in the study and is in accordance with allowed 
concomitant therapy.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented for both parts of this study. Subjects will be 
randomly assigned based on a computer-generated randomization schedule prepared before the 
study by or under the supervision of the sponsor. The randomization will be balanced by using 
randomly permuted blocks. For Part 1, randomization will be stratified by region (Japan versus 
non-Japan). For Part 2, randomization will be stratified by region (Japan versus non-Japan) and 
age (≥18 to <65 years and ≥65 years).
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The interactive web response system (IWRS) will assign a unique treatment code, which will 
dictate the treatment assignment and matching study drug kit for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and will then give the relevant subject details to uniquely identify the subject.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject.
Data that may potentially unblind the treatment assignment (ie, study drug concentrations, study 
drug preparation/accountability data, treatment allocation, biomarker, or other specific laboratory 
data) will be handled with special care to ensure that the integrity of the blind is maintained and 
the potential for bias is minimized. This can include making special provisions, such as 
segregating the data in question from view by the investigators, clinical team, or others as 
appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until the unblinded IDMC review
(see Section 11.12). The blind will also be broken for the interim analyses (see Section 11.11) or 
when all subjects have completed the study and the database is finalized. The investigator may in 
an emergency determine the identity of the treatment by contacting the IWRS. While the 
responsibility to break the intervention code in emergency situations resides solely with the 
investigator, it is recommended that the investigator contact the sponsor or its designee if 
possible to discuss the particular situation before breaking the blind. Telephone contact with the 
sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the blind 
is broken, the sponsor must be informed as soon as possible. The date, time, and reason for the 
unblinding must be documented by the IWRS in the appropriate section of the electronic case 
report form (eCRF), and in the source document. The documentation received from the IWRS 
indicating the code break must be retained with the subject’s source documents in a secure 
manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations. Discontinuation of study treatment should be done only for the reasons 
stated in Section 10.2; unblinding of study treatment should not necessarily lead to study drug 
discontinuation.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, if an interim analysis is specified, the randomization codes 
and, if required, the translation of randomization codes into treatment and control groups will be 
disclosed to those authorized and only for those subjects included in the interim analysis.
6.
DOSAGE AND ADMINISTRATION
The study drug ALS-008176 will be provided as tablets for oral administration. Study drug 
administration should start as soon as possible, but no later than 4 hours after randomization in 
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order to maximize the opportunity for the compound to inhibit viral replication and potentially 
improve outcomes.
Subjects will be dosed with a single LD followed by 9 MDs twice daily (at least 8 hours apart 
and maximum 16 hours apart, with no more than 2 doses per calendar day) during Day 1 to 
Day 5/6 (depending on the timing of the LD administration). In Part 1, subjects will be 
randomized in a 1:2 ratio to Regimen A or B. In Part 2, subjects will be randomized in a 1:1:1 
ratio to Regimen A, B, or C.
Regimen Aa
Regimen Ba
Regimen Ca
Treatment 
Regimen
Placebo
Low-dose ALS-008176: 
750 mg LD/250 mg MD
High-dose ALS-008176: 
1,000 mg LD/500 mg MD
Loading 
Dose
Placebo:
1 intake of 3 tablets
ALS-008176:
1 intake of 3 x 250 mg tablet
ALS-008176:
1 intake of 2 x 500 mg tablet
Placebo:
1 intake of 1 tablet
Maintenance 
Dose
Placebo:
9 intakes of 1 tablet
ALS-008176:
9 intakes of 1 x 250 mg tablet
ALS-008176:
9 intakes of 1 x 500 mg tablet
a
Placebo tablets will be visually identical to their active drug counterparts.
Administration of each dose should occur at approximately the same time each day. ALS-008176 
can be administered without regard to food intake. The date and time of dose administration, the 
date and time of food intake (limited to the food ingested within 30 minutes before or after study 
drug administration), and the type of food will be recorded in the eCRF during hospitalization.
In case the subject is discharged prior to the completion of dosing, study drug administration will 
be continued at home until all doses are administered (Day 5/6), and the date and time of dose 
administration will be recorded in the electronic device used for eCOA. The investigator/study-
site personnel will instruct subjects on how to store the study drug for at-home use as indicated 
for this protocol.
An overdose in this study is defined as a calculated dose exceeding the planned dose.
7.
TREATMENT COMPLIANCE
Study drug will be administered enterally.
In case a dose is missed, the dose may be given up to 6 hours after the scheduled time. If more 
time has elapsed the dose should be skipped and the next dose should be given at the next 
scheduled time point per the initial dose schedule.
The investigator/study-site personnel will maintain a log of all study drug administered. Drug
supplies for each subject will be inventoried and accounted for.
In the event of the subject being discharged (after Day 2 procedures) from hospital during the 
dose period, the subject will administer study drug at home and will be required to document the 
dose of study drug in a study medication log on the electronic device provided during screening.
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The subject will receive instructions on compliance with study drug administration at the 
screening visit. During the course of the study, the investigator or designated study-site personnel 
will be responsible for providing additional instruction to re-educate any subject who is not able 
to ensure compliance with the study drug.
8.
PRESTUDY AND CONCOMITANT THERAPY
Prestudy therapies administered up to 7 days before first dose of study drug must be recorded at 
screening.
All subjects will receive supportive care according to local institution standard. While treatment 
guidelines and standards vary based on local practice and should be considered in the 
management of subjects, within the parameters of this study, it is recommended that 
supplemental oxygen can be administered or withdrawn, as appropriate to maintain an SpO2
≥93% (for subjects whose baseline SpO2 is ≥93% when clinically stable).
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study drug to the Day 28 visit (±2 days). During hospitalization, concomitant medication 
will be recorded by the site staff in the eCRF. Upon discharge, subjects will be required to 
document use of concomitant medication in the electronic device in a medication log, which will 
serve as basis for recording the concomitant medication in the eCRF by the site staff.
Concomitant therapies should also be recorded beyond Day 28 in the subject’s medical notes and 
reported by SAE forms (if applicable) only in conjunction with SAEs that meet the criteria 
outlined in Section 12.3.2.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements, home oxygen therapy; non-pharmacologic therapies such as electrical stimulation, 
acupuncture, special diets, exercise regimens) different from the study drug must be recorded in 
the eCRF. Recorded information will include a description of the type of the drug/therapy, 
treatment phase, the dose regimen, route of administration, and its indication. Modification of an 
effective preexisting chronic therapy should not be made for the explicit purpose of entering a 
subject into the study, however if a subject has received acute doses of a prohibited drug, 
switching to an alternative drug chosen at the discretion of the investigator is allowed.
Concomitant medications are permitted as indicated for the management of study subjects with 
the exception of the medications noted here. The following medications are not permitted during 
the study and for the time period prior to randomization as noted:

Moderate/strong inhibitors of OAT3: diclofenac, diflunisal, gemfibrozil, mycophenolic acid, 
piperacillin, probenecid, and teriflunomide (all within 24 hours prior to randomization until 
24 hours after the last dose of ALS-008176).

P-gp inhibitors and inducers such as, but not limited to: amprenavir, carbamazepine, 
clotrimazole, dexamethasone, fexofenadine, indinavir, morphine, nelfinavir, phenothiazine, 
retinoic acid, rifampin, ritonavir, saquinavir, and St John's wort (all within 24 hours prior to 
randomization (14 days for inducers) until 24 hours after the last dose of ALS-008176).
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
Systemic medications (either chronically [more than 14 days] or within 21 days prior to 
randomization), which are known to modulate the host’s immune response or increase viral 
shedding, such as immunomodulatory therapies, except for systemic corticosteroids as noted 
below.

Systemic corticosteroids if used for >7 consecutive days immediately prior to randomization 
at doses higher than 20 mg/day of prednisone or equivalent. Subjects meeting the eligibility 
criteria at screening but requiring increased doses of systemic corticosteroids (>20 mg/day 
of prednisone or equivalent) for a prolonged period (>7 consecutive days) during the study 
are allowed to continue participating in the study.

Prescription medications intended to prevent or treat the RSV infection itself (eg, ribavirin, 
IV immunoglobulin, palivizumab), an investigational drug, an investigational vaccine, or an 
invasive investigational medical device within 30 days or 5 half-lives (whichever is longer) 
before the planned first dose of study drug. Prescription medications intended to treat the 
symptoms/sequelae of the RSV infection are permitted.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, medical 
resource utilization, health economic, biomarker, and safety measurements applicable to this 
study.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
The eCOA will be provided to the subject at screening to record the subject’s ratings of the 
severity of the symptoms (RI-PRO), additional questions about health and functioning, and
HRQoL (EQ-5D-5L) (see Attachment 2, Attachment 3, and Attachment 4, respectively). The 
subjects will complete the eCOA once daily throughout the study from screening to Day 28 at 
approximately the same time each day. The assessment on Day 1 needs to be recorded predose, 
before the LD. If the screening assessment was performed less than 8 hours prior to the LD, the 
predose assessment does not need to be performed.
The investigator/study-site personnel will provide sufficient information (included in the study 
manual) to enable the subject to complete the eCOA and will ensure that the eCOA is completed 
correctly and on schedule to avoid missing or incorrect data. If the subject is unable to complete 
the assessment on the device, the subject’s spouse, partner, relative, friend or the 
investigator/study-site personnel trained on the eCOA device can read the questions and 
responses aloud to the subject and enter the subject’s responses in the eCOA device on the 
subject’s behalf using the interview administration procedures explained in the eCOA 
completion guide. If the subject is too ill at the time the eCOA is scheduled to be administered to 
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respond to the questions, the subject’s spouse, partner, relative, friend, or the investigator/trained 
study-site personnel should indicate the reason the eCOA was not completed on the eCOA 
device for that assessment. The investigator/study-site personnel will instruct the subject to 
complete the eCOA questionnaires and transmit the eCOA data at approximately the same time 
each day from screening through end of follow-up.
Prior to completing the screening assessment, the subject (or the subject’s spouse, partner, 
relative, or friend on the subject’s behalf) must complete a training module (included as part of 
the eCOA device) on how to enter the subject’s responses to questions in the eCOA device. If in 
the investigator’s opinion, the subject (or the subject’s spouse, partner, relative, or friend) is 
unlikely to reliably enter the information in the eCOA device on a daily basis for the duration of 
the study, the site will retain the eCOA device upon the subject's discharge and arrange for the 
investigator or trained study-site personnel to interview the subject by phone and record the 
subject’s responses in the eCOA device on the subject's behalf each day post discharge to end of 
follow-up.
The Katz ADL questionnaire (see Attachment 5) will be completed by the investigator/study-site 
personnel after interviewing the subject and the data will be entered into the eCRF by the 
investigator/study-site personnel. The Katz ADL questionnaire will be completed twice at 
screening to document retrospectively the subject’s pre-RSV infection functional status (ie, prior 
to first signs/symptoms of RSV) and the subject’s current functional status (ie, after the 
occurrence of RSV signs/symptoms). The Katz ADL questionnaire will be completed once daily 
for the entire duration of hospitalization and on Day 7, Day 10, Day 14, and Day 28 if the subject 
is discharged.
If multiple assessments are scheduled for the same time point, it is recommended that procedures 
be performed in the following sequence: noninvasive procedures should be collected first before 
invasive procedures (eCOA completion/Katz ADL
questionnaire/ECG first, then vital 
signs/SpO2, then mid-turbinate nasal swab, with blood draw last). However, mid-turbinate nasal 
swabs for RSV RNA viral load and blood collections for PK assessments should be kept as close 
to the specified time as possible. Other measurements may be done earlier than specified time
points if needed. Actual dates and times of assessments will be recorded in the source 
documentation and eCRF.
If treatment duration is extended to up to 10 days, subjects will have an additional clinic visit 
1 day (+2 days) after their last dose.
Medical resource utilization and health economics data will be collected. Refer to Section 9.6, 
for details.
The maximum amount of blood drawn from each subject in this study will not exceed 110 mL.
9.1.2.
Screening Phase
The procedures specified in the Time and Events Schedule will only be performed after written 
informed consent has been obtained. Screening may be conducted in part via a sponsor- and 
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Independent Ethics Committee (IEC)/Institutional Review Board (IRB)-pre-approved non-study 
specific screening consent process, but only if these pre-screening procedures are identical to the 
per protocol screening tests and are within the 48 hours window prior to screening completion. 
However, no study specific procedures, other than screening assessments, will be performed 
until the subject has signed the study-specific ICF. The non-study specific ICF will be 
considered source data.
Screening should be completed as soon as possible and the subject will be randomized within 
5 days of RSV symptom onset to ensure the eligibility of the subject. Procedures that are 
standard of care and performed within approximately 48 hours prior to randomization may be 
used in determining study eligibility or determining baseline values. The results of the safety 
laboratory tests performed at the local laboratory must be in accordance with Section 4. The 
investigator may consider the subject eligible if the previously abnormal laboratory test result is 
within normal range on a repeat testing in the local laboratory. Repeat testing is only allowed 
once.
During screening 1 mid-turbinate nasal swab (if non-intubated) or 1 endotracheal sample (if 
intubated) will be collected and aliquoted for:

RSV diagnosis using a PCR-based assay (at the local laboratory).

RSV diagnosis confirmation using a PCR-based assay (at the central laboratory).

Examination of viral and bacterial co-infection using multiplex PCR (at the central 
laboratory).

Leftover mid-turbinate nasal swabs will be stored and may be used for biomarker research if 
warranted. Details on the purpose of the biomarker research are described in Section 9.5.
9.1.3.
Double-blind Treatment Phase
Assessments to be performed during the treatment phase are specified in the Time and Events
Schedule.
Day 1/Day of Randomization
Eligible subjects will be randomized on Day 1. Study drug administration should start as soon as 
possible, but no later than 4 hours after randomization. Subjects will be dosed with a single oral 
LD on Day 1. Depending on the time of screening/enrollment, subjects will receive the first MD
of study drug on Day 1. Subjects will receive no more than 2 doses per calendar day.
Assessments to be performed on Day 1 are specified in the Time and Events Schedule. The local 
nasal swab sample can be used as the screening sample for the study if it fulfills the sample 
requirements for nasal swabs collected for study assessments. If the local sample or screening 
sample was taken less than 8 hours prior to the administration of the LD, the predose sample 
assessment (Day 1 swab) does not need to be performed. The mid-turbinate nasal swab (if non-
intubated) or the mid-turbinate nasal swab and endotracheal sample (if intubated) should be 
taken as close as possible to and before the LD on Day 1. The timing of the LD will determine 
the timing of the nasal swab and endotracheal sample (if intubated). If the LD is in the morning, 
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all samples will be taken before the morning dose; if LD is in the afternoon, all samples will be 
taken before the afternoon doses but after the morning dose (Figure 3). 
Figure 3:
Two Scenarios for the Timing of Collection of Nasal Swabs and Endotracheal Samples (if 
Intubated)
Green dots represent study drug administration. 
Red stars represent collection of nasal swab, and of endotracheal sample, if intubated.
Day 2 to Day 5/6 (End of Treatment)
Study drug administration continues until 10 doses have been taken. Subjects will receive 9 MDs 
without regard to food intake twice daily (at least 8 hours apart and maximum 16 hours apart, 
with no more than 2 doses per calendar day) through Day 5/6 (depending on the timing of the LD
administration). The date and time of dose administration, the date and time of food intake 
(limited to the food ingested within 30 minutes before or after study drug administration), and 
the type of food will be recorded in the eCRF during hospitalization. The subject may be 
discharged after Day 2 following completion of study procedures. Subjects may also remain 
hospitalized if warranted by the subject’s clinical status. In case the subject is discharged prior to 
the completion of treatment, study drug will continue to be administered at home by the subject 
until all doses are administered (Day 5/6), and the date and time of dose administration will be 
recorded in the electronic device used for eCOA. Instructions will be given to the subject 
regarding drug administration by the investigator or a qualified member of the study-site 
personnel.
Assessments will be performed as detailed in the Time and Events Schedule. The eCOA 
(investigator and subject questionnaires) and the mid-turbinate nasal swabs (if non-intubated) 
(from the same nostril throughout the study) or the mid-turbinate nasal swab and endotracheal 
samples (if intubated) are to be taken once daily prior to study drug administration at 
approximately the same time each day (see (Figure 3). In case of nostril bleeding or irritation 
during the collection of a mid-turbinate nasal swab, all subsequent nasal swabs will be performed 
on the contralateral nostril. Samples will be collected through Day 6 whether the subject is in 
hospital or has been discharged. Should the study drug duration be increased to up to 10 days 
(following review of the data by the IDMC), samples will be taken every day up to and including 
1 day (+2 days) following the last dose of study drug. In case mid-turbinate nasal swabs are 
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collected at home, the subject (or the subject’s spouse, partner, relative, or friend) should collect 
swab specimens after being trained by the investigator/study-site personnel. Subjects will be 
required to document the actual dates and times of collection of the nasal swab at home on the 
electronic device used for eCOA. Nasal swabs collected at home should be stored immediately 
between 2°C and 8°C (in the refrigerator) and brought to the site at the next visit.
Hospitalization duration will not be extended solely for study purposes. Telephone calls to the 
subjects to facilitate compliance with study procedures between outpatient study visits are 
permitted.
9.1.4.
Posttreatment Phase (Follow-up)
Days 7 to 28
Subjects will be evaluated for a total of 28 days after randomization. If they are not hospitalized 
they will be required to return to the hospital for follow-up assessments as an outpatient on 
Day 7, Day 10, Day 14, and Day 28 as indicated in the Time and Events Schedule. On Day 28 all 
subjects will complete the study either as an inpatient or outpatient.
Should the study drug duration be increased to up to 10 days (following review of the data by the 
IDMC, refer to Section 11.12), additional study drug may be provided, if needed.
If a subject is discontinued from study drug, a follow-up visit will be scheduled 2 days (+2 days), 
5 days (+2 days), 9 days (+2 days), and 23 days (±2 days) after the last dose of study drug was 
administered. Assessments should be performed as indicated in the Time and Events Schedule, 
respectively for the Day 7, Day 10, Day 14, and Day 28 visits.
9.2.
Efficacy Evaluations
Viral Load Determination
As an evaluation of antiviral activity of ALS-008176, RSV RNA viral load will be measured in 
mid-turbinate nasal swabs (obtained from non-intubated subjects) or in mid-turbinate nasal 
swabs and endotracheal samples (obtained from intubated subjects or via suction through 
tracheostomy or other sampling methods) using qRT-PCR performed at the central laboratory. 
Samples for the determination of RSV viral load will be taken as specified in the Time and
Events Schedule and Section 9.1.3.
RSV infectious viral load may be measured in mid-turbinate nasal swabs (if non-intubated) or in 
mid-turbinate nasal swabs and endotracheal samples (if intubated) using a quantitative culture 
method (plaque assay) in a selected number of subjects and samples at the sponsor’s discretion.
Changes in viral load will be evaluated but will not be regarded as AEs or SAEs.
Viral L-gene Sequencing for Viral Resistance
Viral sequencing analysis will be performed by sequencing the polymerase L-gene and other 
regions of the RSV genome (may be performed if no mutations are seen in the L-gene) in 
samples taken before treatment (at baseline), during treatment, and posttreatment, to identify 
preexisting sequence polymorphisms and to characterize emerging RSV variants.
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The L-gene will be sequenced pretreatment in all subjects and postbaseline in subjects not 
achieving viral suppression. The sequencing of postbaseline samples may be triggered at the 
discretion of the sponsor’s virologist, based on the changes in RSV RNA viral load observed in 
each individual subject and the limits of the sequencing assay. The impact of newly identified 
mutations on in vitro antiviral activity of ALS-008176 or other RSV molecules may be assessed 
in in vitro studies.
Other regions of the RSV genome may also be sequenced at the sponsor’s discretion. 
Changes in the viral sequence will be evaluated but will not be regarded as AEs or SAEs.
Clinical Course of RSV Infection
The study will include the following evaluations of the clinical course of RSV infection:

Clinical evaluation including, but not limited to:

Oxygen requirement type (eg, supplemental oxygen, noninvasive positive pressure 
ventilation, 
endotracheal-mechanical 
ventilation, 
mechanical 
ventilation 
by 
tracheostomy), duration, and amount.

Body weight.

Respiratory rate, heart rate, systolic blood pressure (SBP), diastolic blood pressure 
(DBP), and body temperature (method should be noted in the eCRF).

SpO2.

Level of hospital care (eg, ICU, transitional care unit, ward floor).

Duration of hospitalization.

Need for hydration, and feeding by IV catheter/nasogastric tube.

Functional status (Katz ADL score).
Subject Evaluation

Evaluation of RSV disease-related signs and symptoms and additional questions about 
health and functioning.

HRQoL (EQ-5D-5L).
9.3.
Pharmacokinetics
Plasma samples will be used to evaluate the PK of ALS-008112 and ALS-008144 (and other 
metabolites, if applicable). Samples collected for PK may additionally be used to evaluate safety 
or efficacy aspects that address concerns arising during or after the study period. DNA analyses 
will not be performed on these samples. Subject confidentiality will be maintained.
9.3.1.
Evaluations
Plasma 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 
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of indwelling catheters. The exact time of sample collection will be noted on the source 
document and the data collection tool.
Additional 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, at the discretion of the investigator or at the request of the sponsor.
Additional information about the collection, handling, and shipment of biologic samples can be 
found in the laboratory manual.
9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of ALS-008112 and ALS-008144 
(and other metabolites, if applicable) using a validated, specific, and sensitive liquid 
chromatography/mass spectrometry method by or under the supervision of the sponsor.
To maintain the study blind during the study, results of the individual PK analyses will not be 
shared with the investigator or sponsor representatives directly involved in managing the study.
9.3.3.
Pharmacokinetic Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of ALS-008112 will be derived 
using popPK modeling. The estimated model parameters and individual post hoc exposure 
parameters (AUC, Cmin, Cmax) will be provided for each subject as appropriate. Baseline 
covariates (eg, body weight, age, sex, creatinine clearance, race) may be included in the model, if 
relevant.
Intensive PK sampling in Part 1 of this study will be used to update and confirm the popPK 
model that was developed based on the data from healthy volunteers. Based on the PK data from 
hospitalized adult subjects infected with RSV from Part 1 of this study, the PK sampling for 
Part 2 was optimized. The popPK model may be further modified or adapted as needed.
Exposure estimates (AUC24h, C0h, Cmax) will be obtained by empirical Bayesian feedback using 
the popPK model for ALS-008112 to assess the appropriateness of the PK and the selected 
doses, throughout the conduct of the study. Plasma concentration data versus time after dose of 
each individual will be plotted. A previously developed popPK model based on adult data from 
several studies will be used to overlay with the raw data. If the data fall outside the prediction 
interval of the model, the model will be updated. Furthermore, potential covariates (not present 
in the previously developed model) will be investigated graphically and can be included into the 
popPK model based on a significant decrease in objective function using the likelihood ratio test 
for nested models.
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9.4.
Pharmacokinetic/Pharmacodynamic Evaluations
The relationship between the PK and PD (antiviral activity, clinical outcomes, and selected 
safety parameters) after single and repeated oral administration of ALS-008176 will be 
evaluated.
9.5.
Biomarkers
Blood samples will be collected for exploratory biomarker analyses (host RNA), on the premise 
that these markers may play a role in the treatment response, PK, safety of ALS-008176, or the 
status and change of the RSV-related disease. In addition, leftover mid-turbinate nasal swabs or 
blood samples collected for other testing may be used for biomarker analysis (eg, proteins 
including cytokines) if available on the same premise.
Analyses of biomarkers may be conducted at the sponsor’s discretion and reported separately 
from this study.
No human DNA analyses will take place on these samples.
9.6.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data, associated with medical encounters, will 
be collected by the investigator and study-site personnel for all subjects throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be 
used to conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient).

Duration of hospitalization (total days length of stay, including duration by wards
[eg, ICU]).

Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications).

Need for, and duration of, nursing home or health services from baseline to Day 28.
9.7.
Safety Evaluations
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards 
until the last study-related activity (end of study/early withdrawal).
An IDMC will be established for this study to monitor the safety of subjects. Details regarding 
the IDMC are provided in Section 11.12.
Any clinically relevant changes occurring during the study must be recorded in the AE section of 
the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
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Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, ECGs, physical examinations, clinical laboratory tests, and other safety 
evaluations at specified time points as described in the Time and Events Schedule.
In the event that an invasive procedure such as a blood draw, mid-turbinate nasal swab, vital 
signs assessments, and/or ECG are required at the same time, the order of completion should be 
ECG first, then vital signs/SpO2, then mid-turbinate nasal swab, then blood draw, with the 
mid-turbinate nasal swab and blood draw being obtained as close to the scheduled time as 
possible.
Adverse Events
Adverse events will be reported by the subject or the subject’s legally acceptable representative 
for the duration of the study. Adverse events will be followed by the investigator as specified in 
Section 12.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected and analyzed by a local 
laboratory. The investigator must review the laboratory results, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.
The following tests will be performed by a local laboratory as initiation of treatment is 
time-critical:
Hematology Panel
-hemoglobin
Percentage and absolute counts of:
-hematocrit
-basophils
-mean corpuscular hemoglobin 
-eosinophils
-mean corpuscular hemoglobin concentration
-lymphocytes
-platelet count
-monocytes
-red cell distribution width
-neutrophils
-reticulocytes
-RBC count
-white blood cell (WBC) count
Serum Chemistry Panel
-alkaline phosphatase
-creatinine
-ALT
-creatine kinase
-AST
-glucose
-bicarbonate (optional)
-potassium
-blood urea nitrogen 
-sodium
-chloride
-total (direct and indirect) bilirubin
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Urinalysis
Dipstick
Sediment (if dipstick result is abnormal)
-specific gravity
-RBCs
-pH
-WBCs
-glucose
-epithelial cells
-protein
-crystals
-blood
-casts
-ketones
-bacteria
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
Dipstick will be performed as per the Time and Events Schedule. If dipstick is abnormal, 
microscopic evaluation should be performed, with evaluation of sediment as listed above.
In the microscopic examination, observations other than the presence of WBCs, RBCs, and casts 
may also be reported by the laboratory and need to be captured in the eCRF.
Other:

Calculation of estimated GFR (CKD-EPI equation).

