A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Pimodivir in Combination With the Standard-of-Care Treatment in Adolescent, Adult, and Elderly Hospitalized Patients With Influenza A Infection
Phase: PHASE3
Conditions: Influenza A
Sponsor: Janssen Research & Development, LLC

1
Status: Approved, Date: 11 June 2019
Janssen Research & Development *
Clinical Protocol
A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate 
the Efficacy and Safety of Pimodivir in Combination With the Standard-of-care Treatment 
in Adolescent, Adult, and Elderly Hospitalized Patients With Influenza A Infection
Protocol 63623872FLZ3001; Phase 3
AMENDMENT 2
JNJ-63623872-ZCD  Pimodivir
*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.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2017-002156-84
Status:
Approved
Date:
11 June 2019
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-121941709, 10.0
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.
NCT03376321

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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT FIGURES ........................................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 10
TIME AND EVENTS SCHEDULES ............................................................................................................ 22
1. TIME AND EVENTS SCHEDULE – DURING HOSPITALISATION (UP TO DISCHARGE)................. 22
2. TIME AND EVENTS SCHEDULE – AFTER DISCHARGE FROM HOSPITAL..................................... 26
3. TIME AND EVENTS SCHEDULE – DURING HOSPITALIZATION (UP TO DISCHARGE), 
FOR PATIENTS WHO ENTERED THE OPTIONAL DOUBLE-BLIND EXTENSION 
TREATMENT ARM............................................................................................................................28
4. TIME AND EVENTS SCHEDULE – AFTER DISCHARGE FROM HOSPITAL, FOR PATIENTS 
WHO HAD ENTERED THE OPTIONAL DOUBLE-BLIND EXTENSION TREATMENT ARM ........ 30
ABBREVIATIONS ...................................................................................................................................... 32
DEFINITIONS OF TERMS..........................................................................................................................33
1.
INTRODUCTION................................................................................................................................34
1.1.
Background.................................................................................................................................... 34
1.2.
Standard-of-care ............................................................................................................................41
1.3.
Overall Rationale for the Study...................................................................................................... 41
1.4.
Benefits and Risks Management ................................................................................................... 42
Known Benefits of Pimodivir....................................................................................................... 42
1.4.1.
Potential Benefits of Pimodivir.................................................................................................... 42
1.4.2.
Known Risks of Pimodivir ........................................................................................................... 42
1.4.3.
Potential Risks of Pimodivir ........................................................................................................ 43
1.4.4.
Overall Benefit/Risk Assessment ...............................................................................................45
1.4.5.
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 46
2.1.
Objectives and Endpoints .............................................................................................................. 46
Objectives ................................................................................................................................... 46
2.1.1.
Endpoints.................................................................................................................................... 47
2.1.2.
2.2.
Hypothesis ..................................................................................................................................... 50
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 50
3.1.
Overview of Study Design.............................................................................................................. 50
3.2.
Study Design Rationale.................................................................................................................. 53
4.
SUBJECT POPULATION.................................................................................................................. 54
4.1.
Inclusion Criteria ............................................................................................................................54
4.2.
Exclusion Criteria ...........................................................................................................................57
4.3.
Treatment Extension Criteria ......................................................................................................... 59
4.4.
Prohibitions and Restrictions ......................................................................................................... 59
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 59
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 60

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7.
TREATMENT COMPLIANCE............................................................................................................ 63
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 63
9.
STUDY EVALUATIONS.................................................................................................................... 64
9.1.
Study Procedures...........................................................................................................................64
Overview..................................................................................................................................... 64
9.1.1.
Screening Phase ........................................................................................................................64
9.1.2.
Double-blind Treatment Phase................................................................................................... 66
9.1.3.
Double-blind Extension Phase ................................................................................................... 67
9.1.4.
Post-treatment Phase (Follow-up)..............................................................................................68
9.1.5.
After Discharge From the Hospital .............................................................................................68
9.1.6.
9.2.
Efficacy........................................................................................................................................... 68
Evaluations ................................................................................................................................. 68
9.2.1.
9.2.1.1.
Hospital Recovery Scale Assessment..................................................................................... 68
9.2.1.2.
Complications of Influenza ...................................................................................................... 71
9.2.1.3.
Patient-reported Outcomes ..................................................................................................... 72
9.2.1.4.
Viral Kinetics............................................................................................................................74
Efficacy Endpoints ...................................................................................................................... 74
9.2.2.
9.3.
Resistance Evaluations.................................................................................................................. 74
Viral Sequencing.........................................................................................................................74
9.3.1.
Phenotyping................................................................................................................................75
9.3.2.
9.4.
Pharmacokinetics...........................................................................................................................75
Evaluations ................................................................................................................................. 75
9.4.1.
Analytical Procedures................................................................................................................. 75
9.4.2.
Pharmacokinetic Endpoints ........................................................................................................ 75
9.4.3.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Evaluations.................................... 75
9.4.4.
9.5.
Taste and Swallowability................................................................................................................ 76
9.6.
Safety Evaluations .........................................................................................................................76
Adverse Events...........................................................................................................................76
9.6.1.
Clinical Laboratory Tests ............................................................................................................ 76
9.6.2.
Electrocardiogram (ECG) ........................................................................................................... 78
9.6.3.
Vital Signs................................................................................................................................... 78
9.6.4.
Physical Examination.................................................................................................................. 80
9.6.5.
Specific Toxicities .......................................................................................................................80
9.6.6.
9.7.
Biomarker Evaluations ................................................................................................................... 81
9.8.
Pharmacogenomics Evaluations.................................................................................................... 81
9.9.
Sample Collection and Handling.................................................................................................... 81
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY...........................................................................................................................82
10.1.
Completion..................................................................................................................................... 82
10.2.
Discontinuation of Study Treatment...............................................................................................82
10.3.
Withdrawal From the Study............................................................................................................ 82
10.4.
Withdrawal From the Use of Research Samples........................................................................... 83
11.
STATISTICAL METHODS................................................................................................................. 83
11.1.
Analysis Sets.................................................................................................................................. 84
11.2.
Subject Information ........................................................................................................................84
11.3.
Sample Size Determination ........................................................................................................... 84
11.4.
Efficacy Analyses...........................................................................................................................85
11.5.
Resistance Analyses...................................................................................................................... 88
11.6.
Biomarker Analyses .......................................................................................................................89
11.7.
Pharmacogenomic Analyses ......................................................................................................... 89
11.8.
Pharmacokinetic Analyses............................................................................................................. 89
11.9.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 90
11.10.
Taste and Swallowability................................................................................................................ 90
11.11.
Safety Analyses .............................................................................................................................90

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11.12.
Interim Analysis..............................................................................................................................92
11.13.
Independent Data Monitoring Committee ...................................................................................... 93
11.14.
Adjudication Committee ................................................................................................................. 93
12.
ADVERSE EVENT REPORTING ...................................................................................................... 93
12.1.
Definitions ...................................................................................................................................... 93
Adverse Event Definitions and Classifications ........................................................................... 93
12.1.1.
Attribution Definitions.................................................................................................................. 94
12.1.2.
Severity Criteria ..........................................................................................................................95
12.1.3.
12.2.
Special Reporting Situations.......................................................................................................... 95
12.3.
Procedures..................................................................................................................................... 96
All Adverse Events...................................................................................................................... 96
12.3.1.
Serious Adverse Events ............................................................................................................. 97
12.3.2.
Pregnancy................................................................................................................................... 98
12.3.3.
12.4.
Contacting Sponsor Regarding Safety...........................................................................................98
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 98
13.1.
Procedures..................................................................................................................................... 98
13.2.
Contacting Sponsor Regarding Product Quality............................................................................ 99
14.
STUDY DRUG INFORMATION......................................................................................................... 99
14.1.
Physical Description of Study Drug(s) ...........................................................................................99
14.2.
Packaging ...................................................................................................................................... 99
14.3.
Labeling.......................................................................................................................................... 99
14.4.
Preparation, Handling, and Storage...............................................................................................99
14.5.
Drug Accountability ...................................................................................................................... 100
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 100
16.
ETHICAL ASPECTS .......................................................................................................................101
16.1.
Study-specific Design Considerations .........................................................................................101
16.2.
Regulatory Ethics Compliance..................................................................................................... 101
Investigator Responsibilities..................................................................................................... 101
16.2.1.
Independent Ethics Committee or Institutional Review Board ................................................. 102
16.2.2.
Informed Consent and Assent Form.........................................................................................103
16.2.3.
Privacy of Personal Data .......................................................................................................... 104
16.2.4.
Long-term Retention of Samples for Additional Future Research............................................ 105
16.2.5.
Country Selection ..................................................................................................................... 105
16.2.6.
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................105
17.1.
Protocol Amendments.................................................................................................................. 105
17.2.
Regulatory Documentation .......................................................................................................... 106
Regulatory Approval/Notification ..............................................................................................106
17.2.1.
Required Prestudy Documentation...........................................................................................106
17.2.2.
17.3.
Subject Identification, Enrollment, and Screening Logs ..............................................................107
17.4.
Source Documentation................................................................................................................. 107
17.5.
Case Report Form Completion .................................................................................................... 108
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 109
17.7.
Monitoring .................................................................................................................................... 109
17.8.
Record Retention .........................................................................................................................110
17.9.
Study Completion/Termination..................................................................................................... 110
Study Completion/End of Study................................................................................................110
17.9.1.
Study Termination..................................................................................................................... 110
17.9.2.
17.10.
On-site Audits...............................................................................................................................111
17.11.
Use of Information and Publication..............................................................................................111
REFERENCES.......................................................................................................................................... 113
ATTACHMENTS....................................................................................................................................... 114