Urine pregnancy testing for all female subjects.
Sites should attempt to collect all safety labs as defined in this protocol. In some instances, 
individual laboratory assessments are not routinely run at a local site. If it is not practical to 
obtain the results for a particular assessment due to local considerations, the sponsor study 
responsible physician or delegate may on a case by case basis permit individual sites to not 
collect that assessment.
Electrocardiogram
In Part 1 of the study, triplicate 12-lead ECGs (three 10-s recordings at approximately 60-s 
intervals) will be collected and analyzed by a central laboratory at screening, on Day 1, on 
Day 7, on Day 28, and when clinically indicated. On Day 1, triplicate ECGs will be collected at 2 
time points: approximately 30 to 60 minutes and 3 to 6 hours after the LD. If an ECG is 
abnormal at Day 7, an additional ECG should be performed at Day 14.
In Part 2 of the study, a single 12-lead ECG will be collected and analyzed by a central 
laboratory at screening, on Day 4 (for subjects who remain hospitalized at this time), on Day 28, 
and when clinically indicated. If discharged earlier than Day 4, the subject needs to have an ECG 
recorded on the day of discharge. The ECG will be performed 30 minutes to 3 hours after the 
first dose of study drug of that day.
During the collection of ECGs, subjects should be in a quiet setting without distractions 
(eg, television, cell phones). Subjects should rest in a supine position for at least 5 minutes 
before ECG collection and should refrain from talking or moving arms or legs. If blood sampling 
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or vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, SpO2, mid-turbinate nasal 
swabs, blood draw.
Electrocardiograms may be repeated at the investigator’s discretion to account for erroneous 
readings.
Clinically relevant abnormalities (as defined in Attachment 6) occurring during the study should
be recorded by the investigator in the AE section of the eCRF.
Vital Signs
Temperature, heart rate, respiratory rate, SBP, and DBP (methods to be noted in the eCRF) are to 
be collected at the time points specified in the Time and Events Schedule.
Blood pressure and heart rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
Blood pressure and heart rate measurements should be preceded by at least 5 minutes of rest in a 
sitting or supine position and in a quiet setting without distractions (eg, television, cell phones).
They should not be performed immediately following the administration of beta-mimetics or any 
supportive drug, which could affect the measurement.
Clinically relevant abnormalities (as defined in Attachment 6) occurring during the study should 
be recorded by the investigator in the AE section of the eCRF.
Physical Examination
A complete physical examination (including all body systems, height [only at screening], and 
body weight measurement) or a directed physical examination including respiratory system, 
nose, ear, throat, facial and neck lymph nodes, and skin examination will be performed at the 
visits indicated in the Time and Events Schedule.
A skin examination includes an examination of the mucous membranes, but does not include a 
vaginal or rectal examination. However, if the subject develops a cutaneous reaction/rash, 
vaginal and rectal examinations may be done if clinically relevant.
The investigator must review the physical examination results, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the eCRF.
9.7.1.
Specific Toxicities
Subjects reporting skin changes or subjects with laboratory parameter changes should be 
followed until resolution of the toxicity and necessary standard management should be 
undertaken.
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Skin Changes
In case there are skin changes, a correct diagnosis has to be made by the investigator or a 
dermatologist, preferably within 24 hours of detection. An assessment of severity grade should 
be made using the criteria specified in the draft DMID adult toxicity tables (see Attachment 1).
Rashes should be managed as indicated in Attachment 7.
Laboratory Parameter Changes
If one (or more) of the following changes occur, the subject should discontinue study drug and 
should be followed until resolution (return to baseline) or stabilization of change (to be agreed 
upon with the sponsor). The sponsor should be informed even if the change occurs outside of the 
treatment period (but before the end of the study). Refer to Section 10.2 for study drug 
discontinuation criteria.

Liver enzymes
o
ALT ≥3 times the ULN AND bilirubin ≥2×ULN (direct >35%) OR ALT 
≥5×ULN

Hematologic parameters
o
Hemoglobin <8.0 g/dL
o
Platelet count <50,000/mm3
o
Absolute neutrophil count <750/mm³
9.8.
Other Evaluations
Mid-turbinate nasal swabs (if non-intubated) or endotracheal samples (if intubated) will be used 
to determine the presence of viral and bacterial co-infections (both by multiplex PCR) at 
screening.
Spirometry and DLCO tests will only be performed if the test is available at the study site and 
the clinical condition of the subject allows testing as judged by the investigator.
9.9.
Benefit-risk Evaluations
9.9.1.
Known Benefits
ALS-008176 demonstrated a significant antiviral effect and reduced the signs and symptoms of 
RSV infection in the RSV human challenge model. However, the clinical benefit of this 
compound in the treatment of RSV infection remains to be fully established.
9.9.2.
Potential Benefits
Subjects participating in this study might have a benefit regarding the clinical course of their 
RSV infection. Results from ALS-008176 clinical studies may be useful in developing a new 
therapy for RSV infection.
9.9.3.
Known Risks
All therapies have the potential to cause adverse experiences.
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A formal adverse drug reaction analysis has not yet been conducted for ALS-008176, known 
risks associated with ALS-008176 have not been identified.
9.9.4.
Potential Risks
The nonclinical toxicity profile for ALS-008112 was similar to that previously observed for 
other marketed nucleoside analogs, where hematopoietic changes and genotoxicity were noted.
The toxicity profile established for ALS-008112 in nonclinical toxicology studies indicates a 
reversible and dose-related effect on the hematopoietic system where changes in bone marrow 
cytology were associated with changes in hematological parameters. Specifically, decreased 
circulating reticulocytes, changes in RBC-related parameters, and hypocellularity of erythroid 
cell lines in the bone marrow were observed, next to changes on white blood cells, mostly 
lymphocytes and neutrophils, along with changes in the bone marrow myeloid cells and 
lymphoid organs. Thrombocytopenia was seen in the dog at very high exposure. 
As of 02 January 2018, in adult subjects hospitalized with RSV, 2 hematological serious/severe 
AEs have occurred and subsequently resolved. In these 2 cases (pancytopenia SAE in 
Study 64041575RSV2003; severe neutropenia in Study ALS-8176-510), the subject received 
ALS-008176, but both cases were confounded by multiple medical comorbidities and 
recent/concomitant use of multiple medications that have been reported to cause bone marrow 
toxicity. In addition, two Grade 4 SAEs of (febrile) neutropenia (laboratory Grade 4) considered 
possibly related to the study drug were reported in hospitalized pediatric subjects infected with 
RSV
(1 subject in the MAD part of 
Study 
ALS-8176-503 and 1 subject in 
Study 64041575RSV2004). 
Based on the available information, hematopoietic toxicity is considered a potential risk for 
ALS-008176 for adult and pediatric subjects, for which continued close monitoring of 
hematological parameters and clinical status in both RSV- and hMPV-infected and healthy 
subjects is warranted, as additional data are being collected in ongoing/future studies with 
ALS-008176. Importantly, these hematological side effects observed in both nonclinical and 
clinical studies with ALS-008176 were reversible.
In addition, in nonclinical studies, ALS-008112 has been shown to cause clastogenicity, 
specifically breakage of chromosomes, through a non-DNA-reactive, indirect mechanism, 
resulting from an imbalance of intracellular nucleotide pools. The threshold of clastogenicity for 
ALS-008112, as defined by the lowest concentration where an effect was observed, from in vitro 
studies was 10 μg/mL and from in vivo studies was an AUC of 107,983 ng.h/mL. The NOEL for 
genotoxicity of ALS-008112 from in vitro studies was 5 μg/mL and for in vivo studies was an 
AUC of 57,595 ng.h/mL.
Considering the clastogenicity changes in animal studies, clastogenicity is considered a potential 
risk for ALS-008176, and therefore ALS-008112 plasma exposures for human subjects will be 
limited to a maximum average AUC0-24h of 20,000 ng.h/mL (or 25,200 ng.h/mL in whole blood) 
for any given dose. With this threshold, exposures for adults and infants are respectively at least 
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2.5-fold and 4.7-fold lower than the lowest systemic NOAEL exposure obtained in nonclinical 
toxicity studies, thereby providing an adequate safety margin. 
The effect of ALS-008176 on developmental and reproductive parameters in animals appears to 
be primarily a decrease in fetal weights in rats at high doses of 400 mg/kg twice daily and an 
increase in post-implantation losses in pregnant rabbits at doses of 20 mg/kg twice daily and 
higher, with no teratogenic effects in fetuses in either rats or rabbits. In addition, there were no 
adverse effects on fertility endpoints in male rats up to the highest dose tested of 250 mg/kg 
twice daily or in female rats up to 75 mg/kg twice daily.
Potential risks associated with ALS-008176 administration that might occur in humans are based 
on theoretical known risks associated with other nucleoside analogs. Theoretical risks for 
nucleoside analogs are neuropathy, mitochondrial dysfunction, myopathy (including 
cardiomyopathy), lactic acidosis, hepatomegaly with steatosis, and pancreatitis. None of these 
theoretical risks have been observed in ALS-008176 studies to date.
All antivirals carry the potential risk of inducing drug resistance. However, it is not expected that 
the clinical course of the subject will be substantially influenced by the emergence of resistance, 
as RSV infection is a self-limiting disease and the subject’s immune system will be able to 
eventually clear the virus.
Heterosexually active women must be of non-childbearing potential, defined as being 
postmenopausal or permanently sterile (see Section 4.1), or can be of childbearing potential 
when practicing a highly effective method of contraception, and must agree not to donate eggs 
(ova, oocytes) during the study and for at least 44 days after receiving the last dose of study drug.
During the study and until the end of relevant systemic exposure, plus a minimum of 
1 spermatogenesis cycle (ie, 104 days in total) after receiving the last dose of study drug, a man 
who is sexually active with a woman of childbearing potential must agree to use a barrier method 
of contraception. A man who is sexually active with a pregnant woman must use a condom, and 
must not donate sperm.
9.9.5.
Overall Benefit/Risk Assessment
Based on the available data and proposed safety measures, the overall benefit/risk assessment for 
this study is acceptable for the following reasons:

Careful study of the safety, PK, and preliminary efficacy of ALS-008176 as an antiviral 
treatment for RSV is the first step in addressing an unmet medical need.

No safety concerns have previously been raised based on the safety information from 
healthy adult subjects and most observed AEs and laboratory abnormalities were mild to 
moderate in severity and considered not related to ALS-008176 by the investigator.

Safety concerns have been raised based on safety information from hospitalized adult 
subjects infected with RSV. To reduce risk to subjects, the design of the study has been 
adapted to explore the PK, safety, and tolerability of the low-dose ALS-008176 dosing 
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regimen before proceeding with Part 2 of the study including a high-dose ALS-008176 
dosing regimen.

To reduce risk to subjects, ALS-008112 plasma exposures for human subjects will be 
limited to a maximum average AUC0-24h of 20,000 ng.h/mL (or 25,200 ng.h/mL in whole 
blood) for any given dose. This threshold provides safety margins that are at least 2.5-fold 
and 4.7-fold lower for adults and infants, respectively, than the lowest systemic NOAEL 
exposure obtained in nonclinical toxicity studies.

Several safety measures have been implemented to minimize potential risk and stress to 
subjects, including:

Only subjects who meet all of the inclusion criteria and none of the exclusion criteria 
(as specified in the protocol) will be allowed to participate in this study. The selection 
criteria include adequate provisions to minimize the risk and protect the well-being of 
subjects in the study.

Utilization of discontinuation and withdrawal criteria (see Section 10.2).

Subjects are to be hospitalized upon treatment initiation allowing for intensive 
monitoring.

Close monitoring of subjects throughout the study (see Section 17.9).

Safety surveillance in this study will monitor standard safety parameters associated with 
investigational drug development, known possible risks of ALS-008176 exposure and 
theoretical risks attributed to the nucleoside drug class.

Utilization of data obtained from standard of care samples.

The establishment of an IDMC to monitor data on a regular basis to ensure continuing 
safety of the subjects enrolled in this study.
9.10.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF. If blood samples 
are collected via an indwelling cannula, an appropriate amount (1 mL) of serosanguineous fluid 
slightly greater than the dead space volume of the lock will be removed from the cannula and 
discarded before each blood sample is taken. After blood sample collection, the cannula will be 
flushed with 0.9% sodium chloride, United States Pharmacopeia (or equivalent) or sodium 
heparin of 10 U/mL and charged with a volume equal to the dead space volume of the lock.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Refer to Attachment 8 for details on PK sampling.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
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10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the treatment phase of the study if he or she has 
completed the treatment regimen and the Day 7 visit or the visit 1 day (+2 days) after the final 
dose of study drug if the study drug administration is increased to up to 10 days following IDMC 
review of the data. A subject will be considered to have completed the study if he or she has 
completed assessments of the last follow-up visit.
10.2.
Discontinuation of Study Treatment/Withdrawal From the Study
Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
treatment before the end of the treatment regimen.
A subject’s study treatment must be discontinued if:

The subject withdraws consent.

The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the subject to discontinue study treatment.

The subject becomes pregnant.

The subject has an eGFR ≤30 mL/min/1.73 m² according to the CKD-EPI equation.

The subject experiences any of the laboratory abnormalities as specified in Section 9.7.1.
If a subject discontinues study drug before the end of the treatment phase, the subject will be 
encouraged to continue with end-of-treatment and follow-up assessments in accordance with the 
Time and Events Schedule.
Withdrawal From the Study
Each subject has the right to withdraw at any time for whatever reason without affecting the right 
to treatment by the investigator. The investigator should make an attempt to contact the subjects 
who do not return for scheduled visits or follow-up. Although the subjects are not obliged to give 
reason(s) for withdrawing early, the investigator should make a reasonable effort to ascertain the 
reason(s) while fully respecting the subject’s rights.
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Withdrawal of consent.

Death.

The subject is poorly compliant with study procedures, study drug administration, visits, and 
assessments, after evaluation and discussion between the investigator and sponsor.
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
Decision by the sponsor to stop or cancel the study.

Decision by the investigator to withdraw subjects.

Decision by local regulatory authorities and IEC/IRB to stop or cancel the study.
If a subject withdraws from the study before the end of the treatment phase, the subject will be 
encouraged to continue with end-of-treatment and follow-up assessments in accordance with the 
Time and Events Schedule.
If a subject is lost to follow-up, every reasonable effort must be made by the 
investigator/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. If a 
subject withdraws from the study before the end of the treatment phase, end-of-treatment and 
follow-up assessments should be obtained.
10.3.
Withdrawal From the Use of Research Samples
A subject who withdraws from the study will have the following options regarding research
samples:

The collected (scavenged) samples will be retained and used in accordance with the 
subject’s original informed consent for research samples.

The subject may withdraw consent for exploratory biomarker research, in which case the 
samples will be destroyed and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor study-site contact of withdrawal 
of consent for the research samples and to request sample destruction. The sponsor 
study-site contact will, in turn, contact the biomarker representative to execute sample 
destruction. If requested, the investigator will receive written confirmation from the sponsor 
that the samples have been destroyed.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5). In 
such a case, samples will be destroyed after they are no longer needed for the clinical study. 
Details of the sample retention for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP) that will be 
prepared for each part of the study. The SAP for the IDMC will be separate from the SAP of the 
final analysis. In addition, a separate SAP for the interim analyses of Part 2 will be prepared.
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The primary analysis of Part 1 will be done after a target of approximately 24 subjects have been 
enrolled and have completed treatment, preferably after the end of a hemispheric season. The 
primary unblinded analysis will be performed once the Day 14 PK, safety, and tolerability data 
are available, and data have been locked. Additional data obtained after database lock of this 
analysis will either be analyzed after Part 2 for integrated safety and efficacy purposes or may be 
analyzed in a separate analysis after all subjects enrolled in Part 1 have completed the study. 
Efficacy data of Part 1 will not be included in inferential models of dose finding for Part 2, but 
will be part of an integrated efficacy analysis.
All subjects enrolled into each part of the study who receive at least 1 dose of study drug will be 
included in the safety population. Subjects in this population will be defined by the drug actually 
received, not by randomization assignment. Any subject who receives a single dose of 
ALS-008176 will thus be included in the ALS-008176 arm and all subjects that receive only 
placebo will be included in the placebo arm. The safety population will be used for all safety 
analyses. Furthermore, an integrated analysis of the safety data will be done across both study 
parts using pooled data for active and placebo treatment groups. The 2 subjects who were already 
enrolled before the implementation of this protocol amendment will also be included in this 
analysis.
For each part of the study, all subjects who are randomized, have an RSV infection confirmed by 
central laboratory assessment, and who receive at least 1 dose of study drug will constitute the 
intent-to-treat (ITT) infected population. Treatment assignment for this population will be 
defined by randomization assignment. The ITT infected population will be used for all 
efficacy/virologic analyses. For the analysis of Part 2, only data from Part 2 will be used. For 
data from both Parts 1 and 2 also integrated analyses will be prepared, analogous to those of 
Part 2.
For Part 2, the per-protocol population will be defined as all subjects included in the ITT infected 
population without protocol deviations that affect efficacy assessment. The per-protocol 
population will be established during the blinded data review and may be used to perform 
sensitivity analysis on the primary endpoint.
11.1.
Subject Information
All demographic characteristics and other initial subject characteristics will be tabulated and 
analyzed descriptively. Treatment adherence to ALS-008176 will be derived from the collected 
information.
11.2.
Sample Size Determination
No formal hypothesis is specified for Part 1 of this study. Part 1 is intended to characterize the 
PK and to confirm the popPK model derived from healthy volunteers in hospitalized adult 
subjects infected with RSV. Furthermore the safety and tolerability of the low-dose ALS-008176 
treatment regimen will be assessed. The number of subjects participating in Part 1 is considered 
sufficient to achieve the objectives of the characterization of the PK in Part 1 and allows for 
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updating the PK model, if deemed necessary, based on the results (potential covariates) found in
Part 1.
A total sample size of 15 to 16 subjects on active treatment would provide 80% power to achieve 
a 95% confidence interval within 60% and 140% of the geometric mean estimates of clearance 
and central volume of distribution, assuming a between subject variation of 50% (coefficient of 
variation) as based on 10,000 simulations of the current popPK model.12 For the secondary 
objective of safety assessment the probability was calculated to observe an (S)AE that has a true 
incidence of 1% which would be 15% with a total sample size of 16 subjects on active treatment; 
the probability to observe an (S)AE with a true incidence of 0.1%, 0.5% and 0.8% is 2%, 8% and 
12%, respectively. Therefore, the current sample size of 16 subjects on active treatment is 
deemed adequate for Part 1.
For Part 2, the primary hypothesis is a positive dose-response relationship for the AUC of active 
treatment regimens. The positive dose-response relationship assumes that dose regimens with 
higher exposure with respect to MD will have at least an equal or better effect on viral load. 
Therefore 2 contrasts will be tested at each of the interim analysis points and final analysis; a 
contrast with no difference between the 2 active regimens tested against placebo and a contrast 
with a positive linear dose-response relationship with respect to active regimens. With respect to 
multiple contrast testing, multiplicity will be controlled at the prespecified (interim) alpha level 
by calculating adjusted p-values from the simulated distribution of the maximum or maximum 
absolute value of a multivariate t random vector (ie, using the correlation between the contrasts 
to optimally control for alpha).11 The overall (family-wise) type 1 error rate of 2.5% (1-sided) 
will be adjusted for multiple testing due to formal interim analyses using an O’Brien-Fleming 
alpha spending function with 3 sequential tests (2 interim, 1 final).13
As based on 
10,000 simulations a sample size of 90 subjects randomized in a 1:1:1 ratio (placebo: low-dose
ALS-008176: high-dose ALS-008176) will offer approximately 90% power to detect a positive 
dose-response relationship as defined assuming an effect size of 0.77 using Cohen’s d (ie, the 
effect size expressed as the ratio of the standard deviation of the AUC) and approximately 80% 
power assuming an effect size of 0.67 (Cohen’s d). Based on the results of the ALS-008176 RSV 
human challenge study, these effect sizes were considered plausible.9 The results of Part 1 did 
not lead to changes in the assumptions underlying the sample size determination.
11.3.
Efficacy Analyses
Primary Endpoint
For Part 2, the primary endpoint in this study is RSV RNA log10 viral load (measured by 
qRT-PCR in the mid-turbinate nasal swab specimens) AUC immediately prior to first dose of 
study drug (baseline) over 7 days. Mean log10 viral load values over time will be analyzed using 
a restricted maximum likelihood based repeated measures approach. Analyses will include the 
fixed, categorical effects of treatment, strata, visit, and treatment-by-visit interaction, as well as 
the continuous, fixed covariates of baseline log10 viral load and baseline log10 viral load by-visit 
interaction. An unstructured (co)variance structure will be used to model the within-subject 
errors over time. The differences in the AUCs for active versus placebo will be derived using 
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appropriate contrasts deriving least square mean differences, including the 95% 2-sided 
confidence intervals. For inferential purposes, p-values will be compared with significance levels 
controlling for the (family-wise) type 1 error rate. Details will be provided in the SAP that will 
be finalized before the first formal interim analysis of Part 2.
Secondary Endpoints
The secondary endpoint of time to clinical stability is defined as the time at which the following 
criteria are all met:

normalization of blood oxygen level (return to baseline, pulse oximetry) without 
requirement of supplemental oxygen beyond baseline level

normalization of oral feeding

normalization of respiratory rate

normalization of heart rate
Normalization criteria will be specified in the SAP. Subjects for which no time point could be 
established (eg, withdrawal of informed consent before reaching the endpoint or no clinical 
stability at last observation) will be (right-) censored at the latest time point at which it could be 
established that clinical stability was not reached. The differences in time to clinical stability of 
active dose regimens versus placebo treatment will be estimated using a Cox proportional hazard 
model; as baseline covariates, stratification factors, absence/presence of other viral or bacterial 
infections, baseline log10 viral load, and time from onset of first symptoms to treatment will be 
added. Treatment effect versus placebo will be reported, including 95% confidence intervals. In 
case the proportional hazards assumption is not satisfied, appropriate sensitivity analyses will be 
performed as detailed in the SAP.
The ordinal scale consists of 6 categories that are exhaustive, mutually exclusive, and ordered 
(Table 6). For all subjects, the category at Day 5/6 (depending on the timing of the LD
administration) will be established as the worst category on that day. For example, if a subject is 
discharged on Day 6, the category will be non-ICU and no supplemental oxygen (if there was no 
supplemental oxygen given on that day). The analysis will be performed using a proportional 
odds model, modeling the common odds ratio of the improvement on the ordinal scale of active 
treatment versus control. Baseline covariates that are predictive of the ordinal scale may be 
added to the model to increase the model fit. In case of missing data (>10%), a multiple 
imputation method under the missing-at-random assumption will be employed. Details will be 
provided in the SAP.
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Table 6:
Ordinal Scale on Day 5/6 (Depending on the Timing of the LD Administration)
Outcome
Death
Admitted to ICU
Non-ICU hospitalization requiring supplemental oxygen
Non-ICU hospitalization not requiring supplemental oxygen
Not hospitalized, unable to resume normal activities
Not hospitalized, resumption of normal activities
ICU = Intensive Care Unit
A secondary endpoint of high interest is the length of hospital stay. The length of hospital stay is 
in hours and taken from the start of treatment initiation to discharge and to readiness for 
discharge. The differences of active dose regimens versus placebo treatment will be estimated 
using the accelerated failure time model using appropriate contrasts; baseline covariates such as 
stratification factors, absence/presence of other viral or bacterial pathogens, RSV baseline log10
viral load, and time from onset of first symptoms to treatment will be added when of predictive 
value based on blinded data. Treatment effects versus placebo will be reported as acceleration 
factors including 95% confidence intervals. Subjects for which no time point could be 
established (eg, withdrawal of informed consent before reaching the endpoint) will be 
(right-)censored at the latest time point at which it could be established that the endpoint was not 
reached. Subjects for whom discharge cannot be considered as a marker of adequate recovery 
(eg, subjects who die during hospitalization or who are transferred to a care facility with the 
same level of care as during hospitalization) will be censored at the planned final follow-up visit. 
No adjustments for multiplicity will be made. Analytical details will be provided in the SAP.
While this clinical endpoint is considered of high interest, the current sample size is determined 
by considerations on antiviral activity; for length of hospital stay the anticipation is that there 
will be too much heterogeneity to expect statistically significant separation of active groups 
versus placebo with the current sample size, even if a numerical trend is anticipated.
The impact of the baseline viral genotype and subtype on the antiviral activity will be explored.
Analysis of the viral sequencing results will be described in the SAP.
11.4.
Pharmacokinetic Analyses
Population PK analysis of plasma concentration-time data of ALS-008112 will be performed 
using nonlinear mixed-effects modeling. Data may be combined with those of other selected 
studies to support a relevant structural model. Available baseline subject characteristics (eg, 
demographics, laboratory variables, race) will be tested as potential covariates affecting PK 
parameters. Details will be given in a popPK analysis plan and the key findings of the popPK
analysis will be presented in the final clinical study report.
A snapshot date for PK samples to be analyzed for the planned primary analysis for Part 1 and 
interim analyses for Part 2 will be defined. Samples collected before this snapshot date will be 
analyzed for ALS-008112 and ALS-008144 and included in the popPK analysis (for 
ALS-008112 only). Samples collected after the snapshot date will be analyzed at a later date, and 
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will be included in a popPK re-analysis when they become available after interim analysis 
database lock.
Subjects will be excluded from the PK analysis if their data do not allow for accurate assessment 
of the PK (eg, incomplete administration of the study drug; missing information of dose and 
sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All subjects and samples excluded from the analysis will be 
clearly documented in the study report.
For each treatment group, descriptive statistics, including arithmetic mean, standard deviation, 
CV, median, minimum, and maximum will be calculated for all individual derived PK 
parameters including exposure information of ALS-008112 and ALS-008144, if applicable.
11.5.
Biomarker Analysis
Statistical approaches to explore correlations between clinical outcome and biomarkers in blood 
and mid-turbinate nasal swabs vary and depend on the different data types of the applied 
technology platforms, as well as on the extent of observed differences among study subjects. 
Analyses may be conducted at the sponsor’s discretion and reported separately from this study.
11.6.
Pharmacokinetic/Pharmacodynamic Analyses
Efficacy and safety parameters will be subject to PK/PD analysis at the end of each part of the 
study. ALS-008112 exposures will be evaluated as an independent variable, with selected 
efficacy and selected safety parameters considered as dependent variables. Various approaches, 
including graphical analysis, linear, nonlinear, and logistic regression methods may be utilized.
The key findings of the PK/PD analysis will be presented in the final clinical study report.
11.7.
Subject Clinical Outcome Assessments
Subject-reported eCOA (RI-PRO, additional questions about health and functioning, and HRQoL 
[EQ-5D-5L]) data will be descriptively summarized by treatment group and compared across 
treatment groups.
11.8.
Katz Activities of Daily Living
The investigator-reported Katz ADL data will be descriptively summarized by treatment group 
and compared across treatment groups.
11.9.
Medical Resource Utilization and Health Economics Analyses
Medical resource utilization and health economics will be descriptively summarized by treatment 
group and compared across treatment groups.
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11.10. Safety Analyses
Safety data will be presented descriptively. No statistical testing of safety data is planned. For 
safety, baseline is defined as the last assessment prior to the first intake of study drug.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities. Treatment-emergent AEs are AEs with onset 
during the treatment phase or that are a consequence of a preexisting condition that has worsened 
since baseline. All reported AEs will be included in the analysis. For each AE, the percentage of 
subjects who experience at least 1 occurrence of the given event will be summarized by 
treatment group. In addition, comparisons between treatment groups will be provided if 
appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe AE or an
SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed 
values and changes from baseline at each scheduled time point. Changes from baseline results 
will be presented in pre- versus posttreatment cross-tabulations (with classes for below, within, 
and above normal ranges). Frequency tabulations of the abnormalities will be made. A listing of 
subjects with any laboratory results outside the reference ranges will be provided. A listing of 
subjects with any markedly abnormal laboratory results will also be provided.
The laboratory abnormalities will be determined according to the criteria specified in the draft 
Division of Microbiology and Infectious Diseases Adult Toxicity Table (see Attachment 1) and 
in accordance with the normal ranges of the clinical laboratory if no gradings are available.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline 
values at each scheduled time point (the predose ECG will be used as baseline). Frequency 
tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and corrected QT (QTc) interval using the following correction method: QT corrected according 
to Fridericia’s formula (QTcF). The percentage of subjects with abnormalities as defined in
Attachment 6 will be tabulated.
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Vital Signs
Descriptive statistics of temperature, heart rate, respiratory rate, SBP, and DBP values and 
changes from baseline will be summarized at each scheduled time point. The percentage of 
subjects with values beyond clinically important limits (as defined in Attachment 6) will be 
summarized.
Physical Examination
Physical examination findings will be summarized at each scheduled time point. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. Frequency tabulations of the abnormalities will be made.
11.11. Interim Analysis
For Part 2, a maximum of 2 formal interim analyses are planned to assess the primary endpoint 
for early superiority and futility. The first formal interim analysis will be performed when at least 
45 subjects have completed treatment to ensure that adequate data is available for interim 
analysis review, preferably after the end of a hemispheric RSV season. Up to the final database 
lock, the study team will remain blinded to the results. Details on operational characteristics will 
be provided in the interim analysis charter.
The following situations will be considered based on the results of the analysis of the primary 
endpoint at this stage: that the study is considered futile; that superiority can be concluded (based 
on an O’Brien-Fleming alpha spending function); that the study is considered underpowered; or 
that the study should continue unchanged. In the case of the (unbinding) futility boundary being 
crossed, the IDMC will recommend early termination to the Sponsor Committee. If the study is 
considered underpowered, a sample size increase may be suggested to a maximum of 
180 subjects. This blinded sample size calculation will take the residual error variance into 
account of the primary analysis model.
If early superiority on the primary endpoint can be established, the study may, however, be 
continued in order to accumulate data to allow the selection of the dose regimen or further 
substantiate the benefit-risk profile in this population; in this case the randomization ratio of 
active to placebo treatment may be altered for example, if dose selection is evident from the 
dose-response analysis, subjects randomized to active treatment may all receive the optimal dose. 
However, at the interim analyses or at any time, upon recommendation by the IDMC, a dose 
regimen may be removed or adjusted based on PK, safety, and/or antiviral activity 
considerations.
The Interim Analysis Committee will be responsible for performing the formal interim analysis 
and will consist of sponsor personnel who are not otherwise involved in the study. The IDMC 
will review the data and make recommendations to the Sponsor Committee.
11.12. Independent Data Monitoring Committee
An IDMC will be established to monitor data in both parts of the study and will review data in an 
unblinded manner on a regular basis to ensure the continuing safety of the subjects enrolled in 
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this study and to evaluate whether efficacy objectives are met. A Sponsor Committee will also be 
established and will be responsible for identifying appropriate actions based on the 
recommendations of the IDMC as described in the IDMC charter.
The IDMC will meet periodically to review interim data. After the review, the IDMC will make 
recommendations to the Sponsor Committee regarding the continuation of the study. The details 
will be provided in a separate IDMC charter.
The IDMC will consist of at least 1 medical expert in the relevant therapeutic area and at least 
1 statistician, 1 of whom will chair the committee. The IDMC responsibilities, authorities, and
procedures will be documented in its charter. Other members may be required dependent on the 
nature of the interim analysis (refer to Section 11.11).
For Part 1, the IDMC will review the safety and PK data after approximately 12 subjects have 
completed treatment as per the IDMC charter. When approximately 24 subjects have completed 
the Day 14 follow-up visit, an unblinded primary analysis will be performed by the sponsor for 
review by the IDMC. For Part 2, the IDMC will review the safety data initially after 
approximately 12 subjects have completed treatment and when approximately 12 Japanese 
subjects have completed treatment to assess that treatment may safely continue in each arm and 
will continue to assess PK, efficacy, and safety during the conduct of the study. Enrollment will 
continue while the IDMC reviews the data unless otherwise instructed by the IDMC. The 
frequency of IDMC reviews will be detailed in the IDMC charter.
Given the challenges of ensuring study site preparation in time to recruit for an acute seasonal 
infection like RSV and the delays caused by implementing an amendment during an RSV 
season, the doses, treatment regimen, and/or duration of dosing of ALS-008176 may be modified 
by recommendation of the IDMC at any time for PK, efficacy, or safety reasons based on the 
review of this study and other ongoing studies of ALS-008176. The duration of dosing, if 
extended, will not exceed 10 days and the doses will not exceed those resulting in an expected 
average ALS-008112 plasma AUC0-24h of 20,000 ng.h/mL (or 25,200 ng.h/mL in whole blood), a 
limit that is 2.5-fold lower than the lowest systemic NOAEL exposure observed in nonclinical 
toxicity studies. If the IDMC determines that subjects with a duration of RSV symptoms of 
5 days prior to randomization may not achieve benefit based on interim results, the allowed 
duration of the time of onset of RSV symptoms to the time of randomization may be reduced. In 
addition, if the IDMC determines that subjects with a duration of RSV symptoms longer than 
5 days prior to randomization may achieve benefit based on interim results, this duration may be 
increased to up to 7 days (ie, 7 days from symptom onset to randomization). If such 
modifications are recommended by the IDMC and endorsed by the sponsor, these changes will 
be communicated in writing to investigators, health authorities, and IECs/IRBs and may be 
implemented without amendment to this protocol.
In Part 2, based on the reviews of PK, efficacy, and safety data by the IDMC, changes to 
enrollment in the treatment arms, dose regimen adjustments, sample size adjustments, or an 
increase in dose duration to up to 10 days may be implemented.
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Sponsor personnel involved in this process will not be involved in the conduct of the study. 
Details are provided in the IDMC charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1 for 
time of last AE recording).
Serious Adverse Event
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening.
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)
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
Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Is a suspected transmission of any infectious agent via a medicinal product.

Is medically important*.
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For ALS-008176, expectedness of an AE will be 
determined by whether or not it is listed in the IB.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
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Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug.

Suspected abuse/misuse of a sponsor study drug.

Accidental or occupational exposure to a sponsor study drug.

Medication error involving a sponsor product (with or without subject exposure to the 
sponsor study drug, eg, name confusion).

Exposure to a sponsor study drug from breastfeeding.
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All AE and special reporting situations, whether serious or nonserious, will be reported from the 
time a signed and dated ICF is obtained until completion of the subject’s last study-related 
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procedure, which may include contact for follow-up of safety. Serious adverse events, including 
those spontaneously reported to the investigator within 30 days after the last dose of study drug, 
must be reported using the SAE Form. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the protocol.
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether 
they are protocol-specific assessments.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory 
infection”). Investigators must record in the eCRF their opinion concerning the relationship of 
the AE to study therapy. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). The investigator 
(or sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the 
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be reported 
to regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a 
blinded SUSAR summary, unless otherwise specified.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a “wallet (study) card” and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number.

Statement, in the local language(s), that the subject is participating in a clinical study.

Investigator’s name and 24-hour contact telephone number.

Local sponsor’s name and 24-hour contact telephone number (for medical staff only).

Site number.

Subject number.

Any other information that is required to do an emergency breaking of the blind.
12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by the investigator/study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which must 
be completed and signed by a physician from the study site, and transmitted to the sponsor 
within 24 hours. The initial and follow-up reports of an SAE should be made by facsimile (fax).
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All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the subject’s participation in the study, must be followed until any of the 
following occurs:

The event resolves.

The event stabilizes.

The event returns to baseline, if a baseline value/status is available.

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct.

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts).
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject’s participation in a study must be reported as an SAE, except hospitalizations 
for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not 
be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
If the subject is re-hospitalized after discharge for the same RSV disease, this will constitute an 
SAE.
The cause of death of a subject in a study within 30 days of the last dose of study drug, whether 
or not the event is expected or associated with the study drug, is considered an SAE.
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the investigator/study-site personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy notification form. Abnormal pregnancy outcomes 
(eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and must be reported using the SAE Form. Any subject who becomes pregnant 
during the study must be promptly withdrawn from the study and discontinue further study 
treatment.
Because the study drug may have an effect on sperm, pregnancies in partners of men included in 
the study will be reported as noted above.
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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the investigator/study-site personnel within 
24 hours after being made aware of the event.
If the defect is combined with a SAE, the investigator/study-site personnel must report the PQC 
to the sponsor according to the SAE reporting timelines (refer to Section 12.3.2). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The ALS-008176 and matching placebo supplied for this study is formulated as white to 
off-white film-coated tablets. The active tablets contain 250 mg or 500 mg ALS-008176 and 
have the same appearance of tablet size, shape, and color. Placebo tablets are visually identical to 
their active drug counterparts. It will be manufactured and provided under the responsibility of 
the sponsor. Refer to the IB for a list of excipients.
14.2.
Packaging
The tablets are packaged in round white high-density polyethylene bottles, with an induction seal 
and a white polypropylene child-resistant closure.
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All study drugs will be supplied to the site in blinded containers.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
All study drug should be stored at controlled room temperature.
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the drug 
accountability form. Subjects, or their legally acceptable representatives where applicable, must 
be instructed to return all original containers, whether empty or containing study drug. The study 
drug administered to the subject must be documented on the drug accountability form. All study 
drug will be stored and disposed of according to the
sponsor’s instructions. The 
investigator/study-site personnel must not combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor’s study-site monitor during on-site monitoring visits.
The return to the sponsor of unused study drug, or used returned study drug for destruction, will 
be documented on the drug return form. When the study site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

ALS-008176 IB and any addenda.

Pharmacy manual/study-site investigational product and procedures manual.

Laboratory manual.

Electronic device for investigator and subject eCOA.
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
Completion guide(s) for eCOA.

PCR machine for RSV diagnosis (if needed).

Specimen collection kits for blood (PK and biomarker host RNA) and mid-turbinate nasal 
swab.

Contact information page(s).

IWRS manual.

eCRF completion guidelines.
16.
ETHICAL ASPECTS
16.1.
Study-specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is considered to be acceptable.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments.

Sponsor-approved ICF (and any other written materials to be provided to the subjects).

Investigator’s Brochure (or equivalent information) and amendments/addenda.

Sponsor-approved subject recruiting materials.
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
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable.

Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB).

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects.

Any other documents that the IEC/IRB requests to fulfill its obligation.
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct).

Revision(s) to ICF and any other written materials to be provided to subjects.

If applicable, new or revised subject recruiting materials approved by the sponsor.

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable.

New edition(s) of the IB and any amendments/addenda.

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually).

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug.

New information that may adversely affect the safety of the subjects or the conduct of the 
study.

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects.

Report of deaths of subjects under the investigator’s care.

Notification if a new investigator is responsible for the study at the site.

Development Safety Update Report and Line Listings, where applicable.

Any other requirements of the IEC/IRB.
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF must be signed 
before performance of any study-related activity. The ICF that is used must be approved by both 
the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and 
understand. The informed consent should be in accordance with principles that originated in the 
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, 
and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow-up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, which includes permission to obtain information about 
his or her survival status. It also denotes that the subject agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, and subsequent disease-related treatments, if needed.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject’s or his or her legally acceptable 
representative’s personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
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When prior consent of the subject is not possible and the subject’s legally acceptable 
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and 
well-being of the subject and to ensure compliance with applicable regulatory requirements. The 
subject or legally acceptable representative must be informed about the study as soon as possible 
and give consent to continue.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker and PK research is not conducted under standards appropriate for the 
return of data to subjects. In addition, the sponsor cannot make decisions as to the significance of 
any findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand ALS-008176, to 
understand RSV, to understand differential drug responders, and to develop tests/assays related 
to ALS-008176 and RSV disease. The research may begin at any time during the study or the 
poststudy storage period. No human DNA testing will be performed.
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Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for nonacceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
The doses or treatment regimen of ALS-008176 may be modified by recommendation of the 
IDMC at any time for PK, efficacy, or safety reasons based on the review of this and other 
ongoing studies of ALS-008176. If such modifications are recommended based on IDMC 
review, these changes will be communicated in writing to investigators, health authorities, and 
IECs/IRBs and may be implemented without amendment to this protocol.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
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17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator.

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable.

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.

Documentation of investigator qualifications (eg, curriculum vitae).

Completed investigator financial disclosure form from the principal investigator, where 
required.

Signed and dated Clinical Trial Agreement, which includes the financial agreement.

Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators.

Documentation of subinvestigator qualifications (eg, curriculum vitae).

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable.

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable.
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
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and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with those commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs
and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable.
Additionally; patient-reported outcomes (data for the eCOA will be captured directly in the 
electronic instrument, which will serve as source documentation) and the Katz ADL score (the 
questionnaire will be completed by the investigator after interviewing the subject and the data 
will be entered into the eCRF by the investigator/study-site personnel) will be considered source 
data.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring
guidelines (or other equivalent document).
The following data may be recorded directly into the eCRF and may be considered source data:

Race.

History of smoking and all nicotine use, eg, cigarettes (including e-cigarettes or the 
equivalent of e-cigarettes), cigars, chewing tobacco, patch, gum.

Blood pressure and heart rate.

Height and weight.

Details of physical examination.
The minimum source documentation requirements for Section 4.1 and Section 4.2 that specify a 
need for documented medical history are as follows:

Discharge summaries.
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
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An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All data relating to the study must be recorded in eCRF. All eCRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by the investigator/study-site personnel from the source 
documents onto an electronic CRF, if applicable. Study-specific data will be transmitted in a 
secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject’s source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.
If necessary, queries will be generated in the electronic data capture tool. If corrections to an 
eCRF are needed after the initial entry into the eCRF, this can be done in either of the following
ways:

Investigator and study-site personnel can make corrections in the electronic data capture tool 
at their own initiative or as a response to an auto query (generated by the electronic data 
capture tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
17.5.1.
Katz Activities of Daily Living
The investigator will provide information about the subject’s health status, symptoms, and 
behavior after interviewing the subject at time points noted in the Time and Events Schedule.
The Katz ADL questionnaire (see Attachment 5) will be completed by the investigator after 
interviewing the subject and the data will be entered into the eCRF by the investigator/study-site 
personnel.
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17.6.
Subject Clinical Outcome Assessments
Clinical Outcome Assessments (RI-PRO, additional questions about health and functioning, and 
HRQoL [EQ-5D-5L], see Attachment 2, Attachment 3, and Attachment 4, respectively) will be 
completed on an electronic device provided at the study site. Responses provided will be 
recorded directly in the electronic database. Site coordinators should monitor the site 
management website, provided by the eVendor, on a daily basis to ensure information is 
uploaded from these devices as required.
Each day from screening though end of follow-up, the investigator/study-site personnel will 
monitor whether the subject’s eCOA data were uploaded to the eCOA website provided for this 
study. If more than 36 hours have elapsed since the last eCOA assessment was recorded on the 
eCOA website, the investigator/study-site personnel will contact the subject (or the subject’s 
spouse, partner, relative, or friend) to ensure that the eCOA questionnaires are completed and 
transmitted to the server every day, to identify problems collecting or transmitting the 
assessments, and to instruct the subject/person entering the subject’s responses on the eCOA 
device on the way to correct any problems with collecting or transmitting the eCOA data. 
Telephone calls to the subjects to facilitate compliance with the study procedures between 
outpatient study visits are permitted.
Study monitors should monitor completion of the eCOA and follow-up with sites immediately 
should there be any indication that the eCOA is not being completed or if data transfer is not 
being done as scheduled.
The eCOA device includes built-in training for study-site personnel, investigators, and subjects.
The subject will provide information about his/her health status, symptoms, functional status, 
and HRQoL on an electronic device at time points noted in the Time and Events Schedule. In 
addition, after hospital discharge, the subject will record study drug and concomitant medications 
administered on the electronic device in a medication log. All subject assessments and logs will 
be provided in the native language of the subject. The electronic device will include instructions 
and training that will be completed upon first use by the subject (or the subject’s spouse, partner, 
relative, or friend) and will be available on demand thereafter if the subject chooses this option.
If the subject is unable to complete the assessments on the eCOA device, the subject’s spouse, 
partner, relative, friend or the investigator/study-site personnel who has completed the training 
on use of the eCOA device can read the questions and response options aloud to the subject and 
enter the subject’s responses in the eCOA device on the subject’s behalf using the interview 
administration procedures explained in the eCOA completion guide. In case the subject and 
his/her delegate experience problems with entering the data in the electronic device after 
discharge of the subject from the hospital, the investigator or trained study-site personnel can 
provide data entry support by phone. During hospitalization, if the subject is unable to complete 
the assessment on the device and the subject’s spouse, partner, relative, or friend is not available 
to enter the subject’s responses on the device for the subject, the investigator or trained study-site
personnel can read the questions and response options to the subject and record the subject’s 
responses on the device on the subject’s behalf. If in the investigator’s opinion, the subject (or 
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the subject’s spouse, partner, relative, or friend) is unlikely to reliably enter the information in 
the eCOA device on a daily basis for the duration of the study, the site will retain the eCOA 
device upon the subject's discharge and arrange for the investigator or trained study-site 
personnel to interview the subject by phone and record the subject’s responses in the eCOA 
device on the subject's behalf each day post discharge to end of follow-up.
17.7.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor’s data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with the investigator/study-site
personnel before the start of the study. The sponsor will review eCRF for accuracy and 
completeness during on-site monitoring visits and after transmission to the sponsor; any 
discrepancies will be resolved with the investigator or designee, as appropriate. After upload of 
the data into the study database they will be verified for accuracy and consistency with the data 
sources.
17.8.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, and all study documents as specified by the 
applicable regulatory requirement(s). The investigator/institution will take measures to prevent 
accidental or premature destruction of these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
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17.9.
Monitoring
The sponsor will use a combination of monitoring techniques as specified in the monitoring 
guidelines, central, remote, or on-site monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature 
and location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and the investigator/study-site 
personnel and are accessible for verification by the sponsor study-site contact. If electronic 
records are maintained at the study site, the method of verification must be discussed with the 
investigator/study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the investigator/study-site personnel. The sponsor expects that, 
during monitoring visits, the investigator and/or relevant study-site personnel will be available, 
the source documents will be accessible, and a suitable environment will be provided for review 
of study-related documents. The monitor will meet with the investigator on a regular basis during 
the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, the investigator/study-site personnel will be available to provide an update 
on the progress of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
17.10. Study Completion/Termination
17.10.1.
Study Completion/End of Study
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.10.2.
Study Termination
The sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines.

Inadequate recruitment of subjects by the investigator.

Discontinuation of further study drug development.
17.11. On-site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.12. Use of Information and Publication
All information, including but not limited to information regarding ALS-008176 or the sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor’s prior 
written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of ALS-008176, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory
biomarker analyses performed after the Clinical Study Report has been issued will be reported in 
a separate report and will not require a revision of the Clinical Study Report. Study subject 
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identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 18 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the ICMJE Recommendations for the Conduct, Reporting, 
Editing and Publication of Scholarly Work in Medical Journals, which state that the named 
authors must have made a significant contribution to the conception or design of the work; or the 
acquisition, analysis, or interpretation of the data for the work; and drafted the work or revised it 
critically for important intellectual content; and given final approval of the version to be 
published; and agreed to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
1.
Afonso CL, Amarasinghe GK, Bányai K, et al. Taxonomy of the order Mononegavirales: update 2016. 
Arch Virol. 2016;161:2351-2360.
2.
ALS-008176 Investigator’s Brochure Edition 6 Addendum 1, October 2016.
3.
ALS-008176 Investigator’s Brochure Edition 6 Addendum 2, November 2016.
4.
ALS-008176 Investigator’s Brochure Edition 6 Addendum 3, January 2017.
5.
ALS-008176 Investigator’s Brochure Edition 6, May 2016.
6.
Bloom-Feshbach K, Alonso WJ, Charu V, et al. Latitudinal variations in seasonal activity of influenza and 
respiratory syncytial virus (RSV): a global comparative review. PLoS One. 2013;8(2):e54445.
7.
Centers for Disease Control and Prevention; CDC 24/7: Saving lives, protecting people™ respiratory syncytial 
virus infection (RSV). Last Revised May 5, 2015. Available at: 
http://www.cdc.gov/rsv/research/us-surveillance.html.
8.
CTFG guidance. 2014. Recommendations related to contraception and pregnancy testing in clinical trials. 
Available at: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/ 
CTFG/2014_09_HMA_CTFG_Contraception.pdf. Accessed: 20 October 2016.
9.
DeVincenzo J, McClure M, Symons J, et al. Activity of oral ALS-008176 in a respiratory syncytial virus 
challenge study. N Engl J Med. 2015;373:2048-2058.
10.
FDA guidance on in vitro substrates/inhibitors/inducers of cellular transporters (diclofenac). Available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/u
cm093664.htm. Accessed: 23 November 2016.
11.
Hsu JC, Nelson BL. Multiple comparisons in the general linear model. J Comput Graph Stat. 1998;7:23-41.
12.
JAN201735 Power analysis for study RSV2003, December 2016 (draft).
13.
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70:659-663.
14.
Lee N, Chan M, Lui G, et al. High viral load and respiratory failure in adults hospitalized for respiratory 
syncytial virus infections. J Infect Dis.2015;212(8):1237-1240.
15.
Levey AS, Stevens LA, Schmid CH, et. al. and CKD-EPI (Chronic Kidney Disease Epidemiology) 
Collaboration. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604-612.
16.
Lumicitabine Investigator’s Brochure Edition 9, March 2018.
17.
Yusuf S, Piedimonte G, Auais A, et al. The relationship of meteorological conditions to the epidemic activity 
of respiratory syncytial virus. Epidemiol Infect. 2007;135(7):1077-1090.
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Attachment 1:
Toxicity Tables
DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT 
TOXICITY TABLE – NOVEMBER 2007 (DRAFT)
ABBREVIATIONS: Abbreviations utilized in the Table:
ULN = Upper Limit of Normal
LLN = Lower Limit of Normal 
Rx = Therapy
Req = Required
Mod = Moderate
IV = Intravenous
ADL = Activities of Daily Living
Dec = Decreased
ESTIMATING SEVERITY GRADE
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity:
GRADE 1
Mild Transient or mild discomfort (< 48 hours); no medical 
intervention/therapy required
GRADE 2
Moderate Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required
GRADE 3
Severe Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible
GRADE 4
Life-threatening Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable
SERIOUS OR LIFE-THREATENINGAEs
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization [WHO]) have been adapted for 
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to 
better meet the needs of participants in DMID trials.

For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade” located above.