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INVESTIGATOR AGREEMENT ............................................................................................................... 128
LIST OF ATTACHMENTS
Attachment 1:
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events 
(Feb 2003) .............................................................................................................................. 114
Attachment 2:
Anticipated Events ....................................................................................................... 119
Attachment 3:
Taste/Swallowability Questionnaire ............................................................................. 120
Attachment 4:
Cardiovascular Safety – Abnormalities........................................................................ 122
Attachment 5:
National Early Warning Score (NEWS) 2: Scoring System......................................... 123
Attachment 6:
Influenza Symptom Diary............................................................................................. 125
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 52

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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
11 Sep 2017
Amendment 1
02 Mar 2018
Amendment 2
11 June 2019
Amendments are listed beginning with the most recent amendment.
Amendment 2 (11 June 2019)
The overall reason for the amendment: The overall reason for the amendment is to comply with local 
regulations and to add clarifications on the informed consent process for incapacitated subjects, ie, subjects 
incapable of consenting due to an acute medical condition.
Rationale: To comply with local regulations, it was clarified how to enroll incapacitated subjects, ie, subjects 
who are unable to give consent due to an acute medical condition (eg, too weak or debilitated, unconscious, 
experiencing severe shortness of breath, or mechanically ventilated). In such case, a legally acceptable 
representative (LAR) of the subject must sign on behalf of the subject. Additionally, a statement was added that 
subjects enrolled in the study based on consent by a LAR, will be required to provide written confirmatory 
consent/assent to continue in the study, as soon as they become capable to do so. In case the subject does not 
consent to continue participation in the study, the subject will be withdrawn from the study and the optional 
withdrawal Safety Follow-up Visit will be offered (refer to Section 10.3).
4.1 Inclusion Criteria
16.1 Study-specific Design Considerations
16.2.3 Informed Consent and Assent Form
Rationale: To comply with local regulations, a statement was added to clarify that biomarker sample collection, 
long term sample storage, and use of leftover nasal swab samples for research purposes is only performed if not 
restricted by local regulations. 
SYNOPSIS
TIME AND EVENTS SCHEDULES
9.1.1 Overview
9.1.2 Screening Phase
9.1.3 Double-blind Treatment Phase
9.7 Biomarker Evaluations
16.2.5 Long-term Retention of Samples for Additional Future Research
Rationale: To comply with local regulations, an exploratory research objective was added corresponding to the 
exploratory endpoint (influenza symptom diary), which was added in Amendment 1.
2.1.1 Objectives
Rationale: Within the secondary endpoint, clarifications to the definitions of ‘clinical response’ and ‘respiratory 
response’ were made. Additionally, within the secondary endpoint of clinical response, the vital signs resolution 
criterium of oxygen saturation was corrected for subjects that had an oxygen saturation <94% before the 
influenza infection to clarify that it requires return to their pre-influenza oxygen status.
2.1.2 Endpoints
11.4 Efficacy Analyses
Rationale: The analysis method of the duration of antibiotic treatment was changed to be similar to the analysis 
method for total length of hospitalization. 
11.4 Efficacy Analyses

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Rationale: The date of Protocol Amendment 1 was corrected to align with the actual approval date.
PROTOCOL AMENDMENTS
Rationale: The rationale ‘a superiority evaluation of pimodivir in combination with oseltamivir (OST)-
containing standard-of-care (SOC) treatment compared to placebo in combination with OST-containing SOC 
treatment was added’ was removed from the amendment table of Amendment 1 because it was not implemented
in Protocol Amendment 1 but in the statistical analysis plan (SAP) instead. 
PROTOCOL AMENDMENTS
Rationale: The National Early Warning Score (NEWS) was updated by a new version (NEWS2) to better assess 
the status of subjects at risk of acute hypercapnia (eg, chronic obstructive pulmonary disease [COPD]). With the 
implementation of NEWS2, subjects with routinely low oxygen saturation will be scored more accurately on 
acute-illness severity.
SYNOPSIS
TIME AND EVENTS SCHEDULES
3.1 Overview of Study Design
3.2 Study Design Rationale
4.1 Inclusion Criteria
5 TREATMENT ALLOCATION AND BLINDING
9.1.2 Screening Phase
9.1.3 Double-blind Treatment Phase
9.6.4 Vital Signs
11.4 Efficacy Analyses
11.11 Safety Analyses
REFERENCES
Attachment 5
Rationale: Minor grammatical, formatting, or spelling changes were made throughout the protocol.
Amendment 1 (02 Mar 2018)
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 implement the 
recommendations from specific Health Authorities.
Rationale: Safety follow-up and monitoring for hepatic dysfunction were updated to optimize the general 
safeguards and practices in clinical studies. The hepatic-related exclusion and the hepatic-related discontinuation 
criteria were updated as well. The potential risks section was updated accordingly.
SYNOPSIS
1.4.4 Potential Risks of Pimodivir
4.2 Exclusion Criteria
9.6.6 Specific Toxicities
10.2 Discontinuation of Study Treatment
Rationale: Based on Health Authority feedback, a blinded Adjudication Committee was added to adjudicate 
adverse events as complications based on predefined criteria.
SYNOPSIS
11.14 Adjudication Committee

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Rationale: Based on Health Authority feedback, the hemagglutinin gene (if applicable) was included in addition 
to neuraminidase and polymerase acidic protein (PA) genes in the comprehensive sequence analysis. PA and 
polymerase basic protein 1 genes of virus from all subjects who meet criteria for reduced response or viral 
rebound will be sequenced as well.
SYNOPSIS
9.3.1 Viral Sequencing
Rationale: Based on Health Authority feedback, “severe dehydration” was removed from the extrapulmonary 
complications. 
2.1 Objectives and Endpoints
9.2.1 Evaluations
Rationale: An influenza symptom diary was added to explore the subjects’ ratings on influenza symptoms.
SYNOPSIS
TIME AND EVENTS SCHEDULES
9.2.1.3 Patient-reported Outcomes
11.4 Efficacy Analyses
ATTACHMENTS
Rationale: Based on Health Authority feedback, the type of pregnancy testing was added (ie, urine or serum). 
TIME AND EVENTS SCHEDULES
4.1 Inclusion Criteria
9.1.1 Overview
9.1.2 Screening Phase
9.1.3 Double-blind Treatment Phase
9.6.2 Clinical Laboratory Tests
Rationale: “Total length” measures of “time from start of study drug to hospital discharge, time from intensive 
care unit (ICU) admission to ICU discharge, and time from start to end of mechanical ventilation” were added as 
objectives. Statistical analyses were updated accordingly.
SYNOPSIS
2.1 Objectives and Endpoints
11.4 Efficacy Analyses
Rationale: Based on internal protocol review, progression of the treatment effect over the full post-baseline 
period up to Day 14 is of interest, ie, including Days 2 and 3.  
SYNOPSIS
2.1 Objectives and Endpoints
9.2.1.1 Hospital Recovery Scale Assessment
11.4 Efficacy Analyses

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Rationale: “Analysis of virologic response by baseline resistance” was deleted as objective/endpoint, as well as 
the pharmacokinetic/pharmacodynamic analyses endpoint, because they reflect an analysis and not a study 
endpoint.
SYNOPSIS
2.1 Objectives and Endpoints
Rationale: Clarifications were made throughout the protocol.
SYNOPSIS
TIME AND EVENTS SCHEDULES
2.1 Objectives and Endpoints
3.1 Overview of Study Design
4.1 Inclusion Criteria
4.2 Exclusion Criteria
4.3 Treatment Extension Criteria
6 DOSAGE AND ADMINISTRATION
9.1.3 Double-blind Treatment Phase
9.1.4 Double-blind Extension Phase
9.2.1.1 Hospital Recovery Scale Assessment
9.2.1.3 Patient-reported Outcomes
9.5 Taste and Swallowability
10.3 Withdrawal From the Study
11.12 Interim Analysis
12.3.2 Serious Adverse Events
17.6 Data Quality Assurance/Quality Control
ATTACHMENTS
Rationale: Minor grammatical, formatting, or spelling changes were made throughout the protocol.

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SYNOPSIS
A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy 
and Safety of Pimodivir in Combination With the Standard-of-care Treatment in Adolescent, Adult, and 
Elderly Hospitalized Patients With Influenza A Infection
Pimodivir (formerly known as VX-787 and JNJ-63623872) is a non-nucleotide inhibitor of the 
polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex and is currently in 
Phase 3 development as treatment for influenza A infection.
OBJECTIVES AND HYPOTHESIS
Objectives
Primary Objective
The primary objective is to evaluate superiority of pimodivir in combination with standard-of-care (SOC) 
treatment compared to placebo in combination with SOC treatment on Day 6, with respect to the clinical 
outcome on the hospital recovery scale.
Secondary Objectives
The secondary objectives are: 

To investigate the safety and tolerability of pimodivir in combination with SOC treatment compared 
to placebo in combination with SOC treatment.

To evaluate superiority with respect to the time from start of study drug to hospital discharge in 
subjects treated with pimodivir in combination with SOC treatment compared to placebo in 
combination with SOC treatment.

To evaluate superiority with respect to the time from intensive care unit (ICU) admission to ICU 
discharge in subjects treated with pimodivir in combination with SOC treatment compared to 
placebo in combination with SOC treatment.

To evaluate superiority with respect to the time from start to end of mechanical ventilation in 
subjects treated with pimodivir in combination with SOC treatment compared to placebo in 
combination with SOC treatment.

To evaluate superiority of pimodivir in combination with SOC treatment compared to placebo in 
combination with SOC treatment assessed each separate day from Days 2 to 14 (excluding the 
primary time point), with respect to the clinical outcome on the hospital recovery scale.

To evaluate superiority with respect to the time to return to daily activities in subjects treated with 
pimodivir in combination with SOC treatment compared to placebo in combination with SOC 
treatment. 

To evaluate superiority with respect to the incidence of complications associated with influenza after 
the start of study treatment in subjects treated with pimodivir in combination with SOC treatment 
compared to placebo in combination with SOC treatment.

To investigate all-cause mortality in the pimodivir in combination with SOC treatment arm, 
compared to the placebo in combination with SOC treatment arm.