Criteria are generally grouped by body system.

Some protocols may have additional protocol-specific grading criteria, which will 
supersede the use of these tables for specified criteria.
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 - 10.5 gm/d L
8.0 - 9.4gm/dL
6.5 - 7.9 gm/d L
< 6.5 gm/dL
Absolute Neutrophil Count
1,000-1,500/ mm3
750-999/ mm3
500-749/ mm3
<500/ mm3
Platelets
75,000-
99,999/ mm3
50,000-
74,999/ mm3
20,000-49,999/ mm3
<20,000/ mm3
WBCs
11,000-13,000/
mm3
13,000-
15,000 / mm3
15,000-
30,000/ mm3
>30,000 or
<1,000 / mm3
% Polymorphonuclear
Leucocytes + Band Cells
> 80%
90 – 95%
>95%
----------
Abnormal Fibrinogen
Low:
100-200 mg/dL
High:
400-600 mg/dL
Low:
<100 mg/dL
High:
>600 mg/dL
Low:
< 50 mg/dL
----------
Fibrinogen
associated with gross 
bleeding or with 
disseminated 
coagulation
Fibrin Split Product
20-40 mcg/ ml
41-50 mcg/ ml
51-60 mcg/ ml
> 60 mcg/ ml
Prothrombin Time (PT)
1.01 - 1.25 x ULN
1.26-1.5 x ULN
1.51 -3.0 x ULN
>3 x ULN
Activated Partial 
Thromboplastin (APPT)
1.01 -1.66 x ULN
1.67 - 2.33 x ULN
2.34 - 3 x ULN
> 3 x ULN
Methemoglobin
5.0 - 9.9 %
10.0 - 14.9 %
15.0 - 19.9%
> 20.0 %
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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130-135 mEq/ L
123-129 mEq/ L
116-122 mEq/ L
< 116 mEq/ L or abnormal sodium 
with mental
status changes or seizures
Hypernatremia
146-150 mEq/ L
151-157 mEq/ L
158-165 mEq/ L
> 165 mEq/ L or abnormal sodium 
with mental
status changes or seizures
Hypokalemia
3.0 - 3.4 mEq/ L
2.5 - 2.9 mEq/ L
2.0 - 2.4 mEq/ L or 
intensive replacement 
therapy or 
hospitalization 
required
< 2.0 mEq/ L or abnormal 
potassium with
paresis, ileus or life-threatening 
arrhythmia
Hyperkalemia
5.6 - 6.0 mEq/ L
6.1 - 6.5 mEq/ L
6.6 - 7.0 mEq/l
> 7.0 mEq/ L or abnormal
potassium with life-threatening 
arrhythmia
Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
<30 mg/d L or abnormal glucose 
with mental
status changes or coma
Hyperglycemia
(nonfasting and no 
prior diabetes)
116 - 160 mg/dL 161- 250 mg/d L
251 - 500 mg/dL
> 500 mg/d L or abnormal glucose 
with ketoacidosis or seizures
Hypocalcemia
(corrected for 
albumin)
8.4 - 7.8 mg/dL
7.7 - 7.0 mg/dL
6.9 - 6.1 mg/dL
< 6.1 mg/dL or abnormal
calcium with life-threatening 
arrhythmia or tetany
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CHEMISTRIES (continued)
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (correct for 
albumin)
10.6 - 11.5 mg/d L
11.6 - 12.5
mg/d L
12.6 - 13.5 mg/d L
> 13.5 mg/dL or abnormal 
calcium with life-
threatening arrhythmia
Hypomagnesemia
1.4 - 1.2 mEq/ L
1.1 - 0.9 mEq/ L
0.8 - 0.6 mEq/ L
< 0.6 mEq/ L or abnormal 
magnesium with life-
threatening arrhythmia
Hypophosphatemia
2.0 - 2.4 mg/dL
1.5 -1.9 mg/dL or
replacement Rx 
required
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required
< 1.0 mg/dL or abnormal
phosphate with life-
threatening arrhythmia
Hyperbilirubinemia (when 
accompanied by any 
increase in other liver 
function test)
1.1 - <1.25 x ULN
1.25 - <1.5 x 
ULN
1.5 – 1.75 x ULN
> 1.75 x ULN
Hyperbilirubinemia (when 
other liver function are in 
the normal range)
1.1 - <1.5 x ULN
1.5 - <2.0 x ULN
2.0 – 3.0 x ULN
> 3.0 x ULN
BUN
1.25 - 2.5 x ULN
2.6 - 5 x ULN
5.1 - 10 x ULN
> 10 x ULN
Hyperuricemia (uric acid)
7.5 – 10.0 mg/dL
10.1 – 12.0 mg/d 
L
12.1 – 15.0 mg/d L
>15.0 mg/d L
Creatinine
1.1 - 1.5 x ULN
1.6 - 3.0 x ULN
3.1 - 6 x ULN
> 6 x ULN or dialysis 
required
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT)
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
ALT (SGPT)
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
GGT
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
Alkaline Phosphatase
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
Amylase
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.1 - 5.0 x ULN
> 5.1 x ULN
Lipase
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.1 - 5.0 x ULN
> 5.1 x ULN
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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+
or
200 mg - 1 gm 
loss/day
2-3+
or
1- 2 gm loss/day
4+
or
2-3.5 gm loss/day
nephrotic syndrome
or
> 3.5 gm loss/day
Hematuria
microscopic only
<10 rbc/hpf
gross, no clots
>10 rbc/hpf
gross, with or without 
clots, OR red blood 
cell casts
obstructive or 
required
transfusion
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Rhythm
asymptomatic, 
transient signs, no
Rx required
recurrent/persistent; 
symptomatic Rx 
required
unstable dysrythmia;
hospitalization
and treatment 
required
Hypertension
transient increase
> 20 mm/ Hg; no 
treatment
recurrent, chronic 
increase
> 20mm/ Hg.
/treatment required
acute treatment 
required; outpatient 
treatment or 
hospitalization
possible
end organ damage or 
hospitalization 
required
Hypotension
transient orthostatic
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 mm 
Hg systolic BP, No 
treatment required
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 mm 
Hg systolic; 
correctable with oral 
flu id treatment
requires IV fluids; no 
hospitalization 
required
mean arterial 
pressure
<60mm/ Hg or end 
organ damage or 
shock; requires
hospitalization and 
vasopressor treatment
Pericarditis
minimal effusion
mild/ moderate 
asymptomatic 
effusion, no treatment
symptomatic 
effusion; pain; EKG 
changes
tamponade; 
pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
1-2 units transfused
massive blood loss; > 
3 units transfused
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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
transient- no 
treatment
persistent cough; 
treatment responsive
Paroxysmal cough; 
uncontrolled with
treatment
--------------------
Bronchospasm, Acute
transient; no 
treatment;
70% - 80% FEV1
of peak flow
requires
treatment; normalizes 
with bronchodilator; 
FEV1 50% -
70%
(of peak flow)
no normalization 
with bronchodilator; 
FEV1 25% - 50%
of peak flow; or
retractions present
cyanosis: FEV1
< 25%
of peak flow or 
intubation necessary
Dyspnea
dyspnea on exertion dyspnea with normal 
activity
dyspnea at rest
dyspnea requiring 
Oxygen therapy
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
mild or transient; 
maintains
reasonable intake
moderate discomfort; 
intake decreased
significantly; some 
activity limited
no significant intake; 
requires IV flu ids
hospitalization 
required;
Vomiting
1 episode in 24 hours
2-5 episodes in
24 hours
>6 episodes in 24
hours or needing IV 
fluids
physiologic 
consequences 
requiring
hospitalization or 
requiring parenteral 
nutrition
Constipation
requiring stool
softener or dietary 
modification
requiring
laxatives
obstipation
requiring manual 
evacuation or enema
obstruction or
toxic megacolon
Diarrhea
mild or transient; 3-4 
loose
stools/day or mild
diarrhea last < 1 
week
moderate or 
persistent; 5-7 loose 
stools/day or diarrhea
lasting >1 week
>7 loose stools/day
or bloody diarrhea; or 
orthostatic 
hypotension or 
electrolyte imbalance 
or >2L IV fluids 
required
hypotensive shock or 
physiologic 
consequences 
requiring
hospitalization
Oral Discomfort/Dysphagia mild discomfort; no 
difficulty
swallowing
some limits on 
eating/drinking
eating/talking very 
limited; unable to 
swallow solid foods
unable to drink flu 
ids; requires IV fluids
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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Neuro-Cerebellar
slight incoordination 
dysdiadochokinesis
intention tremor, 
dysmetria,
slurred speech; 
nystagmus
locomotor ataxia
incapacitated
Psychiatric
mild anxiety or 
depression
moderate anxiety or 
depression; therapy 
required; change in 
normal routine
severe mood changes 
requiring therapy; or 
suicidal ideation; or 
aggressive ideation
acute psychosis 
requiring 
hospitalization; or 
suicidal 
gesture/attempt or 
hallucinations
Muscle Strength
subjective weakness 
no objective
symptoms/ signs
mild objective
signs/symptoms no 
decrease in function
objective weakness 
function limited
paralysis
Paresthesia (burning, 
tingling, etc.)
mild discomfort; no 
treatment required
moderate discomfort;
non-narcotic 
analgesia required
severe discomfort; or 
narcotic analgesia 
required with 
symptomatic 
improvement
incapacitating; or not 
responsive to narcotic 
analgesia
Neuro-sensory
mild impairment in 
sensation
(decreased
sensation, eg, 
vibratory, pinprick, 
hot/cold in great toes) 
in focal area or 
symmetrical
distribution; or 
change in taste, 
smell, vision and/or 
hearing
moderate
impairment (mod 
decreased sensation, 
eg, vibratory, 
pinprick, hot/cold to 
ankles) and/or joint 
position or mild
impairment that is not
symmetrical
severe impairment 
(decreased or loss of 
sensation to knees or 
wrists) or loss of 
sensation of at least 
mod degree in 
multiple
different body areas 
(ie, upper and lower
extremities)
sensory loss involves 
limbs and trunk; 
paralysis; or seizures
NCT02935673


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MUSCULOSKELATEL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia (joint pain)
mild pain not 
interfering with 
function
moderate pain, 
analgesics and/or pain 
interfering with 
function but not with 
activities of daily 
living
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living
disabling pain
Arthritis
mild pain with
inflammation,
erythema or joint
swelling – but not
interfering with
function
moderate pain with
inflammation,
erythema or joint 
swelling – interfering 
with function, but not 
with activities of
daily living
severe pain with
inflammation,
erythema or joint
swelling –and
interfering with
activities of daily
living
permanent and/or 
disabling joint
destruction
Myalgia
Myalgia with no 
limitation of activity
muscle
tenderness (at other 
than injection site) or 
with moderate
impairment of activity
severe muscle
tenderness with
marked impairment of 
activity
frank
myonecrosis
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
erythema; pruritus
diffuse, 
maculopapular rash, 
dry desquamation
vesiculation or
moist desquamation 
or ulceration
exfoliative
dermatitis, mucous 
membrane
involvement or 
erythema,
multiforme or 
suspected
Stevens-Johnson
or necrosis requiring 
surgery
Induration
< 15mm
15-30 mm
>30mm
Erythema
< 15mm
15-30 mm
>30mm
Edema
< 15mm
15-30 mm
>30mm
Rash at Injection Site
< 15mm
15-30 mm
>30mm
Pruritus
slight itching at 
injection site
moderate itching at 
injection extremity
itching over entire 
body
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Approved, Date: 20 March 2018
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria; 
angioedema
anaphylaxis
Headache
mild, no treatment 
required
transient, moderate; 
treatment required
severe; responds to 
initial narcotic 
therapy
intractable; requires 
repeated narcotic 
therapy
Fever: oral
37.7 - 38.5 C or 
100.0 - 101.5 F
38.6 - 39.5 C or 
101.6 - 102.9 F
39.6 - 40.5 C or 103 -
105 F
> 40 C or
> 105 F
Fatigue
normal activity 
reduced < 48 hours
normal activity 
decreased 25-
50% > 48 hours
normal activity
decreased > 50%
can’t work
unable to care for self
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Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Attachment 2: Respiratory Infection Symptom Questionnaire©
What time is it? ______ AM / PM (please circle)
Please rate the extent to which you had each symptom during the past 24 hours. 
Not at all
A little bit
Somewhat
Quite a bit
Very much
Runny or dripping 
nose
☐
☐
☐
☐
☐
Congested or stuffy 
nose
☐
☐
☐
☐
☐
Sinus pressure
☐
☐
☐
☐
☐
Scratchy or itchy 
throat
☐
☐
☐
☐
☐
Sore or painful throat
☐
☐
☐
☐
☐
Difficulty swallowing
☐
☐
☐
☐
☐
Teary or watery eyes
☐
☐
☐
☐
☐
Sore or painful eyes
☐
☐
☐
☐
☐
Eyes sensitive to light
☐
☐
☐
☐
☐
Trouble breathing
☐
☐
☐
☐
☐
Chest congestion
☐
☐
☐
☐
☐
Chest tightness
☐
☐
☐
☐
☐
Dry or hacking cough
☐
☐
☐
☐
☐
Wet or loose cough
☐
☐
☐
☐
☐
Felt nauseous 
(feeling like you 
wanted to throw-up)
☐
☐
☐
☐
☐
Stomach ache
☐
☐
☐
☐
☐





We would like to know about the symptoms you have been experiencing during the past 
24 hours. For each symptom, please mark one box ☐under the response that best 
matches your experience. Mark the “Not at all” box, if you did not have that symptom in 
the past 24 hours.
NCT02935673


ALS-008176 (JNJ-64041575, lumicitabine)  
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Approved, Date: 20 March 2018
Please rate the extent to which you had each symptom during the past 24 hours. 
Not at all
A little bit
Somewhat
Quite a bit
Very much
Felt dizzy 
☐
☐
☐
☐
☐
Head congestion
☐
☐
☐
☐
☐
Headache
☐
☐
☐
☐
☐
Lack of appetite
☐
☐
☐
☐
☐
Sleeping more than 
usual
☐
☐
☐
☐
☐
Body aches or pains
☐
☐
☐
☐
☐
Weak or tired
☐
☐
☐
☐
☐
Chills or shivering
☐
☐
☐
☐
☐
Felt cold
☐
☐
☐
☐
☐
Felt hot
☐
☐
☐
☐
☐
Sweating
☐
☐
☐
☐
☐
In the past 24 hours, how often have you had any of the following symptoms?
Never
Rarely
Sometimes
Often
Always
Sneezing
☐
☐
☐
☐
☐
Coughing
☐
☐
☐
☐
☐
Coughed up mucus 
or phlegm
☐
☐
☐
☐
☐
0 times
1 time
2 times
3 times
4 or more 
times
How many times did 
you vomit? 
☐
☐
☐
☐
☐
How many times did 
you have diarrhea?
☐
☐
☐
☐
☐
© Respiratory Infection Symptom Questionnaire, adapted from the FLU-PRO questionnaire by 
permission of the developer.
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ALS-008176 (JNJ-64041575, lumicitabine)  
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Approved, Date: 20 March 2018
Attachment 3: Additional Questions About Health and Functioning
Adult RSV Additional Questionsa
For each of the following questions please select one response only
1. Did you take any medicine for your respiratory infection symptoms today?
Yes
No
2. Did you use any rescue medicine today for asthma or COPD?
I do not take medicine for asthma or COPD
Yes
No
3. Since this time yesterday, how much of the time did you breathe oxygen from an oxygen 
tank?
None of the time
Less than an hour
1 to 4 hours
More than 4 hours
4. Overall, how severe were your respiratory infection symptoms today?
No respiratory infection symptoms today
Mild
Moderate
Severe
Very Severe
5. Overall, how were your respiratory infection symptoms today compared to yesterday?
Much better
Somewhat better
A little better
About the same
A little worse
Somewhat worse
Much worse
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ALS-008176 (JNJ-64041575, lumicitabine)  
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Approved, Date: 20 March 2018
6. How much did your respiratory infection symptoms interfere with your usual activities 
today?
Not at all
A little bit
Somewhat
Quite a bit
Very much
7. Have you returned to your usual activities today?
Yes
No
8. In general, how would you rate your physical health today?
Excellent
Very good
Good
Fair
Poor
9. Have you returned to your usual health today?
Yes
No
a Questions 1, 2, 4-9 adapted for RSV from the FLU-PRO User Manual; question 3 adapted from Janssen 
Observational Protocol NOPRODRSV0004.
Questions 1-3 are only completed during outpatient follow-up as this information will be collected in the eCRF 
during hospitalization.
NCT02935673


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Approved, Date: 20 March 2018
Attachment 4: EuroQol 5-Dimension Questionnaire (EQ-5D)
Health Questionnaire
English version for the USA
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
NCT02935673


ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Under each heading, please check the ONE box that best describes your health TODAY
MOBILITY
I have no problems walking

I have slight problems walking 

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework,
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 

USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018

We would like to know how good or bad your health is 
TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box 
below.
YOUR HEALTH TODAY =
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health       
you can imagine
The worst health
you can imagine
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Attachment 5: Katz Activities of Daily Living
Katz index of independence in activities of daily living
Activities 
Independence 
Dependence 
Points (1 or 0) 
Points (1)
NO supervision, direction, or personal 
assistance
Points (0)
WITH supervision, direction, personal 
assistance or total care
Bathing 
(1 point) Bathes self completely or needs help in 
bathing only a single part of the body such as the 
back, genital area or disabled extremity. 
(0 points) Needs help with bathing more 
than one part of the body, getting in or out of 
the tub or shower. Requires total bathing. 
POINTS:_____ 
Dressing 
(1 point) Gets clothes from closets and drawers 
and puts on clothes and outer garments complete 
with fasteners. May have help tying shoes. 
(0 points) Needs help with dressing self or 
needs to be completely dressed. 
POINTS:_____ 
Toileting 
(1 point) Goes to toilet, gets on and off, arranges 
clothes, cleans genital area without help. 
(0 points) Needs help transferring to the 
toilet, cleaning self or uses bedpan or 
commode. 
POINTS:_____ 
Transferring 
(1 point) Moves in and out of bed or chair 
unassisted. Mechanical transferring aides are 
acceptable. 
(0 points) Needs help in moving from bed to 
chair or requires a complete transfer. 
POINTS:_____ 
Continence 
(1 point) Exercises complete self control over 
urination and defecation. 
(0 points) Is partially or totally incontinent 
of bowel or bladder. 
POINTS:_____ 
Feeding 
(1 point) Gets food from plate into mouth without 
help. Preparation of food may be done by another 
person. 
(0 points) Needs partial or total help with 
feeding or requires parenteral feeding. 
POINTS:_____ 
Total points:_____ 
6 points: high (patient independent).
0 points: low (patient very dependent).
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Approved, Date: 20 March 2018
Attachment 6: Cardiovascular Safety - Abnormalities
ECG
All important abnormalities from the ECG readings will be listed.
Abnormality Code
ECG parameter
HR
PR
QRS
QTcorrected
Abnormalities on actual values
Abnormally low
< 45 bpm
< 110 ms
-
-
Abnormally high
120 bpm
> 220 ms
120 ms
-
Borderline prolonged QT (males)
-
-
-
450 ms < QTc 480 ms
Borderline prolonged QT (females)
-
-
-
470 ms < QTc 480 ms
Prolonged QT
-
-
-
480 ms < QTc < 500 ms
Pathologically prolonged QT
-
-
-
QTc > 500 ms
Abnormalities on changes from baseline (∆QTc)
Normal QTc change
-
-
-
∆QTc < 30 ms
Borderline QTc change
-
-
-
30 ms < ∆QTc < 60 ms
Abnormally high QTc change
-
-
-
∆QTc > 60 ms
For absolute QTc parameters the categories are defined based on the ICH E14 Guidance13F13F13F13F13Fa
Vital Signsb
The following abnormalities will be defined for vital signs:
Abnormality Code
Vital Signs parameter
Pulse
DBP
SBP
Abnormalities on actual values
Abnormally low
< 45 bpm
50 mmHg
90 mmHg
Grade 1 or mild
-
> 90 mmHg - < 100 mmHg
> 140 mmHg - < 160 mmHg
Grade 2 or moderate
-
100 mmHg - < 110 mmHg
160 mmHg - < 180 mmHg
Grade 3 or severe
-
110 mmHg
180 mmHg
Abnormally high
120 bpm
-
-
                                                
a The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs 
CHMP/ICH/2/04, May 2005.
b The classification of AEs related to hypotension and hypertension will be done according to the WHO grading 
scale.
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Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Attachment 7: Visit Schedule for Rash Management for Adult Subjects
This visit schedule summarizes the visits and assessments to be performed in case of rash. At the investigator’s discretion, additional visits 
and assessments can be performed.
Grade 1 Rash
Grade 2 Rash
Grade 3 or 4 Rash
Day 1 of rash1

Study medication may be continued.

Unscheduled visit for initial rash 
evaluation REQUIRED.

Digital pictures REQUIRED (preferably 
within 24h).

Referral to dermatologist (preferably 
within 24h) ONLY IF rash diagnosis or 
relationship with study medication is 
uncertain. 

Study medication MUST be permanently 
DISCONTINUED. Rechallenge is NOT 
ALLOWED.

Unscheduled visit for initial rash 
evaluation REQUIRED.

Digital pictures REQUIRED (preferably 
within 24h).

Referral to dermatologist (preferably 
within 24h) ONLY IF rash diagnosis or 
relationship with study medication is 
uncertain.

Study medication MUST be permanently 
DISCONTINUED. Rechallenge is NOT 
ALLOWED.

Unscheduled visit for initial rash 
evaluation REQUIRED.

Digital pictures REQUIRED (within 24h).

Referral to dermatologist REQUIRED
(preferably within 24h).

At discretion of the investigator or at 
request of the dermatologist, assessment of 
safety blood sample.

Biopsy ONLY IF required by 
dermatologist.
Day 2 

Follow-up visit REQUIRED.2

Digital pictures REQUIRED.

Follow-up visit REQUIRED.2

Digital pictures REQUIRED.

Follow-up visit REQUIRED.

Digital pictures REQUIRED.
Day 3 
No rash follow-up visit required.2
No rash follow-up visit required.2

Follow-up visit REQUIRED.

Digital pictures REQUIRED.

At discretion of the investigator or at 
request of the dermatologist, assessment of 
safety blood sample.
Day 4 
No rash follow-up visit required.2
No rash follow-up visit required.2

Follow-up visit REQUIRED.

Digital pictures REQUIRED.

At discretion of the investigator or at 
request of the dermatologist, assessment of 
safety blood sample.
Day 5 
No rash follow-up visit required.2
No rash follow-up visit required.2

Follow-up visit REQUIRED.

Digital pictures REQUIRED.

At discretion of the investigator or at 
request of the dermatologist, assessment of 
safety blood sample.
Day 6
No rash follow-up visit required.2
No rash follow-up visit required.2

Follow-up visit REQUIRED.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
128
Approved, Date: 20 March 2018
Grade 1 Rash
Grade 2 Rash
Grade 3 or 4 Rash

Digital pictures REQUIRED.

At discretion of the investigator or at 
request of the dermatologist, assessment of 
safety blood sample.
Day 7
No rash follow-up visit required.2
No rash follow-up visit required.2
No rash follow-up visit required.
Day 8

Follow-up visit REQUIRED.2

Digital pictures REQUIRED.

Follow-up visit REQUIRED.2

Digital pictures REQUIRED.
No rash follow-up visit required.
Further Visits
If rash is unresolved after second follow-up 
visit, further visits (with digital pictures) at the 
investigator’s discretion.2
If rash is unresolved after second follow-up 
visit, further visits (with digital pictures) at the 
investigator’s discretion.2
Weekly follow-up visits REQUIRED (with 
digital pictures) until resolution of grade 3-4 
rash to grade ≤2 rash (further follow-up visits 
according to grade 1 or grade 2 rash 
instructions).
1 Note that Day 1 of the rash is the first day of investigator assessment and not the first day of rash as reported by the subject and that the following days are in relation 
to this first assessment (not study days).
2 In case rash progresses from a grade 1 or a grade 2 to a higher grade, start follow-up schedule for grade 2, 3, or 4 rash as appropriate.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
Attachment 8: Details for Pharmacokinetic Sampling and Collection of Food Intake Information
These tables summarize the details on PK sampling and collection of food intake information.
Part 1
Dose #
Dose Name
Day
PK Samplea
Food Intake Information 
Collected (Yes/No)?a,b
1
LD
1
3 samples
postdose at 0.5-1h, 2-3h, and 4-6h 
Yesc
2
MD 1
1 or 2
3 samples
predose, and postdose at 0.5-1.5h and 3-6h
Yesc
3
MD 2
2
1 sample
if patient has not been discharged:
predose (preferable), or random sample
Yesc
4
MD 3
2 or 3
No
No
5
MD 4
3
No
No
6
MD 5
3 or 4
No
No
7
MD 6
4
No
No
8
MD 7
4 or 5
No
No
9
MD 8
5
No
No
10
MD 9
5 or 6
1 sample
Yesc
NA
NA
7
1 sample (random sample at visit)
No
NA
NA
10
1 sample (random sample at visit)
No
Part 2
Dose #
Dose Name
Day
PK Samplea
Food Intake Information 
Collected (Yes/No)?a,b
1
LD
1
2 samples 
postdose at 0.5-1h and 2-3h
Yesc
2
MD 1
1 or 2
2 samples 
predose, and postdose at 3-6h
Yesc
3
MD 2
2
1 sample
if patient has not been discharged:
predose (preferable), or random sample
Yesc
4
MD 3
2 or 3
No
No
5
MD 4
3
No
No
6
MD 5
3 or 4
No
No
7
MD 6
4
No
No
8
MD 7
4 or 5
No
No
9
MD 8
5
No
No
10
MD 9
5 or 6
1 sample
if patient has not been discharged:
predose (preferable), or random sample
Yesc
NA
NA
7
1 sample (random sample at visit)
No
NA
NA
10
1 sample (random sample at visit)
No
Abbreviations: LD: loading dose; MD: maintenance dose; NA: not applicable, PK: pharmacokinetic(s).
a
At the day of discharge, if subject is receiving study drug, a random PK sample is required and also food intake 
needs to be recorded.
b
Record the food intake 30 minutes before or after study drug administration.
c
For hospitalized subjects only.
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ALS-008176 (JNJ-64041575, lumicitabine)  
Clinical Protocol 64041575RSV2003 Amendment 4
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Approved, Date: 20 March 2018
INVESTIGATOR AGREEMENT
I have read this document and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the document and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Guy De La Rosa
Institution:
Janssen Research & Development
Signature:
electronic signature appended at the end of the document
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT02935673


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Guy De la rosa
20Mar2018, 12:15:21 PM, UTC
Document Approval
NCT02935673

SAP_001.pdf: 
1
Approved, Date: 19 October 2016
Janssen Research & Development
Statistical Analysis Plan
A Phase 2b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral 
Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally 
Administered ALS-008176 Regimens in Adult Subjects Hospitalized with Respiratory 
Syncytial Virus
Protocol 64041575RSV2003; Phase 2b
ALS-008176 (JNJ-64041575)
Status:
Approved
Date:
19 October 2016
Prepared by:
Janssen Research & Development, a Division of Janssen Pharmaceutica NV.
Document No.: EDMS-ERI-127084587
Compliance: The study described in this report will be conducted according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Approved, Date: 19 October 2016
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 8
1.4.
Sample Size Justification ................................................................................................................. 8
1.5.
Randomization and Blinding ............................................................................................................ 9
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 10
2.1.
Visit Windows, Phase Definitions and Baseline............................................................................. 10
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 11
2.3.
Analysis sets .................................................................................................................................. 12
2.4.
Statistical Methods......................................................................................................................... 13
2.5.
Definition of Subgroups.................................................................................................................. 13
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 15
4.
ANALYSES........................................................................................................................................ 16
4.1.
SUBJECT INFORMATION............................................................................................................. 16
4.1.1.
Demographics and Baseline Characteristics.............................................................................. 16
4.1.2.
Disposition Information ............................................................................................................... 17
4.1.3.
Treatment Compliance ............................................................................................................... 17
4.1.4.
Extent of Exposure ..................................................................................................................... 17
4.1.5.
Protocol Deviations..................................................................................................................... 17
4.1.6.
Medical History ........................................................................................................................... 18
4.1.7.
Preplanned Surgeries/Procedures ............................................................................................. 18
4.1.8.
Prior and Concomitant Medications............................................................................................ 18
4.2.
EFFICACY ..................................................................................................................................... 19
4.2.1.
Analysis Specifications ............................................................................................................... 21
4.2.1.1.
Level of Significance................................................................................................................ 21
4.2.2.
Data Handling Rules................................................................................................................... 21
4.2.3.
Primary Efficacy Endpoint........................................................................................................... 22
4.2.3.1.
Definition.................................................................................................................................. 22
4.2.3.2.
Analysis Methods .................................................................................................................... 22
4.2.4.
Secondary Efficacy Endpoints.................................................................................................... 25
4.2.4.1.
Definition.................................................................................................................................. 25
4.2.4.2.
Analysis Methods .................................................................................................................... 31
4.2.5.
Patient Reported Outcomes ....................................................................................................... 36
4.2.5.1.
Respiratory Infection Symptom Questionnaire (RSV-PRO).................................................... 36
4.2.5.1.1.
Definition .............................................................................................................................. 36
4.2.5.1.2.
Analysis Methods ................................................................................................................. 37
4.2.5.2.
Adult RSV Additional Questions.............................................................................................. 38
4.2.5.2.1.
Definition .............................................................................................................................. 38
4.2.5.2.2.
Analysis Methods ................................................................................................................. 39
4.2.5.3.
EQ-5D...................................................................................................................................... 39
4.2.5.3.1.
Definitions............................................................................................................................. 39
4.2.5.3.2.
Analysis Methods ................................................................................................................. 40
4.2.5.4.
Katz-ADL ................................................................................................................................. 41
4.2.5.5.
Definition.................................................................................................................................. 41
4.2.5.5.1.
Analysis................................................................................................................................ 41
4.2.6.
Other Efficacy Variable(s)........................................................................................................... 42
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Approved, Date: 19 October 2016
4.2.6.1.
Definition.................................................................................................................................. 42
4.2.6.2.
Analysis Methods .................................................................................................................... 42
4.2.7.
Exploratory Analyses of Special Interest.................................................................................... 43
4.2.7.1.
Relationship between onset of symptoms and viral load ........................................................ 43
4.3.
SAFETY ......................................................................................................................................... 44
4.3.1.
Adverse Events........................................................................................................................... 44
4.3.2.
Clinical Laboratory Tests ............................................................................................................ 46
4.3.3.
Vital Signs................................................................................................................................... 49
4.3.4.
Physical Examination Findings................................................................................................... 51
4.3.5.
Electrocardiogram....................................................................................................................... 51
4.4.
VIROLOGY .................................................................................................................................... 53
4.4.1.
Analysis Time Points .................................................................................................................. 53
4.4.2.
Virus Strain Typing ..................................................................................................................... 53
4.4.2.1.
Analysis Methods .................................................................................................................... 53
4.4.3.
Viral Sequencing......................................................................................................................... 53
4.4.3.1.
Analysis Methods .................................................................................................................... 55
4.5.
MEDICAL RESOURCE UTILIZATION........................................................................................... 55
4.6.
OTHERS ........................................................................................................................................ 55
ATTACHMENT ........................................................................................................................................... 56
REFERENCES............................................................................................................................................ 58
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Approved, Date: 19 October 2016
AMENDMENT HISTORY
Not applicable
ABBREVIATIONS
ADL
Activities of Daily Living
AE
Adverse Event
ANCOVA
Analysis of Covariance
AST
Safety Set or All Subjects Treated
AUC
Area Under the Curve
BMI
Body Mass Index
CAD
Coronary Heart Disease
CI
Confidence Interval
CPAP
Clinical Pharmacology Analysis Plan
CRF
Case Report Form
CRF
Chronic Renal Failure
CSR
Clinical Study Report
CTP
Clinical Trial Protocol
DMC
Data Monitoring Committee
DMID
Division of Microbiology and Infectious Diseases
DLCO
Diffusing capacity of the Lung for Carbon Monoxide
ECG
Electrocardiogram
eCRF
electronic Case Report Form
eCOA
electronic Clinical Outcome Assessment
FDA
Food and Drug Administration
HRQoL
Health-Related Quality of Life
ICH
International Conference on Harmonization
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
ITT
Intention-to-Treat
ITT-i
Intention-to-Treat-infected
IWRS
Interactive Web Response System
LD
Loading Dose
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
MD
Maintenance Dose
OBF
O’Brien-Fleming
PD
Pharmacodynamic
PI
Principal Investigator
PK
Pharmacokinetic(s)
PP
Per Protocol
PT
Preferred Term
qRT-PCR
Quantitative real-time Reverse Transcriptase-polymerase chain reaction
RAND
Randomized Analysis
RNA
Ribonucleic Acid
RSV
Respiratory Syncytial Virus
RT
Randomized or Treated
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
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Approved, Date: 19 October 2016
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables and 
statistical methods for the analysis of efficacy and safety of the investigational compound 
ALS-008176 (also known as JNJ-64041575). The SAP is to be interpreted in conjunction with 
the protocol. A detailed analysis plan for the Interim Analysis will be described in the Interim 
Analysis 
Plan 
(IAP). 
A 
detailed 
analysis 
plan 
for 
the 
pharmacokinetic 
and 
pharmacokinetic/pharmacodynamics data will be described in a Clinical Pharmacology Analysis
Plan (CPAP).
ALS-008176 is a 3’,5’-bisisobutyrate prodrug, which is readily metabolized to the cytidine 
nucleoside analog, ALS-008112. Subsequently, inside cells, ALS-008112 is efficiently converted 
to its nucleoside triphosphate, ALS-008136. This nucleoside triphosphate is a potent inhibitor of 
respiratory syncytial virus (RSV) ribonucleic acid (RNA)-dependent RNA polymerase activity 
and works via a classic chain termination mechanism. ALS-008144, the uridine metabolite of 
ALS-008112, is the inactive major metabolite noted in systemic circulation.
1.1.
Trial Objectives
Primary Objective
The primary objective is to determine in adults who are hospitalized with RSV infection the 
dose-response relationship of multiple regimens of ALS-008176 on antiviral activity based on 
nasal RSV shedding using quantitative real-time reverse transcriptase-polymerase chain reaction 
(qRT-PCR) assay.
Secondary Objectives
The secondary objectives are to determine in adults who are hospitalized with RSV infection:

The impact of ALS-008176 on the clinical course of RSV infection including:

Duration of hospital stay.

Duration of supplemental oxygen.

Evolution of Activities of Daily Living (ADL) as assessed by Katz ADL score.

Time to clinical stability.

Improvement on the ordinal scale.

Rate of mortality and complications.

The time to cessation of nasal RSV shedding.

The impact of ALS-008176 on the emergence of resistant strains of RSV.

The safety and tolerability of ALS-008176.

The pharmacokinetics (PK) of ALS-008112 and ALS-008144 (and other metabolites, if 
applicable) in plasma.
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Approved, Date: 19 October 2016

The relationship between the PK and pharmacodynamics (PD; antiviral activity, clinical 
symptoms, and selected safety parameters) after single (loading dose [LD]) and repeated 
oral dosing (maintenance dose [MD]) of ALS-008176.
Exploratory Objectives
The exploratory objectives are to evaluate in adults who are hospitalized with RSV infection:

The relationship between viral kinetics and clinical outcome, including the relationship 
between RSV RNA viral load and:

Oxygen supplementation.

Duration of hospitalization.

Katz ADL.

Clinical stability.

The impact of the baseline viral subtype and genotype on the antiviral response.

Onset of complications after initiation of treatment.

The impact of ALS-008176 on the clinical course of RSV during and following 
hospitalization as assessed by the subject in the electronic Clinical Outcome Assessment 
(eCOA) using various scoring systems.

The impact of RSV and its treatment on health-related quality of life (HRQoL) as assessed 
by the subject in the eCOA.

The relationship between the Katz ADL and the subject eCOA responses.

Medical resource utilization to manage subjects.

The comparison of the RSV RNA viral loads measured in mid-turbinate nasal swabs and 
endotracheal samples from intubated subjects.

To explore the evolution of diffusing capacity of the lung for carbon monoxide (DLCO) and 
spirometry in subjects hospitalized due to RSV infection.
Additionally, the impact of ALS-008176 on the infectious viral load may be evaluated using a 
quantitative culture of RSV (plaque assay) on a selected number of subjects and samples.
1.2.
Trial Design
This is a randomized, double-blind, placebo-controlled, parallel-grouped, multicenter, 
dose-finding study of ALS-008176. 
A target of approximately 90 subjects, ≥50 years of age who are hospitalized with RSV, will be 
randomly assigned in this study with 30 subjects planned per treatment regimen.
Subjects will be randomized in a 1:1:1 ratio to Regimen A, B, or C:

Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10) of matching 
placebo, administered twice daily.
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Approved, Date: 19 October 2016

Regimen B (low-dose ALS-008176): a single 750 mg LD (Dose 1) followed by nine 250 mg 
MDs (Doses 2 to 10) of ALS-008176, administered twice daily.

Regimen C (high-dose ALS-008176): a single 1,000 mg LD (Dose 1) followed by nine 
500 mg MDs (Doses 2 to 10) of ALS-008176, administered twice daily.
The randomization will be balanced by using randomly permuted blocks and will be stratified by 
region (Japan versus non-Japan) and age (≥50 to <65 years and ≥65 years).
The study will be conducted in 3 phases: a screening phase, a treatment phase from Day 1 to Day 
5/6 (depending on the timing of the LD), and a follow-up phase for a total of 28 days post 
randomization. In the follow-up phase, subjects will have assessments completed at Day 7, Day 
10, Day 14, and Day 28. Depending on discharge date, assessments will be completed either 
while hospitalized or during outpatient visits. For hospitalized subjects additional assessments 
are done as per the Time and Events Schedule. The duration of the subject’s participation will be 
approximately 28 days, screening period not included.
Screening for eligible subjects will be performed as soon as possible following admission to the 
emergency room or hospitalization, such that subjects are randomized within 5 days of RSV 
symptom onset. Men or women ≥50 years of age diagnosed with RSV infection based on a 
polymerase chain reaction (PCR)-based diagnostic assay (with or without co-infection with 
another respiratory pathogen) who have been (or will be) admitted to the hospital and who have 
signed informed consent will be enrolled.
The study drug ALS-008176 will be provided as tablets for oral administration. Study drug 
administration should start as soon as possible, but no later than 4 hours after randomization in 
order to maximize the opportunity for the compound to inhibit viral replication and potentially 
improve outcomes. Subjects will be dosed with a single oral LD followed by 9 MDs twice daily 
(at least 8 hours apart) during Day 1 to Day 5/6 (depending on the timing of the LD). 
Administration of the doses should occur at approximately the same time each day after the 
collection of the mid-turbinate nasal swabs.
Assessments during the study will include the antiviral activity, measured by mid-turbinate nasal 
RSV RNA viral load using a qRT-PCR assay as well as an evaluation of the clinical course of 
RSV infection as assessed by the clinician and an evaluation of RSV disease-related signs and 
symptoms and HRQoL as assessed by the subject.
Safety and tolerability, including AEs, laboratory assessments, ECGs, physical examination, and 
vital signs will be assessed throughout the study from signing of the informed consent form 
(ICF) until the subject’s last study-related activity.
Pharmacokinetic assessments during the study will be based on sparse sampling and will be 
performed using a population PK (popPK) model.
Sequence analysis will be performed to identify pre-existing sequence polymorphisms, to 
characterize RSV variants of the L-gene and other regions of the RSV genome if warranted, and 
to evaluate emergence of any resistance-associated mutations. Additionally, exploratory 
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Approved, Date: 19 October 2016
biomarkers (derived from blood biomarker samples, leftover mid-turbinate nasal specimens, or 
leftover blood samples) may be assessed to determine the effects of ALS-008176 on markers of 
RSV disease.
An unblinded IDMC will be commissioned for this study and a Sponsor Committee will be 
established. Based on the recommendations of the IDMC following interim analyses/reviews of 
PK, efficacy, and safety data, changes to enrollment in the treatment arms, dose regimen 
adjustments, or an increase in dose duration to 10 days may be implemented. A maximum of 2 
interim analyses are planned to assess the primary endpoint for early superiority and futility. The 
first interim analysis will be performed when at least 45 subjects have been randomized, 
preferably after the end of a hemispheric RSV season. If the study is considered underpowered, a 
sample size increase may be suggested to a maximum of 180 subjects.
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis is that there is a positive dose-response relationship of active treatment 
on the average RSV RNA viral load AUC with the average AUC on at least 1 of the active 
treatments being lower than the average AUC on placebo.
1.4.
Sample Size Justification
The primary endpoint in this study is the AUC of the RSV RNA log10 viral load over 7 days (or 
up to 11 days if the dose duration is extended up to 10 days). 
The primary hypothesis is a positive dose-response relationship for the AUC of active treatment 
regimens. The positive dose-response relationship assumes that dose regimens with higher 
exposure with respect to MD will have at least an equal or better effect on viral load. Therefore 
2 contrasts will be tested at each of the interim analysis points and final analysis; a contrast with 
no difference between the 2 active regimens tested against placebo and a contrast with a positive 
linear dose-response relationship with respect to active regimens. With respect to multiple 
contrast testing, multiplicity will be controlled at the pre-specified (interim) alpha level by 
calculating adjusted p-values from the simulated distribution of the maximum or maximum 
absolute value of a multivariate t random vector (ie, using the correlation between the contrasts 
to optimally control for alpha).1 The overall (family-wise) type 1 error rate of 2.5% (1-sided) will 
be adjusted for multiple testing due to formal interim analyses using an O’Brien-Fleming alpha 
spending function with 3 sequential tests (2 interim, 1 final).5 As based on 10,000 simulations a 
sample size of 90 subjects randomized in a 1:1:1 ratio (placebo: low-dose ALS-008176: 
high-dose ALS-008176) will offer approximately 90% power to detect a positive dose-response 
relationship as defined assuming an effect size of 0.77 using Cohen’s d (ie, the effect size 
expressed as the ratio of the standard deviation of the AUC) and approximately 80% power 
assuming an effect size of 0.67 (Cohen’s d). Based on the results of the ALS-008176 RSV 
human challenge study, these effect sizes were considered plausible.6
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Approved, Date: 19 October 2016
1.5.
Randomization and Blinding
Randomization and stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 3 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by region (Japan versus non-Japan) and 
age (≥50 to <65 years and ≥65 years).
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the Interactive Web Response System (IWRS), which has the functionality to allow the 
investigator to break the blind for an individual subject.
Data that may potentially unblind the treatment assignment (ie, study drug concentrations, study 
drug preparation/accountability data, treatment allocation, biomarker, or other specific laboratory 
data) will be handled with special care to ensure that the integrity of the blind is maintained and 
the potential for bias is minimized. This can include making special provisions, such as 
segregating the data in question from view by the investigators, clinical team, or others as 
appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until the unblinded IDMC review. 
The blind will also be broken for the interim analyses or when all subjects have completed the 
study and the database is finalized. Otherwise, the blind should be broken only if specific 
emergency treatment/course of action would be dictated by knowing the treatment status of the 
subject. In such cases, the investigator may in an emergency determine the identity of the 
treatment by contacting the IWRS. It is recommended that the investigator contact the sponsor or 
its designee if possible to discuss the particular situation, before breaking the blind. Telephone 
contact with the sponsor or its designee will be available 24 hours per day, 7 days per week. In 
the event the blind is broken, the sponsor must be informed as soon as possible. The date, time, 
and reason for the unblinding must be documented by the IWRS in the appropriate section of the 
electronic case report form (eCRF), and in the source document. The documentation received 
from the IWRS indicating the code break must be retained with the subject’s source documents 
in a secure manner.
Subjects who have had their treatment assignment unblinded should continue to return for 
scheduled evaluations. Discontinuation of study treatment should be done only for the reasons 
stated in Section 10.2 of the protocol; unblinding of study treatment should not necessarily lead 
to study drug discontinuation.
In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, if an interim analysis is specified, the randomization codes 
and, if required, the translation of randomization codes into treatment and control groups will be 
disclosed to those authorized and only for those subjects included in the interim analysis.
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Approved, Date: 19 October 2016
2.
GENERAL ANALYSIS DEFINITIONS
All analysis dataset preparations and statistical analyses will be performed using SAS ® version 
9.2.
2.1.
Visit Windows, Phase Definitions and Baseline
Figure 1: Schematic Overview of the Study
Phases will be constructed as follows: 
Trial phase
Start date
End date
Screening 
(phase 0)
00:00 of the date of signing the informed 
consent form
1
minute 
before 
the 
first 
study 
medication intake
Treatment
(phase 1)
Datetime of first study medication intake
Datetime of last study medication intake 
+ 72 hours
Follow-up
(phase 2)
End of the phase 1 +1 minute
23:59 of trial termination date (date of 
last contact).
The last phase, whichever it is for a subject, always ends on 23:59 of the day of trial termination 
(last contact). 
Events will be assigned to phases based on their datetime, but seconds will be ignored overall. If 
the daypart of the start date of the event is present but the timepart is missing, the event will be 
treated as if it started at 00:00 on the day of the event. If the daypart of the end date of the event is 
present but the timepart is missing, the event will be treated as if it happened at 23:59 on the day of 
the event.
The number of days in the study (reldy) will be defined as:
reldy = visit day – reference day+1
for visits on or after the reference day, and 
reldy = visit day – reference day 
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for visits before the reference, where the reference day equals the start date of the treatment 
phase.
All scheduled assessments after first administration of trial medication will be used. 
Unscheduled assessments post-dose will not be used in descriptive statistics or any per-time 
point analysis, but will be used in the determination of the worst-case per treatment, and in 
listings as applicable. 
For assessments on day 1 to 6 and for daily assessments after day 6, the numeric analysis visits 
(AVISITN) will be equal to the relday.
For assessments on Day 7, Day 10, Day 14 and Day 28, the following table will be used to 
allocate analysis time points:
Target Day
Analysis time point 
(numeric version)
Analysis time point
Time interval (days)
7
7
Day 7
[7,9]
10
10
Day 10
[10,12*]
14
14
Day 14
[12*,16]
28
28
Day 28
[17,+∞[
For Katz ADL, DLCO and Spirometry, vital signs and physical examination in outpatients, 12-lead ECG, Mid-
tubinate nasal swabs, blood sampling for hematology and biochemistry
* Depending on the VISIT label, subjects returning on Day 12 should be assigned to Day 10 or Day 14
For the analyses per time point in order to have only one evaluation per subject per analysis time point, the 
following rules will be applied:
In case multiple nasal swabs were taken on a single day, the average on the log scale will be used as the value for 
that subject. For other assessments, if there are two measurements on the same date and/or time, then the 
measurement with the highest sequence number will be used.
If two assessments on different days fall within the same interval, the measurement closest to the target day will be 
used. If they are equidistant, the last measurement within the interval will be used.
The baseline record (day 1) is defined as the last record before the first intake of the study drug.
For RSV RNA viral load, in case a result is available that is no later than 1 hour after treatment 
initiation this may be used, but only if no pre-treatment observation is available.
On-treatment is defined as the period from the first medication intake until last medication intake
+ 72 hours (i.e. Treatment Phase).
2.2.
Pooling Algorithm for Analysis Centers
If positive treatment effects are found in a trial with appreciable numbers of subjects per centre, 
there should generally be an exploration of the heterogeneity of treatment effects across centers, 
as this may affect the generalizability of the conclusions. As it is expected that for this trial 
subjects will be recruited over a large number of centers with a small number of subjects per 
study center, there is no need to check for treatment by center interactions. In addition, the 
primary endpoint is an objective endpoint, which is evaluated by a central viral monitor, and 
thus, no heterogeneity across centers is anticipated. Therefore, no pooling algorithm for analysis 
centers will be specified.
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2.3.
Analysis sets
The analysis populations covered by this SAP will be: 
Randomized Analysis set (RAND): All randomized subjects with a randomization date at or 
before the date of first intake of medication, or with a randomization date and a missing date 
for first medication intake.
Safety Set or All Subjects Treated set (AST): All subjects who received at least 1 dose of study 
drug, analyzed as treated.
Randomized or Treated (RT) set: All subjects who are in the Randomized Analysis Set (RAND) 
and/or the All Subjects Treated (AST) set.
Intention-To-Treat (ITT) set: All randomized subjects who receive at least 1 dose of study drug.
Analyses on the ITT Set will be analyzed as randomized.
Intention-To-Treat-infected (ITT-i) set: All randomly assigned subjects who receive at least 1 
dose of study drug and who have an RSV infection confirmed by a PCR-based assay at the 
central laboratory.
For the interim analysis: a subject is considered to have a confirmed infection with RSV if 
he/she has been diagnosed with RSV infection based on a PCR-based assay at the local
laboratory and for which the RSV infection is confirmed by central laboratory or for which 
the result of the central laboratory testing is not available at cut-off.
Analyses on the ITT-i Set will be analyzed as randomized.
Per-Protocol (PP) Analysis set: All subjects in the ITT-i set who do not have protocol violations 
that may have an impact on the efficacy analysis. Decisions regarding which subjects are 
included in the PP set will be made before database lock on following criteria:
●
Compliance: Subjects must have at most 1 missed dose. On the day of 
randomization at least one dose needs to be taken (so missed dose cannot be the 
first dose).
●
The actual treatment must be the same as the planned treatment.
●
No unblinding may have taken place during the study.
●
Subjects will be excluded from the PP set if they have taken concomitant 
medications that may have affected the efficacy of the trial medication. Subjects 
will be excluded on a case by case basis using a list provided by clinical.
●
Subjects may not violate inclusion criteria 3 or 4, nor exclusion criteria 1, 3, 8, 9, 
10 or 13.
Analyses on the Per-Protocol set will be analyzed as randomized. Note that in the Per-
Protocol set subjects will have been treated as randomized by definition.
The Randomized or Treated Analysis set (RT) will be used in all listings. The Safety set or All 
Subjects Treated set (AST) will be used to perform the evaluation of all safety variables. The 
Intention-To-Treat-infected set (ITT-i) will be used to perform the evaluation of all efficacy 
variables. The Per-Protocol (PP) and Intention-To-Treat (ITT) sets will be used to provide 
supportive analysis of the primary and selected secondary endpoints only (hospital length of stay, 
hospital discharge readiness, need for and duration of supplemental oxygen and time to clinical 
stability, ordinal scale score).
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2.4.
Statistical Methods
This SAP covers the statistical analysis for the final analysis. The interim analysis and IDMC 
analysis will be described in separate SAPs. Details of the single displays are described in the 
Data Presentation Specifications (DPS). 

The analysis population will be indicated in the titles of the displays. 

Unless stated otherwise, all results will be presented per treatment group. Tables on 
subject disposition, exposure, demographic data and baseline disease characteristics will 
include a ‘Total’ group, pooling all subjects. Tables on safety will include a “ALS-
008176“ group.