To investigate the incidence and duration of antibiotic treatment in the pimodivir in combination 
with SOC treatment arm, compared to the placebo in combination with SOC treatment arm.

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
To investigate the number (proportion) of subjects needing extended treatment in the pimodivir in 
combination with SOC treatment arm, compared to the placebo in combination with SOC treatment 
arm. 

To investigate the number (proportion) of subjects requiring re-hospitalization in the pimodivir in 
combination with SOC treatment arm, compared to the placebo in combination with SOC treatment 
arm.

To investigate the number (proportion) of subjects not hospitalized at Day 6 in the pimodivir in 
combination with SOC treatment arm, compared to the placebo in combination with SOC treatment 
arm.

To investigate the time to clinical response in the pimodivir in combination with SOC treatment arm, 
compared to the placebo in combination with SOC treatment arm.

To investigate the time to improvement of respiratory status in the pimodivir in combination with 
SOC treatment arm, compared to the placebo in combination with SOC treatment arm.

To assess the pharmacokinetics (PK) of pimodivir and to explore the PK/pharmacodynamic (PD) 
relationships of pimodivir for efficacy and safety. 

To investigate the acceptability (taste and swallowability) of the pimodivir formulation in 
adolescents. 

To evaluate superiority with respect to the following influenza A viral parameters in the pimodivir
treatment arm compared to the control arm by quantitative real time polymerase chain reaction 
(qRT-PCR) and viral culture:

Time to viral negativity.

Viral load over time. 

To investigate the emergence of viral resistance against pimodivir detected by genotyping and/or 
phenotyping.
Exploratory Objective

To evaluate the measurement performance of the influenza symptom diary for hospitalized influenza 
subjects.
Endpoints
Primary Endpoint
The primary endpoint is the hospital recovery scale as assessed on Day 6.
Secondary Endpoints
The secondary endpoints are:

Safety and tolerability based on assessment of adverse events (AEs), clinical laboratory assessments, 
12-lead electrocardiograms (ECGs), vital signs, and peripheral capillary oxygen saturation.

Time from start of study drug to hospital discharge and total length of hospital stay.

Time from ICU admission to ICU discharge and total time in ICU. 

Time from start to end of mechanical ventilation and total time on mechanical ventilation.

The hospital recovery scale as assessed each separate day from Days 2 to 14 (excluding the primary 
time point).

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
Time to return to daily activities.

Incidence of complications associated with influenza after the start of study treatment.

All-cause mortality.

Incidence and duration of antibiotic treatment.

The number (proportion) of subjects needing extended treatment. 

The number (proportion) of subjects requiring re-hospitalization.

The number (proportion) of subjects not hospitalized at Day 6.

Time to clinical response.

Time to respiratory response.

PK parameters of pimodivir (ie, plasma concentration just prior to the beginning or at the end of a 
dosing interval [Ctrough], Cmax, tmax, and AUC12h), as determined by population PK analysis. 

The acceptability of the pimodivir formulation in adolescents, as measured by a taste and 
swallowability questionnaire.

Time to viral negativity by qRT-PCR and viral culture.

Viral load over time by qRT-PCR and viral culture.

The emergence of viral resistance against pimodivir detected by genotyping and/or phenotyping.
Exploratory Endpoint

A patient-reported outcome (PRO) based on subjects’ ratings on the influenza symptom diary will be 
formulated.
Hypothesis
The outcome on the hospital recovery scale with pimodivir in combination with SOC treatment is 
statistically superior to treatment with placebo in combination with SOC treatment on Day 6 in 
hospitalized subjects with influenza A infection.
OVERVIEW OF STUDY DESIGN
This is a Phase 3 randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy 
and safety of pimodivir in combination with SOC treatment vs placebo in combination with SOC
treatment in adolescent (13 to 17 years), adult (18 to 65 years), and elderly (>65 to ≤85 years) 
hospitalized subjects with influenza A infection.
A target of 600 hospitalized influenza-infected subjects will be randomly assigned in a 1:1 ratio to receive 
1 of the following treatments in this study with 300 subjects planned per treatment arm. The aim is to 
enroll a minimum of 60 adolescent subjects in this study in selected countries and study sites consistent 
with local regulations. The randomization will be stratified for baseline National Early Warning Score 
(NEWS2; 4-5 or >5), type of baseline SOC (including or not including influenza antiviral treatment), and 
time since onset of influenza symptoms (first administration of study drug within 72 hours or between 72 
and 96 hours since onset of influenza symptoms). The study population should consist of at least 75% of 
subjects (75% of the total planned sample size of 600 subjects) with first administration of study drug
≤72 hours since onset of influenza symptoms. 

Treatment Arm 1: pimodivir 600 mg twice daily (bid) for 5 days + SOC treatment*

Treatment Arm 2: pimodivir placebo bid for 5 days + SOC treatment*

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*SOC treatment is determined by the investigator based on local practice, and may include influenza 
antivirals and/or supportive care only. The choice to use influenza antivirals as part of the SOC should be 
made before randomization. The influenza antiviral should be started no later than the day of first study 
drug intake. An influenza antiviral as part of the SOC cannot be changed (eg, switching one influenza 
antiviral for another) during either the treatment period or extension phase, with the exception that an 
influenza antiviral may be discontinued in the case of a suspected AE.
Study drug will be taken orally. During hospitalization, in case of medical need, study drug tablets may be 
dispersed in water before intake (in case of administration via a nasogastric tube or if the subject has 
difficulties swallowing the tablets).
Subjects (1) who complete the 5-day treatment, (2) who are still hospitalized upon treatment completion, 
(3) who are on invasive mechanical ventilation or who have an ongoing respiratory deficiency as 
evidenced by having a peripheral capillary oxygen saturation (SpO2) <94% on room air, or in case of 
known pre-influenza SpO2 <94% (eg, due to COPD), the current blood oxygen saturation on room air is 
lower than pre-influenza infection levels by at least 3%, (4) who, in the opinion of the investigator, are 
expected to derive clinical benefit from extending the treatment period, and (5) for whom the investigator 
agrees to extend treatment with the same SOC will be given the option for treatment extension. In the 
second blinded course of treatment, subjects will continue treatment with pimodivir or placebo for 
another 5 days in combination with continued SOC treatment. If the SOC contained no influenza antiviral 
during the first treatment period, no influenza antiviral can be started in the treatment extension as part of 
the SOC.
The study will consist of a screening/baseline visit, a double-blind treatment period of 5 days (with the 
possibility to extend the treatment period), and a follow-up period of 23 days after the last dosing day. 
The entire study duration for each subject will be 28 days, except for subjects receiving extended 
treatment, for whom the study will last 33 days. The study is considered complete with the completion of 
the last study assessment for the last subject participating in the study.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to monitor
efficacy and safety data on a regular basis. 
SUBJECT POPULATION
Study drug treatment should be started as soon as possible after the start of the influenza infection.
Screening will occur before randomization and the first administration of study drug.
Key Inclusion Criteria

Male or female, 13 to 85 years of age, inclusive. Note: Adolescent subjects (13-17 years) will be 
enrolled in selected countries and study sites consistent with local regulations.

Tested positive for influenza A infection after the onset of symptoms using a polymerase chain 
reaction (PCR)-based or other rapid molecular diagnostic assay. 

Requires hospitalization to treat influenza infection and/or to treat complications of influenza 
infection (eg, radiological signs of lower respiratory tract disease, septic shock, central nervous 
system [CNS] involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney disease, 
severe dehydration, myocarditis, pericarditis, ischemic heart disease, exacerbation of underlying 
chronic pulmonary disease, including asthma, chronic obstructive pulmonary disease [COPD], 
decompensation of previously controlled diabetes mellitus), including subjects admitted to the 
intensive care unit (ICU). Note: For the purpose of the protocol, subjects admitted under 
“observation” status with an anticipated length of stay beyond 24 hours are eligible for enrollment.

Enrollment and initiation of study drug treatment ≤96 hours after onset of influenza symptoms.

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
Being on invasive mechanical ventilation or having an SpO2 <94% on room air during screening. 
Subjects with known pre-influenza SpO2 <94% must have an SpO2 decline ≥3% from pre-influenza 
SpO2 during screening.

Having a screening/baseline NEWS2 of ≥4.
Key Exclusion Criteria

Received more than 3 doses of influenza antiviral medication (eg, oseltamivir [OST] or zanamivir), 
or any dose of ribavirin within 2 weeks, prior to first study drug intake. Received intravenous (IV) 
peramivir more than one day prior to screening.

Unwilling to undergo regular nasal mid-turbinate (MT) swabs or has any physical abnormality which 
limits the ability to collect regular nasal MT specimens.

Unstable angina pectoris or myocardial infarction within 30 days prior to screening (inclusive).

Presence of clinically significant heart arrhythmias, uncontrolled, unstable atrial arrhythmia, or 
sustained ventricular arrhythmia, or risk factors for Torsade de Pointes syndrome.

Known severe hepatic impairment (Child Pugh C cirrhosis) or chronic hepatitis C infection 
undergoing hepatitis C antiviral therapy.

Severely immunocompromised in the opinion of the investigator (eg, known cluster of differentiation 
4+ [CD4+] count <200 cells/mm3, absolute neutrophil count <750/mm3, first course of chemotherapy 
completed within 2 weeks prior to screening, history of stem cell transplant within 1 year prior to 
screening, any history of a lung transplant). 
Treatment Extension Criteria
Subjects will be given the option for treatment extension in case all of the following conditions are met:

The subject completed the 5-day treatment period.

The subject is still hospitalized.

The subject is on invasive mechanical ventilation or has an ongoing respiratory deficiency as 
evidenced by having an SpO2 <94% on room air, or in case of known pre-influenza SpO2 <94% (eg, 
due to COPD), the current blood oxygen saturation on room air is lower than pre-influenza infection 
levels by at least 3%.

The subject is expected to derive clinical benefit from extending the treatment period, in the opinion 
of the investigator. 

The investigator agrees to extend treatment with the same SOC. If the SOC contained no influenza 
antiviral during the first treatment period, no influenza antiviral can be started in the treatment 
extension as part of the SOC.
DOSAGE AND ADMINISTRATION
During the treatment period, all subjects will receive 1 of the following 2 regimens: 

Pimodivir 600 mg bid on Days 1 through 5 (10 doses) + SOC treatment

Pimodivir placebo bid on Days 1 through 5 (10 doses) + SOC treatment
No post-study medication is provided as part of this protocol.

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EFFICACY EVALUATIONS
Hospital Recovery Scale Assessment
The hospital recovery scale assesses a subject’s clinical status and will be assessed as the subject’s 
condition on Day 6 as the primary endpoint. The hospital recovery scale will be assessed on Days 2 to 14 
(excluding the primary time point) as secondary endpoints. 
The hospital recovery scale provides 6 mutually exclusive conditions ordered from best to worst, and the 
score reflects the subject’s worst situation on the day of assessment:
1.
Not hospitalized
2.
Non-ICU hospitalization, not requiring supplemental oxygen
3.
Non-ICU hospitalization, requiring supplemental oxygen
4.
Admitted to the ICU, not requiring invasive mechanical ventilation
5.
Requiring invasive mechanical ventilation
6.
Death
Patient-reported Outcomes
The impact of influenza infection and its treatment (efficacy and safety) on patient-reported symptoms 
will be evaluated at the time points specified in the TIME AND EVENTS SCHEDULES using the Patient 
Global impression of Severity (PGIS), the Patient Global Impression of Change (PGIC), the European 
Quality of Life (EuroQol) 5 Dimensions (EQ-5D) questionnaire, and the influenza symptom diary. These 
questionnaires will be programmed in the electronic PRO (ePRO) device.
Return to daily activities will be assessed once daily by means of the subject’s response to the question 
'Over the past 24 hours, how much has influenza (flu) interfered with your ability to carry out your daily 
activities?' and the associated scale: 
1.
Not at all
2.
A little bit
3.
Somewhat
4.
Quite a bit
5.
Very much
Viral Kinetics (Nasal MT Swabs) 
Influenza viral load will be quantified in nasal MT swab samples (and endotracheal aspirates in subjects 
who are intubated) taken at scheduled times throughout the study as indicated in the TIME AND 
EVENTS SCHEDULES. Nasal MT swabs and endotracheal samples will be analyzed centrally using 
qRT-PCR and viral culture. Influenza A subtype will be determined from the baseline sample.
RESISTANCE EVALUATIONS
Viral Sequencing
Nasal MT swabs and endotracheal samples will be collected at the time points specified in the TIME 
AND EVENTS SCHEDULES and will be used for sequence analysis of the PB2 region of the influenza 
polymerase gene, and of neuraminidase (and hemagglutinin, if applicable) gene for subjects using a
neuraminidase inhibitor as part of their SOC. For subjects who meet criteria for reduced virologic 
response or viral rebound, the acidic protein and PB1 regions of the influenza polymerase will be 

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sequenced as well. Exploratory sequencing of other regions of the influenza virus genome may also be 
performed.
Phenotyping
Nasal MT swabs and endotracheal samples will be used for the analysis of phenotypic resistance against 
pimodivir, and other antivirals if applicable, at the time points specified in the TIME AND EVENTS 
SCHEDULES.
PHARMACOKINETIC EVALUATIONS
Sparse PK sampling for the measurement of plasma concentrations of pimodivir will be performed at the 
time points specified in the TIME AND EVENTS SCHEDULES. 
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
A population PK and PK/PD analysis of plasma concentration-time data of pimodivir will be performed 
using the nonlinear mixed-effects modeling approach. The relationship between the PK and PD (clinical 
outcomes, safety parameters, and antiviral activity) after repeated oral administration of pimodivir will be 
explored.
TASTE AND SWALLOWABILITY
A taste and swallowability questionnaire will be completed by adolescent subjects, within approximately
15 minutes after the first and last intake of the pimodivir or placebo tablet (not applicable when tablets are 
administered via nasogastric tube).
SAFETY EVALUATIONS
Safety and tolerability will be evaluated throughout the study from signing of the ICF/assent form
onwards until the last study-related activity. The evaluations of safety and tolerability will include 
monitoring of AEs, clinical laboratory tests, ECGs, vital signs, peripheral capillary oxygen saturation
measurements, and (symptom-directed) physical examinations at the time points specified in the TIME 
AND EVENTS SCHEDULES.
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.
Adverse events and laboratory abnormalities will be graded according to the WHO Toxicity Grading 
Scale.
A blinded Adjudication Committee (AC) will be established to adjudicate AEs as complications based on 
predefined criteria (pulmonary versus extrapulmonary, major versus minor, as well as infectious versus 
non-infectious complications). The AC will receive data on AEs, including medical assessments 
(eg, chest X-ray results, lab results) and concomitant therapy of cases selected from the AEs. Details will 
be provided in an AC charter.
BIOMARKER EVALUATIONS
Samples for biomarker analysis will only be obtained and used if not restricted by local regulations. At 
the time points specified in the TIME AND EVENTS SCHEDULES, a blood sample will be collected for 
exploratory analyses of biomarkers (host RNA). In addition, leftovers from MT nasal swabs or blood 
samples may be used for other biomarker analyses (eg, proteins including cytokines). 
Samples can only be used for research related to safety, PK, and efficacy of the influenza treatment, or 
influenza disease. They may also be used to develop tests/assays related to influenza treatment, or 
influenza disease.

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Analyses of biomarkers may be conducted at the sponsor’s discretion and may be reported separately 
from this study.
PHARMACOGENOMICS EVALUATIONS
A pharmacogenomic blood sample may be collected for future exploratory pharmacogenomic analyses
(where local regulations permit). This pharmacogenomic sample collection is optional. The sample will 
be collected only from subjects who consent separately to this component of the study. Pharmacogenomic 
samples will be analyzed if it is hypothesized that this may help understand the clinical outcomes.
Samples can only be used for research related to safety, PK, and efficacy of the influenza treatment, or 
influenza disease. They may also be used to develop tests/assays related to influenza treatment, or 
influenza disease.
Pharmacogenomics analyses may be conducted at the sponsor’s discretion and may be reported separately 
from this study.
STATISTICAL METHODS
The primary analysis will be performed when all randomized subjects have completed the final study visit 
or discontinued earlier.
Sample Size Determination
The study will enroll 600 subjects between the ages of 13 and 85 years, inclusive. Subjects will be 
randomized 1:1 to one of the treatment arms.
The sample size is based on the primary endpoint of the hospital recovery scale at Day 6. Based on the 
proportional odds model and assuming a benefit of approximately 38% reduction of the common odds 
ratio, a total sample size of 600 subjects (randomized 1:1) is required to obtain 90% power. Inclusion of 
stratification factors would provide some improvement on the derived power.
Efficacy Analyses
The efficacy endpoints will be analyzed on the Intent-to-Treat-infected (ITT-i) and by randomized 
treatment. 
The ITT-i set consists of all subjects who were randomized and treated and had a confirmed influenza A 
infection. 
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment arm and 
stratification factors (baseline NEWS2, type of baseline SOC, and time of onset of influenza symptoms).
Subgroup analyses will be performed by, but might not be limited to, treatment extension, region, and age 
group.
As a confirmatory strategy, to account for multiplicity in the statistical evaluation of the most important 
efficacy endpoints, a combination of hierarchical testing and the Bonferroni-Holm testing procedure will 
be applied to control for the overall Type I error rate at the 5% level (2-sided). The following endpoints 
are included in the confirmatory strategy:
1.
Hospital recovery scale at Day 6, ie, primary endpoint
2.
Incidence in post-baseline complications
3.
Time from start of study drug to hospital discharge
4.
Time from ICU admission to ICU discharge

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5.
Time to return to daily activities
6.
Time from start to end of mechanical ventilation
7.
Rate of re-hospitalization
First, the primary endpoint will be tested for superiority of pimodivir in combination with SOC over 
placebo in combination with SOC at the 2-sided 5% significance level. If superiority is shown on the 
primary endpoint, then the 2 secondary endpoints indicated by 2. and 3. in the sequence above will be 
tested for superiority using the Bonferroni-Holm testing procedure: the smallest p-value from the analysis 
of these 2 secondary endpoints will be compared to a significance level of 0.025 and, if statistically 
significant (ie, 2-sided p<0.025), then the 2-sided p-value for the second endpoint will be compared to a 
significance level of 0.05. If both endpoints show superiority, the same Bonferroni-Holm testing 
procedure will be applied to the 2 secondary endpoints indicated by 4. and 5. in the sequence above. If 
both these endpoints show superiority, the secondary endpoint indicated by 6. in the sequence above will 
be tested at the 2-sided 5% significance level. If superiority of this sixth endpoint is shown, the seventh
and last endpoint in the sequence above will be tested at the 2-sided 5% significance level. For the 
primary endpoint, the results from the proportional odds model will be used in the hypothesis testing. For 
the secondary endpoints time from start of study drug to hospital discharge, time from ICU admission to 
ICU discharge, time to return to daily activities, and time from start to end of mechanical ventilation, the 
results of the Gehan-Wilcoxon test will be used in the hypothesis testing. For incidence in post-baseline 
complications and rate of re-hospitalization the results of the logistic regression will be used.
Primary Endpoint
The primary efficacy analysis will consist of the analysis of the hospital recovery scale outcome on Day 6 
using a proportional odds model, including at a minimum treatment, and the stratification factors 
(baseline NEWS2, type of baseline SOC, and time since onset of influenza symptoms).
In case of more than 10% missing data on Day 6, multiple imputation will be employed as sensitivity 
analyses, under the missing-at-random assumption and missing-not-at-random assumption.
Secondary Endpoints
Time from start of study drug to hospital discharge will be analyzed by a stratified Gehan-Wilcoxon test 
(using the stratification factors, ie, type of baseline SOC, time of onset of symptoms and baseline 
NEWS2). Kaplan-Meier curves, overall and by stratum, and a stratified log-rank test for time to symptom 
resolution will also be provided. Additionally, the data will be analyzed using an accelerated failure time 
model. Also a Cox proportional hazards model will be applied. Both models will be adjusted for 
stratification factors. Time from ICU admission to ICU discharge and time from start to end of
mechanical ventilation will be analyzed analogously to that of time from start of study drug to hospital 
discharge. Time from start of study drug to hospital discharge and time from ICU admission to ICU 
discharge will also be derived based on investigator's evaluation of the subjects' clinical status and 
analyzed analogously.
Total length of hospitalization, total time in ICU, and total time on mechanical ventilation will be 
analyzed by the stratified Wilcoxon Rank-Sum test and using the stratification factors. Corresponding 
95% CIs will be derived using the Hodges-Lehman approach.
Time to return to daily activities will be assessed once daily by means of the question 'Over the past 
24 hours, how much has influenza interfered with your ability to carry out your daily activities?' The 
responses will be dichotomized: 'Not at all' and 'A little bit' will be considered as returned to daily 
activities and 'Somewhat', 'Quite a Bit' and 'Very much' will be considered as not having returned to daily 
activities. The time to return to daily activities will be analyzed analogously to that of time from start of 
study drug to hospital discharge.