Listings will be presented by treatment group and ordered by subject number and time 
point (if applicable).

All outputs should be self-explanatory and therefore appropriate footnotes will be 
provided to clarify the contents of each listing, table or graph.

In case the X-axis of a graph shows a time component, the distances between the time 
points will be proportional (not equidistant). Furthermore, when statistics are joined over 
time by a line, the actual statistics will be depicted by means of a symbol.

Unless specified otherwise, continuous parameters will be summarized using the 
following statistics: number of observations, mean, standard deviation, minimum, median 
and maximum. The mean and median will be presented with one decimal place, while the 
standard deviation with two decimal places more than the decimal places of the raw data. 
The minimum and maximum will be presented to the same number of decimal places as 
the raw data.

RSV RNA viral load mentioned in this document refers to the RSV RNA viral load qRT-
PCR from nasal swab, unless otherwise stated.
2.5.
Definition of Subgroups
The following subgroups will be investigated for efficacy (primary and selected secondary 
endpoints):
Region [Japan, non-Japan]
Age category [≥50 to <65 years and ≥65 years] 
Sex [Female, Male]
Baseline RSV Viral load [≤C log10 copies/mL, >C log10 copies/mL] with C = rounded 
median
Comorbidities [Yes, No]
Use of systemic corticosteroids prior to treatment with ALS-008176 [Yes, No]
Duration of RSV symptoms prior to first treatment [≤3 Days; >3 Days]
Baseline viral subtype [RSV A; RSV B]
Completion of planned study therapy 
The following subgroups will be investigated for safety (complete safety for region, selected 
summary tables for age category, race and BMI):
Region [Japan, non-Japan]
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Age category [≥50 to <65 years and ≥65 years] 
Race [Caucasian, Black, Asian, Other]
BMI [<25; 25-<30; ≥30]
Medical review will be done immediately before data base lock on a list with unique coded 
medical history terms (MedDRA Preferred Terms) to indicate which subjects had comorbidities. 
The following list of comorbid disease will be identified and potentially analyzed for efficacy (in 
case at least 15 subjects are enrolled in each of the subgroups):

Comorbid diseases associated with risk for lower respiratory tract disease[1][2]
o
Asthma [Yes/No]
o
COPD [Yes/No]
o
CHF [Yes/No]
o
CAD (coronary artery disease) [Yes/No] 

Other conditions/therapy of potential interest due to risk of infections in general:
o
Diabetes mellitus [Yes/No] 
o
CRF (Chronic Renal Failure) [Yes/No] 
o
Use of systemic corticosteroids (PO, IV) prior to or during the treatment phase 
[Yes/No], based on medical review on a list with unique coded concomitant 
medications.
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3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
The IDMC will review the safety data initially after approximately 12 subjects have completed
treatment and when approximately 12 Japanese subjects have completed treatment to assess that
treatment may safely continue in each arm. A separate SAP will be written that provides details 
on the data package for this purpose. Details on operational characteristics will be provided in 
the IDMC Charter.
In addition, a maximum of 2 interim analyses are planned to assess the primary endpoint for 
early superiority and futility. The first interim analysis will be performed when at least 45 
subjects have been randomized, preferably after the end of a hemispheric RSV season. Up to the 
final database lock, the study team will remain blinded to the results. Details on operational 
characteristics will be provided in the interim analysis charter. An Interim Analysis SAP will be 
written that describes this formal interim analysis, focusing on the rules of futility, early 
superiority and sample size recalculation.
This interim analysis will be based on the subjects randomized up to that timepoint in the ITT-i 
Set. 
The following situations will be considered based on the results of the primary analysis at this 
stage: that the study is considered futile; that superiority can be concluded (based on an 
O’Brien-Fleming alpha spending function); that the study is considered underpowered; or that 
the study should continue unchanged. In the case of the (unbinding) futility boundary or the 
superiority boundary being crossed, the IDMC will recommend early termination to the 
Sponsor Committee. If the study is considered underpowered, a sample size increase may be 
suggested to a maximum of 180 subjects. This blinded sample size calculation will take the 
residual error variance into account of the primary analysis model.
If early superiority on the primary endpoint can be established, the study may, however, be 
continued in order to accumulate data to allow the selection of the dose regimen or further 
substantiate the benefit-risk profile in this population; in this case the randomization ratio of 
active to placebo treatment may be altered for example, if dose selection is evident from the 
dose-response analysis, subjects randomized to active treatment may all receive the optimal dose. 
However, at the interim analyses or at any time, upon recommendation by the IDMC, a dose 
regimen may be removed or adjusted based on PK, safety, and/or antiviral activity 
considerations.
The Interim Analysis Committee will be responsible for performing the formal interim analysis 
and will consist of sponsor personnel who are not otherwise involved in the study. The IDMC 
will review the data and make recommendations to the Sponsor Committee.
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4.
ANALYSES
4.1.
SUBJECT INFORMATION
All general analyses will be done on the ITT-i Set and the Safety Set, unless specified otherwise 
for a specific display.
4.1.1.
Demographics and Baseline Characteristics
All demographics and baseline characteristics will be summarized overall and by treatment 
group. Descriptive statistics or frequency tabulation will be provided for the following 
parameters.
Demographic parameters:
Sex (Male, Female, Undifferentiated)
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Other). The specification of the category ‘Other’ 
will only be listed.
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
Country (from [DM] dataset)
Geographic region (based on country: North America [to include Puerto Rico], Europe,
South America, Asia-Pacific)
Age (years)
Weight at baseline (kg)
Height at baseline (cm)
BMI at baseline = Weight at baseline (kg) / (Height at baseline (m))2 
(rounded to 1 decimal. Even if available in the raw data, BMI will be recalculated from 
baseline weight and height)
Baseline disease characteristics:
Duration of RSV symptoms prior to first treatment (days)
Presence of comorbidities (yes, no)
Comorbid diseases associated with risk for lower respiratory tract disease[1][2] (yes, no) and  
proportion of subjects suffering from each of the following diseases:
o
Asthma
o
COPD
o
CHF
o
CAD (coronary artery disease) 
Other conditions/therapy of potential interest due to risk of infections in general (yes, no) and 
proportion of subjects with each of the following conditions/therapies:
o
Diabetes mellitus 
o
CRF (Chronic Renal Failure)
o
Use of systemic corticosteroids (PO, IV) prior to or during the treatment
Baseline RSV Viral load (log10 copies/mL) 
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Previous use of aerosolized ribavirin (yes, no)
Previous use of IV immunoglobulin (yes, no)
Oxygen Saturation (%)
Receiving Supplemental Oxygen (yes, no)
Intravenous or enteral tube feeding (yes, no)
Intravenous or enteral tube hydration (yes, no)
Respiratory Rate (breaths/min)
Heart Rate (beats/min)
4.1.2.
Disposition Information
Summaries will be provided for the following disposition information:

Number of subjects screened, screen failures, randomized or treated, not randomized, 
randomized and not treated, treated and not randomized, safety set, randomized and 
treated, treated but not RSV infected, treated and RSV infected and per protocol set.

Number of subjects who completed or discontinued treatment and the trial, with a 
breakdown of the reasons of discontinuation.

Number of subjects per phase and per visit in the trial.
4.1.3.
Treatment Compliance
Dosing compliance is calculated as the actual number of doses taken, as a percentage of the 
planned number of doses. The actual number of doses can be calculated from the number of 
doses dispensed (18 tablets) minus the number of doses returned (from [da] data set: number of 
tablets returned). The planned number of tablets is 12. In case the length of duration is increased, 
the calculation will take the new planned number into account.
Dosing compliance will be summarized descriptively by treatment group.
4.1.4.
Extent of Exposure
The treatment duration is defined as date/time of last study drug intake – date/time of first study 
drug intake + 72 hours.
Note: treatment interruptions will not be taken into account for the above definition.
Actual treatment duration will be summarized descriptively by treatment group.
4.1.5.
Protocol Deviations
Only major protocol deviations will be defined in this trial. All major protocol deviations will be
listed, including the deviations to the inclusion-exclusion criteria, and the violations to the
prohibitions and restrictions, if any.
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Note that the Per-protocol set definition takes into account any deviation from the protocol that 
could affect the efficacy. These are not necessarily major deviations, nor are major deviations 
considered to always affect efficacy and to warrant exclusion from the PP analysis.
4.1.6.
Medical History
The medical history records will be listed; separate listings will be generated for conditions of
interest (allergic/immunologic, dermatological)
4.1.7.
Preplanned Surgeries/Procedures
Preplanned surgeries and procedures will be listed.
4.1.8.
Prior and Concomitant Medications
Medications taken 14 days before the Screening Visit and up to the Safety Follow-up Visit will 
be summarized by preferred term using the World Health Organization-Drug Dictionary for the 
ITT-i Set as frequency tables in 2 parts: 
1. Prior medication: medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended 
2. Concomitant medication: medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date. 
(Medication that started before the first dose of study drug and continued after the first dose of 
study drug will be summarized as prior medication and separately as concomitant medication.) 
The part on concomitant medication will be shown by ATC class level up to level 3. 
If a prior/concomitant therapy record misses components of its start and/or stop dates (time 
and/or day and/or month and/or year), the following actions will be taken: 
1. In case of partial start or stop datetimes, the concomitant therapy records will be allocated 
to prior/concomitant using the available partial information, without imputations. 
2. In case of a completely missing start date, the prior/concomitant therapy will be 
considered as having started before the trial. 
3. In case of a completely missing end date, the prior/concomitant therapy will be 
considered as ongoing at the end of the trial. 
Separate tables will be made for medication related to fever and not related to fever. Medication 
related to fever will be categorized as Acetaminophen/paracetamol, Ibuprofen, or other.
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4.2.
EFFICACY
The efficacy analyses include the following primary, secondary and exploratory endpoints.
Primary endpoint

RSV RNA log10 viral load (measured by qRT-PCR in the mid-turbinate nasal swab 
specimens) AUC from immediately prior to first dose of study drug (baseline) until Day 7 (or 
up to 11 days if the dose duration is extended to up to 10 days).
Secondary endpoints

RSV clinical course endpoints:
-
Length of hospital stay from admission to discharge and from study treatment initiation to 
discharge.
-
Length of hospital stay from admission to readiness for discharge and from study treatment 
initiation to readiness for discharge, with readiness for discharge defined by the investigator.
-
Need for and duration of intensive care unit (ICU) stay.
-
Need for and duration of supplemental oxygen (regardless of method used).
-
Number of hours until peripheral capillary oxygen saturation (SpO2) ≥93% on room air
among subjects who were not on supplemental oxygen prior to current hospitalization.
-
Respiratory rate, SpO2, and body temperature return to pre-RSV disease level.
-
Need for and duration of noninvasive ventilator support (eg, continuous positive airway
pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation or
mechanical ventilation via tracheostomy).
-
Time to return to pre-RSV functional status (Katz ADL score).
-
Need for hydration and feeding by IV catheter/enteral tube.
-
Time to clinical stability defined as the time at which the following criteria are all met:
o
normalization of blood oxygen level (return to baseline; by pulse oximetry) without
requirement of supplemental oxygen beyond baseline level
o
normalization of oral feeding
o
normalization of respiratory rate
o
normalization of heart rate
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-
Improvement on the ordinal scale
-
All-cause mortality.

RSV RNA viral load as measured by qRT-PCR of the mid-turbinate nasal swab specimens
which will be used to determine the following: 
-
Viral load over time. 
-
Peak viral load, time to peak viral load, rate of decline of viral load, and time to RSV RNA 
viral load being undetectable.
-
Proportion of subjects with undetectable viral load at each time point.
-
RSV RNA viral load AUC from immediately prior to first dose of study drug (baseline) until 
Day 10 and until Day 14.
Exploratory endpoints

The amount of:
-
Supplemental oxygen above pre-RSV disease level (regardless of method used) from study 
treatment initiation to Day 7. 
-
Oxygen delivered by noninvasive ventilator support (eg, continuous positive airway
pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation or
mechanical ventilation via tracheostomy). 
-
Subjects (proportion) who started antibiotic use after the first dose of the study drug. 

Disease status and presence of complications with onset after treatment initiation: 
-
Bacterial superinfections reported as AEs (eg, pneumonia, acute otitis media, sinusitis,
bronchitis, bacteremia). 
-
Exacerbations of underlying pulmonary disease (eg, asthma, chronic obstructive pulmonary 
disease). 
-
Cardiovascular and cerebrovascular events (eg, myocardial infarction, congestive heart
failure exacerbation, arrhythmia, stroke). 
-
Respiratory failure
-
Clostridium difficile associated diarrhea
-
Other
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
Duration and severity of signs and symptoms of RSV infection as assessed by the respiratory 
infection patient-reported outcome (RI-PRO) questionnaire and additional questions about 
health and functioning completed by the subject in the eCOA.

HRQoL assessed by the EuroQoL 5 Dimension visual analogue scale (EQ-5D VAS)
completed by the subject in the eCOA.

Hospital readmission for respiratory reasons up to the Day 28 follow-up visit.

RSV RNA viral load (AUC) as measured by qRT-PCR of endotracheal samples in intubated
subjects. 

Lung function measured by the DLCO and spirometry test. 

RSV infectious viral load as measured using a quantitative viral culture (plaque assay). 
4.2.1.
Analysis Specifications
All efficacy analyses will be analyzed in the ITT-i set (except for the primary endpoints and 
selected secondary endpoint which will also be analyzed on the ITT and PP Sets) and will be 
tabulated per treatment group for each stratum separately (region and age) and per treatment 
group overall (over all strata).
4.2.1.1.
Level of Significance
The primary hypothesis is a positive dose-response relationship for the AUC of active treatment
regimens. The positive dose-response relationship assumes that dose regimens with higher
exposure with respect to MD will have at least an equal or better effect on viral load. Therefore 2 
contrasts will be tested at each of the interim analysis points and final analysis; a contrast with no 
difference between the 2 active regimens tested against placebo and a contrast with a positive
linear dose-response relationship with respect to active regimens. With respect to multiple
contrast testing, multiplicity will be controlled at the prespecified (interim) alpha level by 
calculating adjusted p-values from the simulated distribution of the maximum or maximum
absolute value of a multivariate t random vector (ie, using the correlation between the contrasts
to optimally control for alpha)1.The overall (family-wise) type 1 error rate of 2.5% (1-sided) will
be adjusted for multiple testing due to formal interim analyses using an O’Brien-Fleming alpha
spending function with 3 sequential tests (2 interim, 1 final)5.
4.2.2.
Data Handling Rules
For analysis purposes the log10 qRT-PCR viral load will be imputed with 0 when the result is 
‘negative’, and the midpoint on the log scale between the limit of detection and limit of 
quantification when the result is ‘positive’ but non-quantifiable.
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4.2.3.
Primary Efficacy Endpoint
4.2.3.1.
Definition
The primary estimates of the AUC will be derived from a mixed model (see section 4.2.3.2 for 
the detailed specification). No imputations of missing data from nasal swabs post-baseline will 
be done in this model, as this mixed model would allow to make inferences under the missing at 
random assumption.
Note that for the primary endpoint the following rules apply:

Only values as provided by the central lab will be used.

Baseline (Day 1) is defined as the last measurement before first intake. In case a result is 
available that is no later than 1 hour after treatment initiation this may be used but only if 
no pre-treatment observation is available.

If for the baseline assessment the central laboratory value is missing, the value that will 
be imputed is based on the average value as based on the analysis population (ITT-i, ITT 
or PP population).

For all post-baseline days the RSV RNA viral load result of the swab that was performed 
at that day will be used, counting from the Day of first treatment which is defined as Day 
1. 

In case multiple nasal swabs were taken on a single day the average on the log scale will 
be used as the value for that subject.  
As a sensitivity analysis, descriptive statistics will be provided for the viral load AUC calculated 
by the trapezoidal summation rule, based on planned days of sampling (Baseline visit up 
till/including Day 7 visit, or up to 11 days if the dose duration is extended to up to 10 days), 
including the timepoints with (imputed) values available: 
	 
 = 

 ∑
( + ) × ( −)


  
where i=1,2,3,…n are the time points when post baseline samples are collected, yi is the log 10 
viral load at the time and ti is the time in hours post baseline.  yo is the baseline log 10 viral load.  
t0 is time 0. 
The following additional rules, on top of the rules of the primary analysis, will be applied to deal 
with missing values post-baseline before calculating the Viral load AUC:

Missing value between baseline and day 7 will be imputed by intrapolation.

If the last observations are missing, the last available observation will be carried forward. 
Unscheduled assessments will be included and will be eligible for carrying forward.
4.2.3.2.
Analysis Methods
Mean log10 viral load values over time will be analyzed using a restricted maximum likelihood 
based repeated measures approach. Analyses will include the fixed, categorical effects of 
treatment, strata, visit, and treatment-by-visit interaction, as well as the continuous, fixed 
covariates of baseline log10 viral load and baseline log10 viral load by-visit interaction. An 
unstructured covariance structure will be selected. In case this model will not converge, the 
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following list of covariance structures will be applied and a selection will be based on the Akaike 
Information Criterion for those that do converge:

Unstructured [UN] 

Ante-dependence [ANTE(1)] 

Heterogenous Toeplitz [TOEPH] 

Heterogeneous CS [CSH] 

Heterogeneous AR(1) [ARH(1)] 

Toeplitz [TOEP] 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom.
The testing of the dose-response relation is based on the expectation that higher dose regimens 
will be at least as efficacious as lower dose regimens with respect to efficacy on the viral load 
over time. Therefore, two contrasts on the dose regimens have been selected that are consistent 
with this expectation: a contrast with no difference between the 2 active regimens tested against 
placebo and a contrast with a positive linear dose-response relationship with respect to active 
regimens. A multiple comparison approach will be taken testing the 2 contrasts combined versus 
placebo, adjusted for multiplicity.
The SAS mock code used to test the primary hypotheses will be as follows:
proc mixed data=viral_load;
where avisitn in (2,3,4,5,6,7)
class avisitn trt usubjid stratum;
model logtiter = trt|avisitn stratum base|avisitn /ddfm=kr s;
repeated avisitn/subject=usubjid type=un;
lsmestimate trt*avisitn
"Plateau" -4 2 2 -4 2 2 -4 2 2 -4 2 2 -4 2 2 -2 1 1,
"Linear" -4 0 4 -4 0 4 -4 0 4 -4 0 4 -4 0 4 -2 0 2
/divisor=4 adjust=simulate seed=3369 alpha=α* lower cl;
run;
The variable trt denotes the placebo, low dose regimen, and high dose regimen treatment groups, 
the avisitn variable denotes the swabbing visits at Days 2 through 7, and the base variable is the 
baseline log10 viral load measured at Day 1.
The significance level of alpha (α*) will have to be calculated based on the information fraction 
at the time of the test using the pre-specified O’Brien-Fleming (OBF) spending function. 
α*(t’) = 2 - 2ϕ (Zα/2 /√t′)
where t’=n/N, n is the ITT-i set size and N is the expected ITT-i set size at the end of study (=90)
and ϕ denotes the standard normal cumulative distribution function.
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The lower option is selected as the contrast needs to have a value below zero (ie, there needs to 
be a reduction in AUC comparing active treatment to placebo). In summary, a positive dose-
response relationship will be concluded if based on this analysis for any of the two estimations 
the resulting adjusted p-value is lower than the associated OBF critical value. 
The differences in the AUCs for active versus placebo will be derived using appropriate contrasts 
deriving least square mean differences, including the 95% 2-sided confidence intervals.
The individual AUC as calculated using the trapezoidal rule will be considered as a supportive 
analysis and will be analyzed using a linear model with AUC as a dependent variable and 
treatment group and stratum as fixed factors, and baseline log10 viral load as fixed covariate. For 
this analysis no adjustments for multiplicity will be applied, that is the differences versus placebo 
will be estimated using appropriate contrasts with 95% confidence intervals.
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4.2.4.
Secondary Efficacy Endpoints
4.2.4.1.
Definition
Formulae to be used for derived variables, including data conversions, are provided in Table 1.  
In the derivation of durations described below, no imputation of the start and/or end date/time 
will be performed.
Table 1. Calculations and Conversion Formulae
Measurement
Formula
Length of hospital stay
(hours) [Time-to event]
Time 
to 
readiness 
for 
discharge (hours) [Time-to-
event]
(Date and time of event or censoring -  date and time of first dose 
of study drug)/3600, rounded to one decimal
Subjects who complete or withdraw from the study prior to the
event will be censored at the date of completion or withdrawal. If 
the time is not available they will be censored at 12:00. In case of 
death prior to an event the time of death will be taken as censoring 
time (or 12:00 if not available).
Length of hospital stay 
since hospital admission
(hours) [Time-to event]
Time 
to 
readiness 
for 
discharge 
since 
hospital 
admission (hours) [Time-
to-event]
(Date and time of event or censoring -  date and time of hospital 
admission)/3600, rounded to one decimal
Subjects who complete or withdraw from the study prior to the
event will be censored at the date of completion or withdrawal. If 
the time is not available they will be censored at 12:00. In case of 
death prior to an event the time of death will be taken as censoring 
time (or 12:00 if not available).
ICU 
duration 
of
stay 
(hours) [Duration]
Duration of supplemental 
oxygen (hours) [Duration]
(3 
separate 
parameters: 
supplemental 
oxygen, 
invasive ventilator, non-
invasive ventilator)
Need for feeding, hydration
by IV catheter/enteral tube 
(hours)
[Duration]
(2 separate parameters)
sum of [(end date and time of event - start date and time of 
event)/3600], rounded to one decimal 
If the end date is missing, the end date is considered to be after 
study completion or withdrawal.
If the initial start time is prior to the first dose of study drug, the 
duration prior to the first dose of study drug will be deducted from 
the overall duration.
If 
the 
end 
date 
and 
time 
is 
after 
the 
study 
completion/discontinuation, the duration after the date and time of 
study completion/discontinuation will be deducted from the overall 
duration. If the time is not available it will be put at 12:00.
Time to end of Oxygen 
supplementation
(hours)
(Date and time of event or censoring - date and time of first dose of 
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[Time-to-event]
(3 
separate 
parameters: 
overall, 
invasive,
non-
invasive)
Time 
to 
end 
of  
supplementation 
feeding, 
hydration (hours) [Time-to-
event] 
(2 separate parameters)
study drug)/3600, rounded to one decimal
The event is defined as the last end date and time of the measured 
parameter (supplemental oxygen, invasive oxygen, non-invasive 
oxygen, feeding or hydration). If this date is missing, the end date 
is considered to be after study completion or withdrawal.
Subjects who complete or withdraw from the study prior to the last 
end date and time of the measured parameter will be censored at 
the date of completion or withdrawal. If the time is not available 
they will be censored at 12:00. In case of death prior to the last end 
date and time of the measured parameter, the time of death will be 
taken as censoring time (or 12:00 if not available).
If no oxygen supplementation, supplemental feeding or hydration
was necessary post baseline, the value will be set to 0.
Time point of SpO2 ≥ 93% 
on room air
The first time point with SpO2 ≥ 93%, where no supplemental 
oxygen supplementation is given at or after this time point and 
where no value < 93% are measured after this time point. 
Time to SpO2 ≥ 93% 
(hours) on room air [Time-
to-event]
minimum[date and time of time point with SpO2 ≥ 93% on room 
air, date and time of last SpO2 measurement] -  date and time of 
first dose of study drug)/3600†, rounded to one decimal
Subjects with SpO2<93% on room air or who are still on oxygen 
supplementation at the last SpO2 assessment will be censored at 
the date and time of the last SpO2 assessment.
This parameter will only be calculated for subjects who were not 
on supplemental oxygen prior to current hospitalization
Time point of return to pre-
RSV disease level (hours) 
for 
HR, 
RR, 
SpO2 
(3 separate parameters)
The first time point where it is indicated by the investigator that the 
observed value is normal for the subject, and for none of the time 
points after this point in time the values are indicated to be 
abnormal for the subject (separate for HR, RR or SpO2).
Time to return to pre-RSV 
disease level (hours) for 
HR, RR, SpO2 [Time-to-
event]
(minimum[date and time of time point of return to pre-RSV disease 
level, date and time of last measurement] -  date and time of first 
dose of study drug)/3600, rounded to one decimal
If none of the values are indicated to be abnormal for the subject, 
this value will be set at time 0.
Subjects with an abnormal value at the last assessment will be 
censored. Subjects for which this last assessment is the baseline 
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assessment will be censored at time 0.
Time to return to pre-RSV 
disease 
feeding 
status 
(hours) [Time-to-event]
(Date and time of event or censoring -  date and time of first dose 
of study drug)/3600, rounded to one decimal
All subjects are assumed to have no supplemental feeding pre-
RSV.
The event is defined as the last available end date and time 
supplemental feeding was provided. If this date is missing, the end 
date is considered to be after study completion or withdrawal
Subjects who complete or withdraw from the study prior to the 
event will be censored at the date of completion or withdrawal. If 
the time is not available they will be censored at 12:00. In case of 
death prior to an event the time of death will be taken as censoring 
time (or 12:00 if not available).
If no supplemental feeding was necessary post baseline, the value 
will be set to 0.
Time to Clinical Stability
[Time-to-event]
maximum[time to return to pre-RSV disease level for SpO2, RR 
and HR, feeding] 
Subject will be censored if the subject is censored for at least 1 of 
the 4 time to parameters at the minimum of the available data. If no 
data are available the time will be censored at 0 hours.
Time point of return to
normal temperature (hours)
[Time-to-event]
All subjects are assumed to have a normal temperature level pre-
RSV disease
Time point of return to pre-RSV disease level temperature is 
defined as the first time point with a normal temperature and no 
time points after that time point with an abnormal value.
The normal limits to be used are: 
-
Axillary: 36.1 – 38.0
-
Forhead: 36.1 – 38.0
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-
Oral: 36.1 – 38.0
-
Rectal: ≤ 37.2
-
Tympanic: ≤ 37.8
If there were no abnormal values post baseline, the value will be 
set at 0 hours.
Time 
to 
normal 
temperature (hours) [Time-
to event]
Minimum[date and time of Time of return to pre-RSV disease level 
temperature, date and time of last measurement] -  date and time of 
first dose of study drug)/3600†, rounded to one decimal
If none of the values are abnormal for the subject, this value will be 
set at time 0.
Subjects with an abnormal value at the last assessment will be 
censored. Subjects for which this last assessment is the baseline 
assessment will be censored at time 0.
Time point of return to pre-
RSV 
functional 
status 
(KATZ ADL score)
The first time point where the KATZ ADL score is equal or higher 
than the pre-RSV disease KATZ ADL score and no lower scores 
are measured after this time point.
Functional status is the total points on the KATZ Index of 
Independence in Activities of Daily Living (KATZ ADL score)
Time to return to pre-RSV 
functional status (KATZ 
ADL score) (days) [Time-
to-event]
minimum[date and time of time of return to pre-RSV functional 
status, date and time of last measurement] -  date and time of first 
dose of study drug)/3600, rounded to one decimal
If the KATZ ADL score is never lower than the pre-RSV score, 
this value will be set at time 0.
Subjects with a functional status lower than the pre-RSV disease 
functional status at the last KATZ ADL assessment will be 
censored. Subjects for which this last assessment is the baseline 
assessment will be censored at time 0.
Ordinal scale score
The value as collected in the eCRF on the day of last dose (Day 5/6 
depending on timing of LD) will be used as score on the day of last 
dose. Only in case of a missing score, the score will be calculated 
based on the available information in the eCRF.
The 6 categories to be considered are:
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
Death