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To compare the incidence of treatment-emergent complications a logistic regression model will be used. 
Stratification factors will be added to the model. A similar model will be applied for all-cause mortality,
the incidence of antibiotic treatment, number (proportion) of subjects needing extended treatment, number 
(proportion) of subjects requiring re-hospitalization, and number (proportion) of subjects not hospitalized 
at Day 6. The duration of antibiotic treatment will be analyzed analogously to the total length of 
hospitalization.
Time to viral negativity by qRT-PCR and viral culture will be analyzed analogously to that of time from 
start of study drug to hospital discharge. The viral load over time will be analyzed using mixed-effects 
modeling. Stratification factors will be added to the model and additional predictive baseline factors, 
including but not limited to baseline viral load, baseline resistance parameters and influenza A subtype,
may be added. 
The hospital recovery scale outcome on each separate day from Days 2 to 14 (excluding the primary time 
point) will be analyzed similarly to the primary endpoint.
Time to clinical response and time to respiratory response will be analyzed analogously to time from start 
of study drug to hospital discharge.
Exploratory Endpoint
Data analysis, validation and anchor-based analysis of the influenza symptom diary will be defined,
analyzed, and reported in a separate report.
Other Analyses
Descriptive statistics by day of assessment will be provided for PGIS and PGIC questionnaires. The 
EQ-5D total scores and EQ-5D visual analog scale ‘thermometer’ scores will be evaluated at each time 
point.
The PGIS and PGIC questionnaire responses will be used as anchors to perform responder analyses for 
selected PROs. 
For the EQ-5D questionnaire a post-hoc analysis plan will be developed when the economic model 
structure is finalized, and results of this analysis will be reported separately.  
Resistance Analyses
Development of resistance against pimodivir (and other antivirals in the SOC if applicable) will be 
determined by viral sequencing and phenotypic testing. All baseline samples as well as the last evaluable 
post-baseline samples will be analyzed. Additional genotypic and phenotypic testing might be requested 
by the sponsor virologist.
The presence of baseline polymorphisms potentially affecting virologic response will be analyzed. The 
incidence of emerging mutations as well as changes in drug susceptibility (fold change in EC50 value) will 
be described and compared between treatment arms. Results of resistance analysis may be reported in a 
separate report.
Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary and 
depend on the different data types of the applied technology platforms, as well as on the extent of 
observed differences between subjects. Analyses will be conducted at the Sponsor’s discretion and may 
be reported separately from this study.

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Pharmacogenomic Analyses
Pharmacogenomic samples may be used for research related to pimodivir or influenza A. They may also 
be used to develop tests/assays related to pimodivir or influenza A. Pharmacogenomic research may 
consist of the analysis of one or more candidate genes or of the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate) in relation to pimodivir clinical endpoints.
Results of pharmacogenomic analysis will be reported in a separate report.
Pharmacokinetic Analyses
Population PK analysis of plasma concentration-time data of pimodivir will be performed using nonlinear 
mixed-effects modeling. Data may be combined with those of other selected studies (ie, Phase 1 and 2 
studies) to support a relevant structural model. Available baseline subject characteristics (eg, 
demographics, body weight, laboratory variables, race, etc.) will be tested as potential covariates affecting 
PK parameters. The results of the population PK analysis will be reported in a separate report. 
Pharmacokinetic/Pharmacodynamic Analyses
The PK/PD relationship of pimodivir exposure (area under the plasma concentration-time curve from 
time 0 to 12 hours after dosing [AUC12h], maximum plasma concentration [Cmax,], or plasma 
concentration just prior to the beginning or at the end of a dosing interval [Ctrough]) with selected efficacy 
(eg, time from start of study drug to hospital discharge, change in viral load from baseline and in other 
virologic response parameters) and safety (including AEs and laboratory abnormalities) parameters will 
be explored. If there is any visual trend in graphical analysis, suitable models will be applied to describe 
the exposure-effect relationships. Results of PK/PD analyses will be reported in a separate report.
Taste and Swallowability
Taste and swallowability questionnaire results (collected for adolescents who take pimodivir or placebo
tablets; not applicable when tablets are administered via nasogastric tube) will be summarized per tablet 
intake (first and last intake of the study drug) by means of frequency tabulations. For overall taste, a 
dichotomization will be made for the overall question, categorizing ‘bad’ and ‘almost acceptable’ vs
‘acceptable’ and ‘good’. For the swallowability, a dichotomization will be made of ‘slightly difficult’ or 
worse vs ‘neither difficult nor easy’ or better. The number of subjects (%) will be presented by category.
Safety Analyses
All safety endpoints will be evaluated on the Safety population, consisting of all subjects who received at 
least one dose of study drug and will be analyzed by actual treatment received. Safety will be evaluated 
by means of AEs, clinical laboratory tests, ECGs, vital signs, peripheral capillary oxygen saturation, and 
(symptom-directed) physical examinations. The safety analysis will be performed for each study phase 
separately (treatment, treatment extension, follow-up, and combined). Descriptive statistics and frequency 
tabulations will be provided.
Interim Analysis
An interim analysis will be implemented to assess lack of efficacy in the subgroup with time since onset 
of influenza symptoms between 72 and 96 hours. This interim analysis will be implemented through an 
IDMC, providing recommendations to a Sponsor Committee. Only the IDMC and the independent
statistical support group will be unblinded to the data.

In case lack of efficacy is concluded for the subgroup with time since onset of influenza symptoms 
between 72 and 96 hours:

Enrollment in this subgroup will be stopped.

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
Sample size re-estimation will be performed based on the subgroup with time since onset of 
influenza symptoms ≤72 hours and consequently, the sample size of this subgroup may be 
increased. The maximum number of subjects that may be enrolled in this subgroup will be 
approximately 900.

Futility will be assessed in the subgroup with time since onset of influenza symptoms ≤72 hours 
based on re-estimated sample size. 

At the final analysis, hypotheses will be evaluated in the subgroup with time since onset of 
influenza symptoms ≤72 hours.

In case no lack of efficacy is concluded for the subgroup with time since onset of influenza 
symptoms between 72 and 96 hours:

The subgroup with time since onset of influenza symptoms between 72 and 96 hours will be 
continued in the study.

Sample size re-estimation will be performed based on all subjects. The sample size may be 
increased. The maximum total number of subjects that may be enrolled in the study will be 
approximately 900. The study population should consist of at least 75% of subjects with first 
administration of study drug ≤72 hours since onset of influenza symptoms.

Futility will be assessed in all subjects based on re-estimated sample size. 

At the final analysis, hypotheses will be evaluated in all subjects.
Details on the statistical decision rules will be provided in a separate Modeling and Simulation Report. 
The interim analysis will be conducted at the end of the first influenza season when between 300 and 450 
subjects have been enrolled or during the season when 450 subjects have been enrolled. Further details 
will be specified in the IDMC charter.

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TIME AND EVENTS SCHEDULES
1. TIME AND EVENTS SCHEDULE – DURING HOSPITALISATION (UP TO DISCHARGE)
Phase
Screening / 
Baseline
Treatmenta
Follow-upa
Day
0-1b
1
2
3
4
5
6
7-13
14
15-27
28
Safety Follow-up Visit 
/ Final Study Visita
Screening/Administrative/Safety
ICF/assent form
X
Inclusion/exclusion criteria
Xc
Medical and surgical history, 
demographics, influenza 
vaccination status, substance use
X
Physical exam
X
X
Symptom-directed physical exam
1x daily until discharge or through Day 14 (whichever comes first)
Height and weightd
X
12-lead ECGe
X
X
Pregnancy test (female subjects of 
childbearing potential)
Xf
X
X
Treatment extension criteriag
X
Randomization/Administration
Randomization
X
Administration of study drug 
Xh
X
X
X
Xh
Virology
Nasal swab for local virology 
testingi
Xj
Nasal MT swab for central testingk
X
X
Xl
X
Xl
X
X
Endotracheal aspirate (only if 
intubated)k
X
X
Xl
X
Xl
X
X
Efficacy/Safety
Vital signs/pulse oximetrym
Xn
3x daily until discharge or through Day 14 (whichever comes first)o
X
Level of consciousness by ACVPU
Xn
3x daily until discharge or through Day 14 (whichever comes first)o
X
Influenza Symptom Diaryz,aa
X
2x daily from Day 2 through the Final Study Visit/Safety Follow-up Visit
Assessment of daily activities 
resumptionp,aa
X
1x daily from Day 2 through the Final Study Visit/Safety Follow-up Visit
PGISq, aa
X
1x daily from Day 2 through the Final Study Visit/Safety Follow-up Visit
PGICr, aa
X
X
X
EQ-5Ds, aa
X
X
X
X
Hematology, chemistry
Xt,u
Xu
Xu
Xu
Xu
Urinalysis
X
X
X
X
X

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Phase
Screening / 
Baseline
Treatmenta
Follow-upa
Day
0-1b
1
2
3
4
5
6
7-13
14
15-27
28
Safety Follow-up Visit 
/ Final Study Visita
Pharmacokineticsv
X
Xl
Xl
Blood biomarker sampling (host 
RNA)w
X
X
Pharmacogenomic sampling (host 
DNA)w,x
X
Taste and swallowability
Xy
Xy
Adverse events recording
X
X
X
X
X
X
X
X
X
X
X
Prestudy and concomitant 
medication recording
X
X
X
X
X
X
X
X
X
X
X
Assessment of readiness for 
hospital discharge
1x daily until discharge or through Final Study Visit/Safety Follow-up Visit (whichever comes first)
Assessment of ICU level of care 
requirement
1x daily while in the ICU or through Final Study Visit/Safety Follow-up Visit (whichever comes first)
Abbreviations: ACVPU: alert, new confusion, voice, pain, unresponsive; DNA: deoxyribonucleic acid; EQ-5D: European Quality of Life 5 Dimensions; ECG: 
electrocardiogram; ICF: informed consent form; MT: mid-turbinate; PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; RNA: 
ribonucleic acid.
a.
Subjects who prematurely discontinue study drug treatment for any reason (except withdrawal of consent) will be asked to continue with their remaining study 
visits and assessment schedule. Subjects who withdraw consent during the treatment or follow-up phase will be offered an optional Safety Follow-up Visit. The 
optional Safety Follow-up Visit will occur the day of consent withdrawal or the day after and will consist of the same assessments as at the Final Study Visit 
(Day 28), with optional patient-reported outcome (PRO) completion.
b.
Screening/baseline assessments start at signing of the ICF/assent form and can continue the next calendar day if needed. All screening/baseline procedures should 
take place prior to the first study drug intake.
c.
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 they no longer meet all eligibility criteria, 
they should be excluded from participation in the study.
d.
Height and body weight are only to be measured at screening if not already available in the subject’s chart and if practically feasible.
e.
Subjects should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital signs measurement is scheduled for the same time point as ECG recording, the procedures should be performed in the following order: ECGs, vital signs, 
blood draw. An ECG recorded within 1 calendar day before signing of the ICF/assent form can be used in lieu of the baseline ECG requirement.
f.
The result of a prior pregnancy test (urine or serum) that occurred within 1 calendar day before signing of the ICF/assent form can be used in lieu of the baseline 
requirement.
g.
Subjects who meet the treatment extension criteria and agree to participate in the treatment extension arm, should be switched to the 3. TIME AND EVENTS 
SCHEDULE – DURING HOSPITALIZATION (UP TO DISCHARGE), FOR PATIENTS WHO ENTERED THE OPTIONAL DOUBLE-BLIND EXTENSION 
TREATMENT ARM on Day 6, and then switched to the 4. TIME AND EVENTS SCHEDULE – AFTER DISCHARGE FROM HOSPITAL, FOR PATIENTS 
WHO HAD ENTERED THE OPTIONAL DOUBLE-BLIND EXTENSION TREATMENT ARM after discharge from hospital.

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h.
Depending on the time of screening/enrollment, subjects will receive 1 dose (evening) or 2 doses (morning and evening) of study drug on Day 1. For subjects who 
receive only 1 dose of pimodivir or placebo on Day 1 (evening), dosing should continue until the morning of Day 6 so that all subjects receive 10 doses in total.
i.
Polymerase chain reaction (PCR)-based or other rapid molecular diagnostic assay performed locally. It is recommended to use MT swabs for local virology testing, 
although nasopharyngeal (NP) swabs are allowed if required by local procedures. Nasal swabs for local virology testing should be obtained from the left and right 
nostrils (from both nostrils if feasible, but from only one nostril otherwise) and pooled into the same collection tube If available, leftovers from the local virology 
sample (with the exception of “an earlier sample”, see footnote j) will be shipped to and stored at the central lab for further testing, regardless of local influenza test 
result.
j.
The results of an earlier sample collected and tested positive for influenza A infection after the onset of symptoms using a PCR-based or other rapid molecular 
diagnostic assay can be used in lieu of the local virology testing at screening. This sample is used to determine eligibility. 
k.
Central virology testing: Nasal MT swabs should be obtained from the left and the right nostrils (from both nostrils if feasible, but from only one nostril otherwise) 
and pooled into the same collection tube. In case the subject is intubated, endotracheal samples should be taken as well, at the same time as the nasal MT swab. 
The samples will be collected at screening/baseline and on Days 2, 3, 4, 5, 8, 10, and 14. The screening/baseline sample needs to be collected predose, as close as 
possible to the first dose. Sampling should be done at approximately the same time (±4 hours) on each sampling day. Leftovers from nasal MT swabs and 
endotracheal samples collected for virology testing may be used for protein biomarker analysis, if not restricted by local regulations.
l.
At the time points where both nasal MT swabs/endotracheal aspirate and pharmacokinetic (PK) samples are obtained, these samples should be obtained as close 
together in time as possible. 
m.
Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure. For peripheral capillary oxygen saturation, it should be recorded whether the 
measurement was with or without supplemental oxygen. The SpO2 should be measured either in a sitting or supine position after 5 minutes of rest in a quiet 
environment.
n.
National Early Warning Score (NEWS2) should be calculated before randomization as NEWS2 at baseline is an inclusion criterion (≥4) as well as a stratification 
factor (4-5 or >5).
o.
Vital signs/peripheral capillary oxygen saturation (pulse oximetry)/ACVPU are to be evaluated 3 times daily: in the morning (prior to study drug intake if 
applicable), approximately half-way in the middle of the day, and in the evening (prior to study drug intake if applicable).
p.
Questionnaire (Return to daily activities) to be completed at screening/baseline (as close as possible to the first dose) and then once daily onto the ePRO device.
q.
Questionnaire (PGIS) to be completed at screening/baseline (as close as possible to the first dose) and then once daily onto the ePRO device. 
r.
Questionnaire (PGIC) to be completed on Days 6, 14, and 28 onto the ePRO device.
s.
Questionnaire (EQ-5D) to be completed at screening/baseline (as close as possible to the first dose) and on Days 6, 14, and 28 onto the ePRO device.
t.
Follicle-stimulating hormone (FSH) will be tested at screening for female subjects who are amenorrheic for 12 months or less.
u.
If feasible, safety blood samples will be collected after fasting for at least 10 hours. 
v.
Sparse PK sampling will be performed as follows (during hospitalization):
On Day 1: between 1.5 and 6 hours after the morning or evening dose (preferably the morning dose).
On Day 3: predose (≤1 hour prior to morning or evening dose).
On Day 5: predose (≤1 hour prior to dosing) and between 1.5 and 6 hours after the dose. Either the morning or evening dose (whichever is the most convenient) 
can be considered for this sampling.
Leftovers from samples collected for PK testing may be used for protein biomarker analysis, if not restricted by local regulations.
w.
If not restricted by local regulations. 
x.
This pharmacogenomic sample collection is optional. The pharmacogenomic sample should preferably be collected at the specified time point, however if 
necessary it may be collected at another time point without constituting a protocol deviation.

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y.
The taste and swallowability questionnaire for pimodivir or placebo should only be completed by adolescent subjects. The questionnaire should be completed
within approximately 15 minutes after the first and last pimodivir or placebo intake (not applicable when tablets are administered via nasogastric tube). For 
subjects who receive the last dose of pimodivir or placebo on Day 6 (see footnote h), the questionnaire should be completed on Day 6.
z.
Influenza symptom diary to be completed at screening/baseline (prior to the first dose) and then twice daily onto the ePRO device.
aa.
PRO assessments will be completed by all subjects at sites where appropriate PROs and translations are available and approved.

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2. TIME AND EVENTS SCHEDULE – AFTER DISCHARGE FROM HOSPITAL
Note: This Time and Events Schedule should start with the study day number following the day of discharge from the hospital (for example: 
subjects discharged on Study Day 3 would start with Day 4 procedures on this schedule). After subjects are discharged, the remainder of the 
study visits should be carried out as outpatient visits (preferably on-site or, if not feasible, at the subject’s home) or by telephone follow-up 
as indicated in the table below. Every effort should be made to perform all of the assessments as outlined below (either on-site or at the 
subject’s home), if practically feasible. In case of readmission to the hospital, subjects will continue to follow this Time and Events 
Schedule until the end of the study.
Phase
Treatmenta,b
Follow-upb
Day
2/3/4/5
6c
7-9
10
+/-1 Day
11-13
14
+/-1 Day
15-27
28
+/-1 Day
Phone 
Follow-upe
Phone 
Follow-upf
Safety Follow-up Visit / Final Study 
Visitb
Clinic or home visit
X
X
X
X
Administration
Administration of study druga,g
X
Virology
Nasal MT swab for central testingh
Xi
X
X
Efficacy/Safety
Vital signs/pulse oximetryj
X
X
Physical exam
X
Symptom-directed physical exam
X
X
X
12-lead ECGk
X
Pregnancy test (female subjects of 
childbearing potential)
Xl
X
Influenza Symptom Diarys,t
2x daily through the Final Study Visit/Safety Follow-up Visitd
Assessment of daily activities resumptionm,t
1x daily through the Final Study Visit/Safety Follow-up Visitd
PGISn,t
1x daily through the Final Study Visit/Safety Follow-up Visitd
PGICo,t
Xd
Xd
X
EQ-5Dp,t
Xd
Xd
X
Hematology, chemistry
Xq
Xq
Xq
Urinalysis
X
X
X
Pharmacokinetics
Xi
Taste and swallowability
Xr
Adverse events recording
X
X
X
X
X
X
Prestudy and concomitant medication 
recording
X
X
X
X
X
X