Admitted to ICU

Non-ICU hospitalization requiring supplemental oxygen

Non-ICU hospitalization not requiring supplemental 
oxygen

Not hospitalized, unable to resume normal activities

Not hospitalized, resumption of normal activities
Subjects will receive a score ranging from 1 (=subject died on or 
before of their day of last dosing) to 6 (=subject was not-
hospitalized, resumptions of normal activity) depending on his 
status on day of last dosing
For days 3 to 14, the ordinal scale will be calculated on each day, 
using the algorithm described above.
All-cause mortality
Subjects who died during the study will receive code 1, subjects 
who survive will receive code 0
Peak viral load
Highest value of viral load at or after the baseline measurement.
Time to peak viral load
(hours) [Time-to-event]
Defined as the relative time in hours from the first dose of study 
drug until the first time point when the viral load reaches the peak 
viral load. 
Subjects for which the peak was reached at the baseline 
measurement will have time 0.
Subjects for whom the peak is reached at the last observed time 
point will be censored. Subjects for which this last assessment is 
the baseline assessment will be censored at time 0.
Rate of decline of viral 
load over the first 24 hours
calculated as a log decline/24 hours defined as: (24-hour log viral 
load after first dose of study drug –
log viral load at 
baseline)/(date/time of 24-hour viral load sample – date/time of 
baseline viral load)
Note, the 24-hour viral load may not have been measured at 
exactly 24 hours following first dose, but the actual date/time 
associated with the 24-hour viral load will be used in computing 
the viral load slope. In case the 24 hour measurement is not 
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available the slope will be calculated using the Day 3 assessment 
(48 hours), using the same definition. If there is no measurement in 
that time frame, the slope will not be calculated.
Time to non-detectability 
(hours) [Time-to-event]
Defined as the relative time in hours from the first dose of study 
drug until the first post baseline time point when the viral load 
reaches non-detectability and no detectable values are measured 
after this time point.
For each subject in the ITT-i it will be assumed that the subject is 
positive at baseline (even if the value is negative).
Subjects whose viral load does not reach non-detectability will be 
censored at the relative time in hours from the first dose of study 
drug until this last RSV assessment. Subjects for which this last 
assessment is the baseline assessment will be censored at time 0.
Time to non-detectability
(hours) [interval censored]
The boundaries of the censoring intervals are defined as the 
number of hours from the start of treatment. The left boundary of 
the interval is the last positive assessment before the first 
confirmed negative sample which is not followed by a confirmed 
positive sample (at baseline every subject is considered positive). If 
no negative samples are observed, the left boundary will be the last 
sample obtained. The right boundary of the interval is the first 
confirmed negative sample which is not followed by a confirmed 
positive sample. If this is not observed, the interval is right 
censored. A confirmed positive sample is defined as two 
consecutive non-negative samples; a confirmed negative sample is 
defined as two consecutive negative samples. Last obtained 
sample, whether positive or negative, is always considered 
confirmed.
Log viral load area under 
the curve from baseline to 
10 days post first dose of 
study drug (AUC0-10 days).
The AUC0–10 days will be derived based on trapezoid method:
 
 = 	 
 +
 
 (	 + )  
where 	 is the log 7 viral load at day 10 and is the log 10 viral 
load at day 10.
The following rules will be applied to deal with missing values 
before calculating the Viral load AUC:

If the last observations are missing, the last available 
observation 
will 
be 
carried 
forward. 
Unscheduled 
assessments will be included and will be eligible for 
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carrying forward until Day 10. 

In case multiple nasal swabs were taken on a single day the 
average on the log scale will be used as the value for that 
subject. 
Log viral load area under 
the curve from baseline to 
14 days post first dose of 
study drug (AUC0-14 days).
The AUC0–14 days will be derived based on trapezoid method:
! 
 =  
 +
!
 ( + !)  
where  is the log 10 viral load at day 10 and !is the log 10 
viral load at day 14.
The following rules will be applied to deal with missing values 
before calculating the Viral load AUC:

If the last observations are missing, the last available 
observation will be carried forward until Day 14.

In case multiple nasal swabs were taken on a single day the 
average on the log scale will be used as the value for that 
subject.
4.2.4.2.
Analysis Methods
To compare incidences across treatment groups (for the need for ICU stay, oxygen support, 
supplemental feeding or supplemental hydration, for the all-cause mortality, for the subjects with 
undetectable viral load per time point and for the presence of complications), logistic regressions
will be used, with treatment as fixed effects and strata as part of the stratifying variables (ie.
stratified logistic model). Other covariates and or baseline indicators may be included in the 
model when of predictive value, such as baseline log10 viral load, smoker (yes/no), the 
presence/absence of co-morbid diseases, presence/absence of co-morbid diseases associated with 
risk for lower respiratory tract disease, presence/absence of other conditions/therapy of potential 
interest, days since symptom initiation, RSV subtype, use of costicosteroids, supplemental 
oxygen at baseline and age as continuous variable. Stepwise selection will be used to identify the 
prognostic factors for each of the different models for the different incidence parameters. A 
significance value of 0.05 is required for a variable to enter the model and a significance value of 
0.10 is required to stay in the model. The odds ratios including 95% confidence interval of active 
groups versus placebo will be derived from the final model using appropriate contrasts. Exact 
logistic regression models will be used in case the incidence of the events is low (< 10 events).
Time-to-events variables will be analyzed in an exploratory sense using Kaplan-Meier analysis, 
A summary table including number of subjects included in the analysis, number of subjects 
censored, 25th and 75th percentiles and median time to even, with 95% confidence intervals based 
on log-log transformation method, will be presented. The data will be presented graphically 
using the Kaplan-Meier estimate of the survival function.
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If specified, time-to-events variables will also be compared between each active treatment group 
and placebo using an accelerated failure time (AFT) model. The distribution to be used will be 
determined based on the goodness of fit using Akaike’s information criterion and will be selected 
from the following parametric families: lognormal, log-logistic, or Weibull. The AFT model will 
include the fixed, categorical effects for treatment (with placebo as the reference) and strata, as 
well as the continuous covariates of baseline log10 viral load. Other covariates may be included 
when of predictive value, such as smoker (yes/no), presence/absence of co-morbid diseases, 
presence/absence of co-morbid diseases associated with risk for lower respiratory tract disease, 
presence/absence of other conditions/therapy of potential interest, days since symptom initiation, 
RSV subtype, use of costicosteroids, supplemental oxygen at baseline and age as continuous 
variable. As in the logistic regression, a significance level of 0.05 will be used for a variable to 
enter the model and a significance value of 0.10 to stay in the model. A summary of information 
from the final model will include parameter estimates and associated standard errors, estimated 
accelerated failure time ratios versus placebo and associated 95% confidence intervals, and p-
values.
Length of Hospital Stay/Length of Hospital Need
The Length of Hospital Stay/Need (both since treatment initiation and since hospital admission) 
will be summarized and listed. The Length of Hospital Stay/Need will be analyzed in an 
exploratory manner using Kaplan-Meier analysis. 
Length of Hospital Stay/Need will also be compared between each active treatment group and 
placebo using an accelerated failure time (AFT) model as described above. 
Need and Duration of ICU Stay
The need for ICU stay will be analyzed on the subgroup of subjects who were not in the ICU 
before the first dose of study medication. The duration in the ICU will be analyzed all subjects 
and on both the subgroup who were and who were not in the ICU before the first dose of study 
medication.
The number and percentage of subject with need of ICU stay, and the duration of ICU stay in 
hours, will be summarized descriptively.
To compare incidence of the need for ICU stay across treatment groups, (exact) logistic
regression as described before will be used.
Need and Duration of Oxygen Support, Supplemental Feeding, Supplemental Hydration
The need and duration of supplemental oxygen will be analyzed by splitting the ITT-i population 
into two partitions:
1) Those patients who require supplemental oxygen before treatment initialization
2) Those patients who did not require supplemental oxygen before treatment initialization
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Both partitions will be analyzed separately, answering two different questions: 
1) For those patients who require supplemental oxygen before treatment initiation: Is there a 
treatment difference in the time to no longer requiring supplemental oxygen? This analysis 
will be performed primarily with a Kaplan-Meier analysis and a stratified Gehan test.
2) For those patients who did not require supplemental oxygen before treatment initialization: Is 
there a treatment difference in preventing the use of supplemental oxygen? This partition will 
be analyzed using a stratified (exact) logistic regression model as specified above.
While we cannot integrate these results they are conceptually linked. We will combine the p-
values for both independent tests for the comparison of each active group versus placebo using 
the method of Liptak[3].
In addition to the analysis described above, the time to no longer requiring supplemental O2 will 
be analyzed on the total group of subjects where subjects who do not require supplemental 
oxygen during the study are considered to have their event at time 0. As before, this will be 
analyzed in an exploratory sense using Kaplan-Meier analysis and with a stratified Gehan test to 
test for treatment differences.
This analysis will be repeated by method of administration (invasive, non-invasive).
The analysis for the need and duration of supplemental feeding and supplemental hydration will 
be done in similar fashion as for supplemental oxygen use described above.
Time to SpO2 ≥ 93% (hours) on room air
Time to SpO2 ≥ 93% (hours) on room air will be summarized and listed for subjects who were 
not on supplemental oxygen prior to current hospitalization.
Among subjects who were not on supplemental oxygen prior to current hospitalization, the time 
to SpO2 ≥ 93% (hours) on room air, will be summarized and analyzed in an exploratory sense 
using Kaplan-Meier analysis.
The time from first dose to SpO2 ≥ 93% (hours) on room air will also be analyzed using AFT 
methodology.
Time to return to pre-RSV disease level (hours) for RR, SpO2; body temperature
The time to return to pre-RSV disease level (hours) for RR, SpO2 and body temperature will be 
analyzed using the same approach as for the Time to SpO2 ≥ 93% (hours) on room air.
Time to return to pre-RSV functional status (KATZ ADL score) (days)
Time to return to pre-RSV functional status (KATZ ADL score) (days) will be analyzed using 
the same approach as for the Time to SpO2 ≥ 93% (hours) on room air.
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Time to clinical stability (hours)
The time to clinical stability (hours) will be analyzed using the same approach as for the Time to 
SpO2 ≥ 93% (hours) on room air.
Ordinal scale
The number and percentage of subjects will be summarized for the ordinal scale by treatment 
group at the end of the treatment period (Day 5/6).
The analysis will be performed using a proportional odds model, modeling the common odds 
ratio of the improvement on the ordinal scale of each active treatment versus control. Age 
category (≥50 to <65 years and ≥65 years) and region (Japan, non-Japan) will be added to the 
model as fixed factors. For each of the 5 possible cut-points the odds ratio will also be presented 
(comparing active versus placebo) to verify the common odds assumption.
For the ordinal scale also descriptive statistics will be computed for each post-baseline day (days 
3 to 14 and day of last dose). Here missing data will be imputed using the LOCF approach.
All-cause mortality
The number and percentage of subjects who died will be summarized and compared between
treatment groups using the logistic regression approach described before.
Note that this analysis will only be performed if any deaths did occur.
Viral load over time
Descriptive statistics and mean (SE) plots will be shown for the log10 values of RSV RNA viral 
load and the changes from baseline calculated in log10(copies/ml) by treatment group.
Peak viral load/Rate of decline:
The log peak viral load and rate of decline of RSV RNA viral load will be compared for active 
groups versus placebo groups using a general linear model with treatment and strata included as 
fixed effects. Other covariates and or baseline indicators may be included in the model when of 
predictive value, such as baseline log10 viral load, smoker (yes/no), presence/absence of co-
morbid diseases, presence/absence of co-morbid diseases associated with risk for lower 
respiratory tract disease, presence/absence of other conditions/therapy of potential interest, days 
since symptom initiation, RSV subtype, use of costicosteroids, supplemental oxygen at baseline 
and age as continuous variable. Stepwise selection will be used to identify the prognostic factors. 
A significance value of 0.05 is required for a variable to enter the model and a significance value 
of 0.10 is required to stay in the model.
Residuals of the final model will be plotted in a normal probability plot; in case the model does 
not fit the log peak value data well, the log transformation (ie. the log of log peak viral load) will 
be considered as dependent variable. The data from the model will be reported as (adjusted) 
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differences in least squares (LS) means (in the case of untransformed data) or (adjusted) 
geometric mean ratios (in case of log-transformed data) of active dose groups versus placebo, 
including 95% confidence intervals using appropriate contrasts. 
Time to Peak viral load:
Time to Peak viral load will be analyzed using the same approach as for the Time to SpO2 ≥ 
93% (hours) on room air.
Time to RSV RNA being undetectable:
Time to RSV RNA being undetectable will be analyzed using the same approach as for the Time 
to SpO2 ≥ 93% (hours) on room air.
In addition, the differences in time to RSV RNA being undetectable of active dosing regimens 
versus placebo treatment will be estimated using the accelerated failure time model based on 
interval censored data. Treatment and stratum will be added as fixed categorical effects, while 
log baseline viral titer will be added as a continuous fixed covariate. 
Treatment effect versus placebo will be reported as an acceleration factor including 95% 
confidence intervals for each active treatment group. Estimated survival curves will be created 
based on the mean baseline titer value and weighted average for each stratum.
Proportion of subjects with undetectable viral load at each time point: 
The proportion of subjects with a negative viral shedding titer will be tabulated at each timepoint 
(with corresponding 95% CI). In addition, the same logistic regression approach as described 
before will be used to obtain the odds ratios (95% CI) for each comparison versus placebo.
RSV RNA viral load AUC until Day 10 and until Day 14
The same model used for the primary analysis will be used to test for a dose response 
relationship on the AUC until Day 10 and until Day 14. No corrections for multiplicity will be 
made, thus the significance level of alpha (α*) will be kept at 0.05. 
The differences in the AUCs for active versus placebo will be derived using appropriate contrasts 
deriving least square mean differences, including the 95% 2-sided confidence intervals.
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4.2.5.
Patient Reported Outcomes
4.2.5.1.
Respiratory Infection Symptom Questionnaire (RSV-PRO)
4.2.5.1.1.
Definition
The RSV Patient-Reported Outcome (RSV-PRO) measure is a 32-item patient-reported 
questionnaire used to assess the severity of RSV symptoms over the past 24 hours and is exactly 
the same questionnaire as the FLU-PRO questionnaire.
The presence and severity of RSV signs and symptoms are assessed across 6 body systems 
affected by RSV: Nose (4 items), Throat (3 items), Eyes (3 items), Chest/Respiratory (7 items), 
Gastrointestinal (4 items), and Body/Systemic (11 items) with 5 possible levels (not at all (level 
code = 0), a little bit (level code = 1), somewhat (level code=2), quite a bit (level code=3), very 
much (level code = 4).
The RSV-PRO domain scores are defined as indicated in Table 2. These will be calculated at 
each time point a questionnaire was filled. A change from baseline will also be calculated.
Table 2. RSV-PRO domain scores
Domain
Items
Scoring 
Minimum Data 
Requirement
Nose
Runny or dripping nose
Congested or stuffy nose
Sneezing
Sinus pressure
Arithmetic mean of 
4 items within 
Nose domain
Daily score for 3 of 4 
items must be present to 
calculate domain score
Throat
Scratchy or itchy throat
Sore or painful throat
Difficulty swallowing
Arithmetic mean of 
3 items within 
Throat domain
Daily score for 2 of 3 
items must be present to 
calculate domain score
Eyes
Teary or watery eyes
Sore or painful eyes
Eyes sensitive to light
Arithmetic mean of 
3 items within 
Eyes domain
Daily score for 2 of 3 
items must be present to 
calculate domain score
Chest/Respiratory
Trouble breathing
Chest congestion
Chest tightness
Dry or hacking cough
Wet or loose cough
Coughing
Coughed up mucus or 
phlegm
Arithmetic mean of 
7 items within 
Chest/Respiratory 
domain
Daily score for 5 of 7 
items must be present to 
calculate domain score
Gastrointestinal
Felt nauseous
Stomach ache
How many times did you 
vomit?
How many times did you 
have diarrhea?
Arithmetic mean of 
4 items within 
Gastrointestinal 
domain
Daily score for 3 of 4 
items must be present to 
calculate domain score
Body/Systemic
Headache
Arithmetic mean of Daily score for 8 of 11 
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Head congestion
Felt dizzy
Lack of appetite
Sleeping more than usual
Body aches or pains
Weak or tired
Chills or shivering
Felt cold
Felt hot
Sweating
11 items within 
Body/Systemic 
domain
items must be present to 
calculate domain score
Total
All above 32 items
Arithmetic mean of 
all 32 items within 
RSV-PRO
In the presence of 
missing data, the above 
conditions for the 
calculation of all domain 
scores must be met in 
order to calculate the 
RSV-PRO total score.
Table 3. Calculations and Conversion Formulae
Measurement
Formula
Time to alleviation from 
RSV-like symptoms
Alleviation or “recovery” from RSV-like symptoms in adults with 
acute, laboratory confirmed RSV is defined as the first day a 
subject reports a RSV-PRO total score ≤1.0 AND all domain 
scores are ≤1.0.
Subjects with an abnormal value at the last assessment will be 
censored at the date and time of the last assessment
Time to alleviation from 
systemic and respiratory 
symptoms
Alleviation or “recovery” from systemic and respiratory symptoms 
is defined as the first day a subject reports ‘not at all’ or ‘a little 
bit” as severity for all items in the body/systemic and respiratory 
domain.
Subjects with an at least moderate score at the last assessment for 
these 2 domains will be censored at the date and time of the last 
assessment
4.2.5.1.2.
Analysis Methods
Actual values and changes from baseline will be summarized by treatment group at each 
scheduled time point for the RSV-PRO domain and total scores. Mean±SE graphs over time for 
the actual values and changes from reference will be presented.
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Time-to-alleviation will be analyzed in an exploratory sense using a summary table including 
number of subjects included in the analysis, number of subjects censored, 25th and 75th
percentiles and median time to event, with 95% confidence intervals based on log-log 
transformation method, will be presented. The data will be presented graphically using the 
Kaplan-Meier estimate of the survival function. For each comparison of active versus placebo 
the stratified Gehan test will also be presented.
Frequency tabulation of each of the 32 items at the time point of return to return to usual 
activities and time point of return to usual health as defined in section 4.2.5.2.1.
4.2.5.2.
Adult RSV Additional Questions
4.2.5.2.1.
Definition
Table 4. Calculations and Conversion Formulae
Measurement
Formula
Time to return to usual 
activity 
The time in hours from the first dose of investigational product till 
the first one of 2 successive cases where the response is ‘Yes’ on 
RSV-PRO additional question 7 (“have you returned to your usual 
activities?”) . Time points with missing data are ignored in this 
analysis. The successive recordings cannot be within the same 
window. In case there are 2 recordings within a single window (i.e. 
morning window, afternoon window or evening window) the worst 
case within that window will be taken.
In cases where there are no sufficient recordings, the endpoint will 
be censored. Censoring will be at time of the last assessment if 
ticked as “Yes”; otherwise censoring will be the first window after 
the last assessment (lower limit). One exception is censoring at the 
Day 28 Visit (last study day for the subject). If the subject is not 
returned to usual activities/health on this day, the time of the last 
diary entry will be taken as the time of censoring.
Time to return to usual 
health 
The time in hours from the first dose of investigational product till 
the first one of 2 successive cases where the response is ‘Yes’ on 
RSV-PRO additional question 9 (‘have you returned to your usual 
health?’). Time points with missing data are ignored in this 
analysis. The successive recordings cannot be within the same 
window. In case there are 2 recordings within a single window (i.e. 
morning window, afternoon window or evening window) the worst 
case within that window will be taken.
In cases where there are no sufficient recordings, the endpoint will 
be censored. Censoring will be at time of the last assessment if 
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both items are ticked as “Yes”; otherwise censoring will be the first 
window after the last assessment (lower limit). One exception is 
censoring at the Day 28 Visit (last study day for the subject). If the 
subject is not returned to usual activities/health on this day, the 
time of the last diary entry will be taken as the time of censoring.
Time to full recovery
The maximum of the time to return to usual activity and usual 
health when both have an event, or the minimum of censored 
time(s) if at least one is censored.
4.2.5.2.2.
Analysis Methods
Time to return to usual activity and usual health 
Kaplan-Meier curves will be provided by treatment group. For each comparison of an active 
group versus placebo the stratified Gehan test will also be presented.
Other RSV additional questions
The number and percentage of subjects per category will be tabulated over time by treatment 
group for items 1 to 6 and item 8 of the RSV additional questions.
4.2.5.3.
EQ-5D
4.2.5.3.1.
Definitions
The EQ-5D questionnaire will be analyzed in 3 ways:
1) EQ-5D descriptive system: 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) with 5 possible levels (no (level code = 1), slight 
(level code = 2), moderate (level code=3), severe (level code=4), unable to/extreme (level 
code = 5). 
Dimension
Level
Interpretation
1
Mobility             
1
No problems
I have no problems in walking about
2
Slight problems
I have slight problems walking
3
Moderate 
problems
I have moderate problems walking
4
Severe problems
I have severe problems walking
5
Unable to
I am unable to walk
2
Self-care            
1
No problems
I have no problems washing or dressing myself
2
Slight problems
I have slight problems washing or dressing myself
3
Moderate 
problems
I have moderate problems washing or dressing 
myself
4
Severe problems
I have severe problems washing or dressing myself
5
Unable to
I am unable to wash or dress myself
3
Usual activities 
1
No problems
I have no problems doing my usual activities
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2
Slight problems
I have slight problems doing my usual activities
3
Moderate 
problems
I have moderate problems doing my usual 
activities
4
Severe problems
I have severe problems doing my usual activities
5
Unable to
I am unable to do my usual activities
4
Pain/discomfort 
1
No pain
I have no pain or discomfort
2
Slight pain
I have slight pain or discomfort
3
Moderate pain
I have moderate pain or discomfort
4
Severe pain
I have severe pain or discomfort
5
Extreme pain
I have extreme pain or discomfort
5
Anxiety/
depression 
1
Not anxious
I am not anxious or depressed 
2
Slightly anxious
I am slightly anxious or depressed
3
Moderate 
anxious
I am moderately anxious or depressed
4
Severe anxious
I am severely anxious or depressed
5
Extreme anxious
I am extremely anxious or depressed
2) EQ-5D VAS: a continuous score ranging from 0 to 100.  
3) EQ-5D Valuation index: The information of the 5 dimensions of the descriptive system 
summarized into one index.
a.
Assign the level code 1, 2, 3, 4 and 5 to each level of the 5 dimensions (see table)
b. Create a health state for each patient-time point combination. A health state is a 
combination of 5 level codes; one level code for each dimension. The dimensions 
are 
ordered 
as 
described 
in 
the 
table 
above. 
E.g. health state 12311 indicates ‘no problems in walking about, slight problems 
washing or dressing myself, moderate problems to perform my usual activities, no 
pain or discomfort, not anxious or depressed’.
c.
Assign an index value to each health state as defined on the EUROQol website 
(http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-
sets.html). EQ-5D health state is converted to a single summary index by applying 
a formula that essentially attaches weights to each of the levels in each dimension. 
The algorithm is based on the valuation of EQ-5D health states using the UK TTO 
(=time trade-off method) based value set. Based on the origin of the subjects, 
another method can be used.
4.2.5.3.2.
Analysis Methods
Actual values and changes from baseline will be summarized by treatment group at each 
scheduled time point for the EQ-5D VAS and valuation index. Mean±SE graphs over time for 
the actual values and changes from reference will be generated. 
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The number and percentage of subjects per problem level will be tabulated over time by 
treatment group for each of the 5 dimensions.
This will be done for all subjects and in addition for the following subgroup: ≥50 to <65 years 
and ≥65 years.
4.2.5.4.
Katz-ADL
4.2.5.5.
Definition
Katz-ADL is a status descriptor. A status change will be considered RSV-related if the subject 
evolved from independence before the RSV infection to dependence during or after RSV 
infection for each of the 6 different activities. 
Measurement
Formula
Normalized Katz-Score
The normalized Katz score is the ratio of the actual Katz-score 
over the Katz-score pre-onset of RSV symptoms
4.2.5.5.1.
Analysis
For each day the average Katz score will be presented by treatment group, as well as the change 
from baseline using both raw scores as normalized scores. Data will be presented using a mean 
(SE) plot over time, by treatment group.
The evolution of activities of Daily Living (ADL) as assessed by the Katz ADL will be analyzed 
by analyzing the time to return to pre-RSV functional status (Katz ADL score) as described in 
section 4.2.4.2.
Additionally, a cross-tabulation of the status changes versus the status before the RSV infection 
will be presented for each of the 6 different activities, over time and at the time of hospital 
discharge. This table will show the number and percentage of subjects with dependence and the 
number and percentage of subjects with an RSV-related status change.
The relationship between RSV RNA viral load and Katz ADL
The relationship between the RSV RNA (as measured by the PCR method) will be assessed 
using spearman rank correlation between the viral load and the Katz ADL normalized score for 
each combination of Days. This matrix of correlations will provide information if within each 
day the viral load is predictive of Katz functional status, but will also allow if there is a delayed 
relationship, meaning that viral load is predictive of future Katz functional statuses. 
A second approach will be to correlate the time to virus negativity with the Katz ADL baseline 
score marking censored cases. Other methods may be considered as appropriate.
The relationship between the Katz ADL and the subject eCOA responses.
The relationship between the Katz ADL and the scores of eCOA will be assessed using various 
measures. Katz baseline scores will be correlated with the time to alleviation from systemic and 
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respiratory symptoms as defined by the RSV-PRO. Subjects who are censored will be assumed 
to have alleviation of symptoms 1 day after censoring in this analysis. For the multidimensional 
aspects of the various patient reported measurements and the Katz scores and viral load a 
separate analysis plan will be issued.
4.2.6.
Other Efficacy Variable(s)
4.2.6.1.
Definition
Formulae to be used for derived variables, including data conversions, are provided in Table 5.  
In the derivation of durations described below, no imputation of the start and/or end date/time 
will be performed.
Table 5. Calculations and Conversion Formulae
Measurement
Formula
Time 
to 
onset 
of 
complications 
after 
initiation of treatment
Defined as the relative time in days from the first dose of study 
drug until the first occurrence of any of the following 
complications:
-
Bacterial superinfection, 
-
Exacerbation of underlying pulmonary disease,
-
Cardiovascular and cerebrovascular event, 
-
Respiratory Failure
-
Clodistridium difficile associated diarrhea.
-
Other RSV complications
If a subject has a complication before the first intake, time will be 
set to 0.
Time to onset of complications will be censored at date of study 
completion/discontinuation for subjects without complications
Hospital readmission for 
respiratory reasons
Medical review will be done immediately before data base lock on 
a list with unique coded adverse events (MedDRA Preferred 
Terms) for subjects who are re-admitted to the hospital to indicate 
which subjects were re-admitted for respiratory reasons
4.2.6.2.
Analysis Methods
The amount of supplemental oxygen
The amount of supplemental oxygen will be listed over time. 
Subjects (proportion) who started antibiotic use after the first dose of the study drug
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Frequency tabulations will be given for the need for antibiotics related to RSV infection 
complications, as recorded in the CRF. 
Disease status and presence of complications with onset after treatment initiation
Frequency tabulations will be given for any occurrence of RSV complications (Bacterial 
superinfections, Exacerbations of underlying pulmonary disease, Cardiovascular and 
cerebrovascular events, Clostridium difficile associated diarrhea, Respiratory failure, Other).
To compare incidence in the presence of complications across treatment groups a stratified 
(exact) logistic regression model as specified above will be used.
Detailed information on the type of complications, seriousness, severity and outcome will be 
given as part of the safety analysis (see section 4.3.1).
Hospital readmission for respiratory reasons
Frequency tabulations will be given for Hospitalization readmissions for respiratory reasons.
4.2.7.
Exploratory Analyses of Special Interest
4.2.7.1.
Relationship between onset of symptoms and viral load
It will be investigated if the onset of symptoms (ie., duration of RSV symptoms before treatment 
initiation) (days) is predictive of the treatment effect, or in other words if there is evidence of 
interaction between onset of symptoms and treatment effect. 
To investigate this, the following outputs will be provided:

A trellis plot of the log10 RSV RNA viral load over time by treatment group and day of 
onset of symptoms showing the individual loads over time (spaghetti plots)

A trellis plot of the average log10 RSV RNA viral load over time by treatment group and 
day of onset of symptoms

A trellis plot of the average log 10 RSV RNA viral load over time by treatment group and 
onset of symptoms ≤3 days and >3 days (if this cut is sufficiently close to 50% -
boundary may be adjusted)
If the data permit the primary endpoint will be fitted using the treatment group by day of onset of 
symptoms interaction term. 
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4.3.
SAFETY
All safety analyses will be done on the Safety Set.
4.3.1.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities. Events are looked at on the level of their preferred 
term.
Definitions
Treatment-emergent AEs are AEs with onset during the treatment or the follow-up phase or that 
are a consequence of a pre-existing condition that has worsened since baseline. All reported 
treatment-emergent AEs will be included in the analysis. For each AE, the percentage of subjects 
who experience at least 1 occurrence of the given event will be summarized by treatment group.
Phase Allocation of AE
Step 1: Allocation of Events to the Phases
Adverse events present in the SDTM database are allocated to phases based on their start date. If
the start date of an event falls between (or on) the start and stop date of a phase, the AE is
attributed to that phase (treatment-emergent principle).
Incomplete dates (i.e. time and/or day and/or month and/or year missing):

In case of partial start or stop dates, the events are allocated to the phases using the available
partial information on start and end date; no imputation will be done. If, for instance, for the
AE start date only month and year are available, these data are compared to the month and
year information of the phases. This rule may lead to multiplication of the event as a
consequence of its assignment to multiple phases.

In case of a completely missing start date, the event is allocated to the first active treatment
phase, except if the end date of the AE falls before the start of the first active treatment
phase.

In case of a completely missing end date, the following decision rules apply:
-
in case the date is identified as unknown the date will remain missing; 
-
in case the date is not flagged as unknown the date is imputed by the cut-off date of 
the analysis for subjects still ongoing in the study, and by the end date of the last 
phase for subjects who discontinue. 
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Examples:
Screening phase: start date: 02JAN2017 - stop date: 28JAN2017
Treatment phase: start date: 29JAN2017 - stop date: 12AUG2017
1) Adverse event: start date: JAN2017- stop date: 15JUL2017
As the start date only has information about month and year, only this information will be
used from the phases and therefore the AE will be assigned to the screening phase as well as 
to the treatment phase.
2) Adverse event: start date: JAN2017- stop date 27JAN2017 As the AE stops before or at the 
start of the treatment phase, it is only assigned to the Screening phase.
Remarks:
In addition to the date information, time information is taken into account to allocate AEs to
phases.
Step 2: Combination of Events
Overlapping/consecutive events are defined as events of the same subject with the same
preferred term who have at least 1 day overlap or for which the start date of an event is 1 day
after the end date of the preceding event. Overlapping/consecutive events may be combined into
one AE or not, according to the following rules:
1) In case a non-active phase (e.g. Screening) is followed by an active phase, and the
overlapping/consecutive events start in both phases, they are allocated to their respective
phase and are considered as separate events.
2) In case overlapping/consecutive events start within a single phase, they are considered as one 
and the same AE. The individual events who contribute to this AE are retained as individual 
records in the ADAM database but are assigned the same onset, phase, and total duration.
3) In case an active phase is followed by a non-active phase (e.g. Follow-Up), and the
overlapping/consecutive events start in both phases, they are allocated to the active phase
only and are considered as one and the same AE. The individual events who contribute to
this AE are retained as individual records in the ADAM database but are assigned the same 
onset, treatment phase, and total duration.
Remarks:
1) Events can only be combined into one and the same AE if their start and stop dates are
complete.
2) In case the completely missing end date is imputed, this date is also considered as a complete 
date.
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3) Time is not considered when determining overlap of events.
4) Adverse events will be reported from the informed consent date on (i.e. in the screening
period) until trial termination.
Analysis Methods
A Summary will be provided for the following treatment-emergent adverse events per phase 
(Treatment phase, Follow-up phase) and for the combination of Treatment and Follow-up phase: 
any adverse events, serious adverse events, deaths due to AE, adverse events by toxicity grade, 
AEs at least possibly related to study medication, AEs for which study medication was 
permanently stopped, serious adverse events that were at least possibly related to study 
medication. There will be no formal statistical testing.
Incidence tabulations will be provided for individual adverse events in the above categories (in 
case there are at least 5 events).
Listings will be provided for at least the following categories: all AEs, serious AEs, AEs leading 
to death, AEs leading to permanent stop, grade 3-4 AEs.
The summary, incidence tabulation for the individual preferred terms and subject listing will be 
provided for the RSV-related complications.
The following adverse events will be tabulated; or listed (in case there are less than 5 events) by 
subgroups (section 2.5): any AE, any RSV-related complications, any grade 1-2, any grade 3-4 
AE, AEs that are at least possibly related to study medication, AEs leading to death, serious AEs, 
AEs leading to permanent stop of study medication.
4.3.2.
Clinical Laboratory Tests
Laboratory parameters of hematology, serum chemistry and urinalysis will be investigated: All 
analyses will be done on SI-converted values as available in the database.
Unifying multiple laboratory values by standardization:
Since local labs are used, the SI-converted values will be standardized using the following 
formula and using the phantom laboratory generalized lab norms (GLN) as proposed by Francis 
Ruvuna, David Flores et all.[13]
 = (" −Li) ∗&' −(&'
) −()
+ (&'
Where 
y =the transformed individual analyte value to a common standard laboratory reference range; 
x =the original value;
Li and Ui = lower and upper limits of normal for individual laboratory analyte; 
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Lcs and Ucs =lower and upper limit for the selected common standard laboratory or phantom 
laboratory GLN proposed by Francis Ruvana et all. [13]
The standardized values, with the phantom laboratory GLN will be used during the analysis.
Toxicity grades and abnormalities for laboratory parameters:
Toxicity grades will be computed according to the DMID adult toxicity grading list (see 
attachment at the end of this document). In case different grades are available for fasted/non 
fasted results, the results are assumed to be taken in the condition as specified in the protocol (i.e. 
not necessarily according to possible remarks indicating a deviation to this). If no condition is 
specified in the protocol, the non-fasting gradings should be used.
In case no toxicity grades are defined for any laboratory test, then non-graded abnormalities
(high/low vs. normal range) will be used instead.
The worst grade over the whole observational period (treatment) will be determined.
Treatment-emergent definition for toxicity grades and abnormalities
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 baseline value. If the baseline 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. 
The treatment emergent definition is applicable in both, the treatment and follow-up phase. 
Special assessments:
Additional laboratory assessments corresponding to the CRF rash-pages (if any and if applicable) 
will only be considered in the main analysis if they are provided by the same laboratory vendor 
as for the main, scheduled assessments.
Otherwise these assessments will only be listed; this also means that these assessments will not 
be considered in the determination of worst-case per treatment, but toxicity grades or non-graded 
abnormalities will anyways be determined as and if applicable.
In case of missing date or time parts:
Laboratory records with missing assessment date- or time-parts (any: day, month or year) will 
not be used in descriptive statistics, unless the scheduled target day or time is known and a 
unique phase allocation is possible taking this additional information into account. These 
assessments will be allocated to the correct phase using the available date(time) information, and 
the information on their assessment schedule. In case it is not possible to assign a unique phase 
(e.g. unscheduled time points), the assessment will be assigned to all possible active phases 
based on the available date and time information. These cases will be flagged in the respective 
listings.
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Imputations of numerical values expressed as characters: 
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. 
This also applies to normal limits expressed as such.
No such imputations will be done for urinalysis parameters as these are usually 
character/categorical expressions.
Missing normal limits: 
Missing normal limits in the data base will be imputed at analysis level using the values specified 
and approved by the sponsor. This only applies if the missing normal limit is critical to 
determine a toxicity grade or an abnormality score, i.e. not for tests whose toxicity grade is based 
on the test value itself. Imputations, if applicable, will be flagged as applicable if shown in 
listings.
Derivation of GFR (CKD-EPI equation): 
Estimated GFR (CKD-EPI equation) will be calculated  using the following formula[14]:
GFR(mL/min/1.73 m²) = 141 x minimum(CREAT / K  ; 1)α x maximum(CREAT / K  ; 1)-1.209 
x 0.993Age  x (1.018 IF SEX = ‘F’) x (1.159 IF RACEGR1 = ‘BLACK’)
Where:
CREAT= Serum Creatinine
Unit CREAT =  mg/dL. 
Conversion CREAT: mg/dL =  umol/L  / 88.4  
Unit WEIGHT = kg, unit HEIGHT = cm  
Use last measurement before intake for weight and height (baseline).
Use age at screening.
K = 0.7 IF SEX= ‘F’ or  0.9 IF SEX=’M’
α = -0.329 IF SEX= ‘F’ or  -0.411 IF SEX=’M’
With the following scores:
Grade 0: GFR > 60 mL/min/1.73m2 (grade 0);
Grade 1: 30 mL/min/1.73m2< GFR <=60 mL/min/1.73m2
Grade 2: 15 mL/min/1.73m2< GFR <=30 mL/min/1.73m2
Grade 3: GFR <=15 mL/min/1.73m2
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Analysis Methods
Actual values and change from baseline will be summarized by treatment group at each 
scheduled time point. 
The number and percentage of subjects will be shown in a cross-tabulation of the 
toxicity/abnormality post-baseline versus baseline at each scheduled time point. 
Additionally, a cross-tabulation of the worst toxicity/abnormality versus baseline will be 
presented per phase (Treatment phase, Follow-up phase) and for the combination of Treatment 
and Follow-up phase. This table will also show the number and percentage of subjects per worst 
toxicity/abnormality, the number and percentage of subjects per treatment-emergent worst 
toxicity/abnormality and the cumulative number of subjects per treatment-emergent 
toxicity/abnormality or worse. 
Mean±SE graphs over time for the actual values and changes from reference will be generated 
for all tests performed. 
A listing of abnormal individual subject hematology and clinical chemistry values from 
scheduled and unscheduled time points will be provided. This listing will include all other time 
points for the corresponding subject/parameter. 
Grade 2 or higher toxicity laboratory values will be listed separately. 
Urinalysis results will be listed. Proteinuria and urine WBCs will be summarized.
4.3.3.
Vital Signs
Systolic and Diastolic blood pressure, pulse rate, respiratory rate, tympanic temperature and
oxygen saturation will be investigated. 
Definitions
The following abnormalities will be defined:
Abnormality Code
Vital Signs parameter
Pulse
DBP
SBP
Abnormalities on actual values
Abnormally low
< 45 bpm
50 mmHg
90 mmHg
Grade 1 or mild
-
> 90 mmHg - < 100 mmHg
> 140 mmHg - < 160 mmHg
Grade 2 or moderate
-
100 mmHg - < 110 mmHg
160 mmHg - < 180 mmHg
Grade 3 or severe
-
110 mmHg
180 mmHg
Abnormally high
120 bpm
-
-
Abnormality Code
Respiratory 
Abnormalities on actual values
Normal
< 17 breaths per minute
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Abnormality Code
Respiratory 
Grade 1 or mild
17-20 breaths per minute
Grade 2 or moderate
21-25 breaths per minute
Grade 3 or severe
> 25 breaths per minute
Grade 4 or potentially life threatening
intubation-
Abnormality Code
Tympanic Temperature (°C)
Abnormalities on actual values
Normal
< 37.5
Abnormally high
37.5
Abnormality Code
Oxygen Saturation (%)
Abnormalities on actual values
Abnormally low
< 95
Normal
95
In determining the abnormalities, the following rules are applied:

worst grades/abnormalities are determined over the whole observational period for each 
trial phase separately, including post-baseline scheduled and unscheduled measurements 
of that phase.

The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered
equally important, i.e. if a subject has as well an abnormally low as an abnormally high 
or graded value post-baseline, both abnormalities are shown in the tables. (This means 
that the sum of the percentages can be more than 100%)
An abnormality will be considered treatment-emergent in a particular phase if it is worse than 
baseline. If baseline is missing, the abnormality is always considered as treatment-emergent. A 
shift from ‘abnormally low’ at baseline to ‘abnormally high’ or ‘grade …’ post baseline (or vice 
versa) is also treatment-emergent.
Analysis Methods
Actual values and change from baseline will be summarized by treatment group at each 
scheduled time point. The number and percentage of will be shown in a cross-tabulation of the 
toxicity/abnormality post-baseline versus baseline at each scheduled time point. 
Additionally, a cross-tabulation of the worst toxicity/abnormality versus baseline will be 
presented per phase (Treatment phase, Follow-up phase) and for the combination of Treatment 
and follow-up phase. This table will also show the number and percentage of subjects per worst 
toxicity/abnormality, the number and percentage of subjects per treatment-emergent worst 
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toxicity/abnormality and the cumulative number of subjects per treatment-emergent 
toxicity/abnormality or worse. 
Mean±SE graphs over time for the actual values and changes from reference will be generated 
for all tests performed. 
A listing of abnormal individual subject VS values will be provided.
4.3.4.
Physical Examination Findings
Abnormal physical examination will be listed.
4.3.5.
Electrocardiogram
PR, QT, QRS, QTc intervals and heart rate will be investigated. QTc values will be used as 
reported, they will not be recalculated.
Definitions
The following abnormalities will be defined:
Abnormality Code
ECG parameter
HR
PR
QRS
QTcorrected
Abnormalities on actual values
Abnormally low
< 45 bpm
< 110 ms
-
-
Abnormally high
120 bpm
> 220 ms
120 ms
-
Borderline prolonged QT (males)
-
-
-
450 ms < QTc < 480 ms
Borderline prolonged QT (females)
-
-
-
470 ms < QTc < 480 ms
Prolonged QT
-
-
-
480 ms < QTc < 500 ms
Pathologically prolonged QT
-
-
-
QTc > 500 ms
Abnormalities on changes from baseline (∆QTc)
Normal QTc change
-
-
-
∆QTc < 30 ms
Borderline QTc change
-
-
-
30 ms < ∆QTc < 60 ms
Abnormally high QTc change
-
-
-
∆QTc > 60 ms
In determining the abnormalities, the following rules are applied:

worst grades/abnormalities are determined over the whole observational period for each 
trial phase separately, including post-baseline scheduled and unscheduled measurements 
of that phase.

The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered
equally important, i.e. if a subject has as well an abnormally low as an abnormally high 
or graded value post-baseline, both abnormalities are shown in the tables. (This means 
that the sum of the percentages can be more than 100%)
An abnormality will be considered treatment-emergent in a particular phase if it is worse than 
baseline. If baseline is missing, the abnormality is always considered as treatment-emergent. A 
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shift from ‘abnormally low’ at baseline to ‘abnormally high’ or ‘grade …’ post baseline (or vice 
versa) is also treatment-emergent.
Analysis Methods
Actual values and change from baseline will be summarized by treatment group at each 
scheduled time point. The number and percentage of will be shown in a cross-tabulation of the 
toxicity/abnormality post-baseline versus baseline at each scheduled time point. 
Additionally, a cross-tabulation of the worst toxicity/abnormality versus baseline will be 
presented per phase (Treatment phase, Follow-up phase) and for the combination of Treatment 
and follow-up phase. This table will also show the number and percentage of subjects per worst 
toxicity/abnormality, the number and percentage of subjects per treatment-emergent worst 
toxicity/abnormality and the cumulative number of subjects per treatment-emergent 
toxicity/abnormality or worse. 
Mean±SE graphs over time for the actual values and changes from reference will be generated 
for all tests performed. 
A tabulation of the worst QT/QTc change versus baseline per treatment per phase will be 
presented
A listing of abnormal individual subject VS values will be provided.
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4.4.
VIROLOGY
The emergence of viral resistance will be evaluated by sequencing the RSV polymerase L-gene 
and other regions (only if no mutations are seen in the L-gene) and looking for changes from 
baseline, defined as before first dose of ALS-008176. All baseline subject samples will be 
sequenced to identify pre-existing mutations in their L gene. All post-baseline subject samples 
that show no viral suppression or viral rebound will be sequenced to identify mutations in the L 
gene that have occurred after the start of treatment with ALS-008176. Ultra deep sequencing will 
be used to sequence the L gene for all the subjects. A cut-off of 10-15% will be used to analyze 
the results. The analysis of the viral resistance data will be documented in a separate clinical 
virology report.
4.4.1.
Analysis Time Points
Virology result will be assigned to the visit windows as described in section 2.1. In addition, the 
below time points will be considered: 

Baseline (BL): Last available pre-dose time point in the study with sequencing data 
available

Time Point of Sequence at End of Treatment (EOTSTPT): Last available post-baseline 
time point during the treatment phase with sequencing data available

Time Point of Sequence at End of Study (EOSSTPT): Last available post-baseline time 
point in the study with sequencing data available

Entire post-baseline phase: Aggregate of all available post-baseline time points in the 
study with sequencing data available
4.4.2.
Virus Strain Typing
RSV will be classified into virus strain subtypes based on a duplex qRT-PCR assay.
4.4.2.1.
Analysis Methods
The analysis RSV Subtype at baseline will be tabulated and used in the subgroup analyses.
4.4.3.
Viral Sequencing
Sequencing of the entire L-gene will be performed to identify pre-existing and/or emerging 
genetic variations. The frequency of these genetic variations as well as the effect of pre-existing 
genetic variations on treatment outcome will be explored.
Definitions
Genetic variations are defined as changes (on amino acid or nucleotide level) in the subject’s 
virus’s sequence compared to a reference sequence. Genetic variations can include substitutions, 
insertions and deletions. The reference sequence to be used is a sequence of the L gene of a wild 
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type strain such as A2 or Long strains in case of comparison to a baseline sample or the baseline 
sample if wild type when comparing to post-baseline sample.

Wild type: If – at certain position – the amino acid/nucleotide in the subject’s virus’s 
sequence matches the reference sequence, that is no genetic variation is present at that 
position, the virus is considered to be wild type at that position.

Emerging genetic variation: If – at certain position - a genetic variation is absent at 
Baseline but present at a later time point, the genetic variation considered to be emerging 
at that time point.

Genetic variation profile: a specific genetic variation or combination of genetic 
variations at one or more time points
When analyzing the pre-existing and/or emerging genetic variations, special attention will be 
payed to the following (combination of) genetic variations: M628L, A789V, L795I, I796V.
Parameters to analyze

Number (%) of subjects with a genetic variations at a specific position.

Number (%) of subjects with a specific genetic variation.

Number (%) of subjects with a specific genetic variation profile.

Number (%) of subjects with a number of genetic variations in a specific genetic area of 
interest.
The following rules will be taken into account to count the number of genetic variations at a 
specific time point:

If, at the selected time point, different genetic variations occur/emerge at the same 
position, this will be counted only once.

Wild type is never counted as a genetic variation.

Insertions and deletions will be counted as a separate genetic variations, even if at the 
same position a genetic variation is already present.

Subjects with viral sequencing data at the selected time point, but without (emerging) 
genetic variations of a specific list, should be classified as having zero (emerging) genetic 
variations for that list.
The focus will be on genetic variations at selected time points, emerging genetic variations and 
reversion to wild type or baseline state.
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4.4.3.1.
Analysis Methods
Frequencies and percentages will be presented at the time points specified above for the specified 
parameters. The denominator is the number of subjects with viral sequencing data, within the 
region, at the selected time point(s). Results will be shown by time point and region.
4.5.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization will be summarized descriptively (number and percentage of 
subjects) by treatment group at each scheduled time point.
4.6.
OTHERS
Relationship between RSV RNA viral load and RSV viral load by qRT-PCR (intubated subjects)
To make a comparison of the RSV RNA viral loads measured in mid-turbinate nasal swabs and
endotracheal samples from intubated subjects, scatter plots will be created plotting the RSV 
RNA viral loads versus the RSV viral load as measured by qRT-PCR of endotracheal samples.
Relationship between viral kinetics and clinical outcome
Kaplan-Meier analysis by quartiles of viral load AUC0-7 days for:

The Length of Hospital Stay/Need (both since treatment initiation and since hospital 
admission)

Time to return to pre-RSV functional status (KATZ ADL score)

Time to clinical stability
A summary table including number of subjects included in the analysis, number of subjects 
censored, 25th and 75th percentiles and median with 95% confidence intervals based on log-log 
transformation method, will be presented by quartiles of viral load AUC0-7 days parameter. 
A Tabulation of the need for additional oxygen supplementation will be presented by quartiles of 
viral load AUC0-7 days.
Evolution of diffusing capacity
To explore the evolution of diffusing capacity of the lung for carbon monoxide (DLCO) and 
spirometry in subjects hospitalized due to RSV infection, descriptive statistics and mean (SE) 
plots will be shown and the changes from baseline calculated by treatment group.
Impact of ALS-008176 on the infectious viral load
The impact of ALS-008176 on the infectious viral load will be evaluated by descriptive statistics 
on the RSV infectious viral load as measured using quantitative viral culture (plaque assay).
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ATTACHMENT
DMID ADULT TOXICITY GRADES FOR LABORATORY PARAMETERS
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