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Abbreviations: ECG: electrocardiogram; EQ-5D: European Quality of Life 5 Dimensions; MT: mid-turbinate; PGIC: Patient Global Impression of Change; 
PGIS: Patient Global impression of Severity.
a.
If the subject is discharged during study treatment, he/she will receive study drug for at-home use.
b.
Subjects who prematurely discontinue study drug treatment for any reason (except withdrawal of consent) will be asked to continue with their remaining study 
visits and assessment schedule. Subjects who withdraw consent during the treatment or follow-up phase will be offered an optional Safety Follow-up Visit. The 
optional Safety Follow-up Visit will occur the day of consent withdrawal or the day after and will consist of the same assessments as at the Final Study Visit 
(Day 28), with optional PRO completion.
c.
The Day 6 visit may be performed on Day 7, although efforts should be made to respect the initial Time and Events Schedule.
d.
PRO completion compliance should be assessed daily by the site staff via the ePRO web platform. Reasons for missing assessment should be documented on the 
web platform by the site after discussion with the subject.
e.
At minimum, a daily phone contact should be established with the subject to document potential adverse events (AEs) and concomitant medications, and to enquire 
about compliance with study drug intake (the need for a face-to-face visit, at-home or on-site, is at the investigator's discretion).
f.
During this period, at minimum one phone contact should be established with the subject to document potential AEs and concomitant medications (the need for a 
face-to-face visit, at-home or on-site, is at the investigator's discretion). 
g.
For subjects who receive only 1 dose of pimodivir or placebo on Day 1 (evening), dosing should continue until the morning of Day 6 so that all subjects receive 
10 doses in total.
h.
Central virology testing: Nasal MT swabs should be obtained from the left and the right nostrils (from both nostrils if feasible, but from only one nostril otherwise) 
and pooled into the same collection tube. Samples will be collected on Days 6, 10, and 14. Sampling should be done at approximately the same time (±4 hours) on 
each sampling day. Leftovers from nasal MT swabs collected for virology testing may be used for protein biomarker analysis, if not restricted by local regulations.
i.
Pharmacokinetic (PK) sampling will be performed on Day 6, preferentially as close as possible to 12h after the last dose of study drug (ie, the evening dose on 
Day 5). If treatment was started in the evening of Day 1, PK sampling will be performed on Day 6 before the last drug intake. The date and time of the evening 
drug intake on Day 5 will be recorded. In case the Day 6 visit is performed on Day 7 (footnote b), the PK sample should be taken as early as possible during the 
visit (date and time of the last study drug intake before PK sampling will be recorded). Leftovers from samples collected for PK testing may be used for protein 
biomarker analysis, if not restricted by local regulations. Nasal MT swabs and PK samples should be obtained as close together in time as possible. 
j.
Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure. For peripheral capillary oxygen saturation, it should be recorded whether the 
measurement was with or without supplemental oxygen.
k.
Subjects should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital signs measurement is scheduled for the same time point as ECG recording, the procedures should be performed in the following order: ECGs, vital signs, 
blood draw.
l.
In case a female subject is discharged on Day 2, a home pregnancy test will be done on Day 3 (urine dipstick).
m.
Questionnaire (Return to daily activities) to be completed once daily onto the ePRO device.  
n.
Questionnaire (PGIS) to be completed once daily onto the ePRO device. 
o.
Questionnaire (PGIC) to be completed on Days 6, 14, and 28 onto the ePRO device.
p.
Questionnaire (EQ-5D) to be completed on Days 6, 14, and 28 onto the ePRO device.
q.
If feasible, safety blood samples will be collected after fasting for at least 10 hours.
r.
The taste and swallowability questionnaire should be only completed by adolescent subjects for pimodivir or placebo. The questionnaire should be completed
within approximately 15 minutes after the first and last intake of the pimodivir or placebo tablet (not applicable when tablets are administered via nasogastric tube).
For subjects who receive the last dose of pimodivir or placebo on Day 6 (see footnote g), the questionnaire should be completed on Day 6.
s.
Influenza Symptom Dairy to be completed twice daily onto the ePRO device.
t.
PRO assessments will be completed by all subjects at sites where appropriate PROs and translations are available and approved.

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3. TIME AND EVENTS SCHEDULE – DURING HOSPITALIZATION (UP TO DISCHARGE), FOR PATIENTS WHO ENTERED 
THE OPTIONAL DOUBLE-BLIND EXTENSION TREATMENT ARM
Note: This Time and Events Schedule is only applicable for hospitalized patients who entered the treatment extension phase (see Sections 
4.3 and 9.1.4 for eligibility criteria), and should be followed up to discharge. 
Phase
Optional Extended Blinded Treatmenta
Follow-upa
Day
6
7
8
9
10
11
12-13
14
15-18
19
20-32
33
Safety Follow-up Visit / 
Final Study Visita
Administration
Administration of study drugb
X
X
X
X
X
Virology
Nasal MT swab for central 
testingc
X
X
X
X
X
X
X
Endotracheal aspirate (only if 
intubated)c
X
X
X
X
X
X
X
Efficacy/Safety
Vital signs/pulse oximetryd
3x daily until discharge or through Day 19 (whichever comes first)e
X
Level of consciousness by 
ACVPU
3x daily until discharge or through Day 19 (whichever comes first)e
X
Physical exam
X
Symptom-directed physical exam
1x daily until discharge or through Day 19 (whichever comes first)
12-lead ECGf
X
Pregnancy test (female subjects 
of childbearing potential)
X
X
Influenza Symptom Diaryl,m
2x daily through the Final Study Visit/Safety Follow-up Visit
Assessment of daily activities 
resumptiong,m
1x daily through Final Study Visit/Safety Follow-up Visit
PGISh,m
1x daily through Final Study Visit/Safety Follow-up Visit
PGICi,m
X
X
X
X
EQ-5Dj,m
X
X
X
X
Hematology, chemistry
Xk
Xk
Xk
Xk
Urinalysis
X
X
X
X
Adverse events recording
X
X
X
X
X
X
X
X
X
X
X
X
Prestudy and concomitant 
medication recording
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of readiness for 
hospital discharge
1x daily until discharge or through Final Study Visit/Safety Follow-up Visit (whichever comes first)
Assessment of ICU level of care 
requirement
1x daily until discharge or through Final Study Visit/Safety Follow-up Visit (whichever comes first)

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Abbreviations: ACVPU: alert, new confusion, voice, pain, unresponsive; ECG: electrocardiogram; EQ-5D: European Quality of Life 5 Dimensions; MT: mid-turbinate;
PGIC: Patient Global Impression of Change; PGIS: Patient Global impression of Severity.
a.
Subjects who prematurely discontinue study drug treatment for any reason (except withdrawal of consent) will be asked to continue with their remaining study
visits and assessment schedule. Subjects who withdraw consent during the treatment or follow-up phase will be offered an optional Safety Follow-up Visit. The 
optional Safety Follow-up Visit will occur the day of consent withdrawal or the day after and will consist of the same assessments as at the Final Study Visit
(Day 33), with optional PRO completion.
b.
On Day 6, subjects will receive 1 dose (evening) or 2 doses (morning and evening) of study drug as part of the extension phase. For subjects who receive only 
1 dose of pimodivir or placebo on Day 6 (evening), dosing should continue until the morning of Day 11 so that the subject receives 10 doses in total during the 
extension phase.
c.
Central virology testing: Nasal MT swabs should be obtained from the left and the right nostrils (from both nostrils if feasible, but from only one nostril otherwise) 
and pooled into the same collection tube. In case the subject is intubated, endotracheal samples should be taken as well, at the same time as the nasal MT swab.
Samples will be collected on Days 6, 7, 8, 9, 10, 14, and 19. Sampling should be done at approximately the same time (±4 hours) on each sampling day. Leftovers 
from nasal swabs and endotracheal samples collected for virology testing may be used for protein biomarker analysis, if not restricted by local regulations.
d.
Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure. For peripheral capillary oxygen saturation, it should be recorded whether the 
measurement was with or without supplemental oxygen.
e.
Vital signs/peripheral capillary oxygen saturation (pulse oximetry)/ACVPU are to be evaluated 3 times daily: in the morning (prior to study drug intake if 
applicable), approximately half-way in the middle of the day, and in the evening (prior to study drug intake if applicable).
f.
Subjects should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital signs measurement is scheduled for the same time point as ECG recording, the procedures should be performed in the following order: ECGs, vital signs, 
blood draw.
g.
Questionnaire (Return to daily activities) to be completed once daily onto the ePRO device.
h.
Questionnaire (PGIS) to be completed once daily onto the ePRO device.
i.
Questionnaire (PGIC) to be completed on Days 6, 14, 19, and 33 onto the ePRO device.
j.
Questionnaire (EQ-5D) to be completed on Days 6, 14, 19, and 33 onto the ePRO device.
k.
If feasible, safety blood samples will be collected after fasting for at least 10 hours.
l.
Influenza Symptom Dairy to be completed twice daily onto the ePRO device.
m.
PRO assessments will be completed by all subjects at sites where appropriate PROs and translations are available and approved.

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4. TIME AND EVENTS SCHEDULE – AFTER DISCHARGE FROM HOSPITAL, FOR PATIENTS WHO HAD ENTERED THE 
OPTIONAL DOUBLE-BLIND EXTENSION TREATMENT ARM
Note: This Time and Events Schedule is only applicable for subjects who entered the treatment extension phase (see Sections 4.3 and 9.1.4
for eligibility criteria) and after they have been discharged. This Time and Events Schedule should start with the study day number 
following the day of discharge from the hospital (for example: subjects discharged on Study Day 6 would start with Day 7 procedures on 
this schedule). After subjects are discharged, the remainder of the study visits should be carried out as outpatient visits (preferably on-site or, 
if not feasible, at the subject’s home) or by telephone follow-up as indicated in the table below. Every effort should be made to perform all 
of the assessments as outlined below (either on-site or at the subject’s home), if practically feasible. In case of readmission to the hospital, 
subjects will continue to follow this Time and Events Schedule until the end of the study.
Phase
Optional Extended 
Blinded Treatmenta
Follow-upa
Day
7-8-9-10
11b
12-13
14
+/-1 Day
15-18
19
+/-1 Day
20-32
33
+/-1 Day
Phone Follow-upc
Phone 
Follow-upd
Safety Follow-up Visit / 
Final Study Visita
Clinic or home visit
X
X
X
X
Administration
Administration of study druge,f
X
Virology
Nasal MT swab for central testingg
X
X
X
Efficacy/Safety
Vital signs/pulse oximetryh
X
X
Physical exam
X
Symptom-directed physical exam
X
X
X
12-lead ECGi
X
Pregnancy test (female subjects of 
childbearing potential)
Xj
X
Influenza Symptom Diarys,t
2x daily through the Final Study Visit/Safety Follow-up Visitr
Assessment of daily activities 
resumptionk,t
1x daily through the Final Study Visit/Safety Follow-up Visitr
PGISl,t
1x daily through the Final Study Visit/Safety Follow-up Visitr
PGICm,t
Xn,r
Xo,r
X
EQ-5Dp,t
Xn,r
Xo,r
X
Hematology, chemistry
Xp
Xp
Xp
Urinalysis
X
X
X
Adverse events recording
X
X
X
X
X
X
Prestudy and concomitant 
medication recording
X
X
X
X
X
X

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Abbreviations: ECG: electrocardiogram; EQ-5D: European Quality of Life 5 Dimensions; MT: mid-turbinate; PGIC: Patient Global Impression of Change; PGIS: 
Patient Global impression of Severity.
a.
Subjects who prematurely discontinue study drug treatment for any reason (except withdrawal of consent) will be asked to continue with their remaining study 
visits and assessment schedule. Subjects who withdraw consent during the treatment or follow-up phase will be offered an optional Safety Follow-up Visit. The 
optional Safety Follow-up Visit will occur the day of consent withdrawal or the day after and will consist of the same assessments as at the Final Study Visit 
(Day 33), with optional PRO completion.
b.
The Day 11 visit may be performed on Day 12, although efforts should be made to respect the initial Time and Events Schedule.
c.
At minimum, a daily phone contact should be established with the subject to document potential adverse events (AEs) and concomitant medications, and to enquire 
about compliance with study drug intake (the need for a face-to-face visit, at-home or on site, is at the investigator's discretion).
d.
During this period, at minimum one phone contact should be established with the subject to document potential AEs and concomitant medications (the need for a 
face-to-face visit, at-home or on-site, is at the investigator's discretion).
e.
If the subject is discharged while on study treatment, he/she will receive study drug for at-home use.
f.
On Day 6, subjects will receive 1 dose (evening) or 2 doses (morning and evening) of study drug as part of the extension phase. For subjects who receive only 
1 dose of pimodivir or placebo on Day 6 (evening), dosing should continue until the morning of Day 11 so that the subject receives 10 doses in total during the 
extension phase.
g.
Central virology testing: Nasal MT swabs should be obtained from the left and the right nostrils (from both nostrils if feasible, but from only one nostril otherwise) 
and pooled into the same collection tube. Samples will be collected on Days 11, 14, and 19. Sampling should be done at approximately the same time (±4 hours) 
on each sampling day. Leftovers from nasal swabs and endotracheal samples collected for virology testing may be used for protein biomarker analysis, if not 
restricted by local regulations.
h.
Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure. For peripheral capillary oxygen saturation, it should be recorded whether the 
measurement was with or without supplemental oxygen.
i.
Subjects should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital signs measurement is scheduled for the same time point as ECG recording, the procedures should be performed in the following order: ECGs, vital signs, 
blood draw.
j.
If the subject is discharged before Day 8, a home pregnancy test will be done on Day 8 (urine dipstick).
k.
Questionnaire (Return to daily activities) to be completed once daily onto the ePRO device.
l.
Questionnaire (PGIS) to be completed once daily onto the ePRO device.
m.
Questionnaire (PGIC) to be completed on Days 14, 19, and 33 onto the ePRO device.
n.
If the visit is performed on Day 13 or 15, a phone contact on Day 14 should be established to ensure compliance with PRO questionnaire completion.
o.
If the visit is performed on Day 18 or 20, a phone contact on Day 19 should be established to ensure compliance with PRO questionnaire completion.
p.
Questionnaire (EQ-5D) to be completed on Days 14, 19, and 33 onto the ePRO device.
q.
If feasible, safety blood samples will be collected after fasting for at least 10 hours.
r.
PRO completion compliance should be assessed daily by the site staff via the ePRO web platform. Reasons for missing assessment should be documented on the 
web platform by the site after discussion with the subject.
s.
Influenza Symptom Dairy to be completed twice daily onto the ePRO device.
t.
PRO assessments will be completed by all subjects at sites where appropriate PROs and translations are available and approved.

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ABBREVIATIONS
AC
Adjudication Committee
AE
adverse events
ADL
activities of daily living
ADR
adverse drug reaction
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC∞
area under the plasma concentration-time curve from time of dosing extrapolated to infinity 
AUC12h
area under the plasma concentration-time curve from time of dosing to 12 hours postdose
AUC24h
area under the plasma concentration-time curve from time of dosing to 24 hours postdose
AUClast
area under the plasma concentration-time curve from time of dosing to time of last observation
ACVPU
alert, new confusion, voice, pain, unresponsive
bid
twice daily
BUN
blood urea nitrogen
C0h
predose plasma concentration 
CD4+
cluster of differentiation 4+
CDC
Centers of Disease Control and Prevention
CI
confidence interval
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CNS
central nervous system
CPK
creatine phosphokinase
COPD
chronic obstructive pulmonary disease
Ctrough
plasma concentration just prior to the beginning or at the end of a dosing interval
CYP
cytochrome P450
DBP
diastolic blood pressure
DDI
drug-drug interaction
EC50
50% effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
eDC
electronic data capture
ePRO
electronic patient-reported outcome
EQ-5D
European Quality of Life 5 Dimensions
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT-i
Intent-to-Treat-infected
ITT-i2
Intent to Treat-infected-2
IUD
intrauterine device 
IUS
intrauterine hormone-releasing system 
IV
intravenous
IWRS
interactive web response system
LAR
legally acceptable representative(s)
LS
least squares
M2
matrix 2
MAR
missing-at-random

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MCH
mean corpuscular hemoglobin
MedDRA
Medical Dictionary for Regulatory Activities 
MT
mid-turbinate
NAI
neuraminidase inhibitor
NAP
not applicable
NEWS
National Early Warning Score
NMAR
missing-not-at-random
NOAEL
no observed adverse effect level
NP
nasopharyngeal
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OC
oral contraceptive
OST
oseltamivir
PB2
polymerase basic protein 2
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PRO
patient-reported outcome
(q)RT-PCR
(quantitative) real time polymerase chain reaction
QTc
corrected QT interval
QTcB
QT interval corrected for heart rate according to Bazett’s correction
QTcF
QT interval corrected for heart rate according to Fridericia’s correction
RBC
red blood cell
RBV
ribavarin
RNA
ribonucleic acid 
SAE
serious adverse events
SBP
systolic blood pressure
SD
standard deviation 
SOC
Standard-of-care
SpO2
peripheral capillary oxygen saturation
SSG
Statistical Support Group
SUSAR
suspected unexpected serious adverse reaction
t1/2term
terminal phase elimination half-life
TCID50
50% tissue culture infective dose
TEAE
treatment-emergent adverse event
tmax
time to reach Cmax
TQT
thorough QT
ULN
upper limit of normal
vp
viral particles
vs
versus
WBC
white blood cell
WHO
World Health Organization
DEFINITIONS OF TERMS
Electronic source 
system (eSource)
Contains data traditionally maintained in a hospital or clinic record to document medical 
care or data recorded in an electronic case report form (eCRF) as determined by the 
protocol. Data in this system may be considered source documentation.
Study drug
Pimodivir or placebo only

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1.
INTRODUCTION
Pimodivir (formerly known as VX-787 and JNJ-63623872) is a non-nucleotide inhibitor of the 
polymerase basic protein 2 (PB2) subunit of the influenza A virus polymerase complex and is 
currently in Phase 3 development as treatment for influenza A infection.
For the most comprehensive nonclinical and clinical information regarding pimodivir, refer to 
the latest version of the Investigator's Brochure (IB) for pimodivir.9
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
Both seasonal and pandemic influenza are a significant cause of morbidity and mortality 
worldwide. For example, the 2009 H1N1 influenza pandemic in the United States was 
responsible for an estimated approximately 61 million cases, 274,000 hospitalizations, and over 
12,500 deaths.16 Because the efficacy of the current annual hemagglutinin-based or modified live 
influenza virus vaccines depends on accurately predicting the viral strains prior to each influenza 
season or pandemic and because vaccines are not provided universally, there remains annually a 
significant burden of disease due to influenza.15
Accordingly, several antiviral drugs have been developed for the treatment of influenza. These 
drugs have been shown to shorten the duration and reduce the severity of symptoms if taken 
early after the onset of symptoms (within 24 to 48 hours). They can also be taken as prophylaxis 
against infection. The 2 main classes of antiviral drugs used against influenza are the 
neuraminidase inhibitors (NAIs), such as Tamiflu® (oseltamivir [OST]), RapivabTM (peramivir), 
and Relenza® (zanamivir), and the viral matrix 2 (M2) protein inhibitors, such as Symmetrel® 
(amantadine) and Flumadine® (rimantadine). Unfortunately, these drugs have several limitations. 
Influenza strains have emerged that show resistance to both of these classes of drugs, especially 
the M2 protein inhibitors. In addition, these drugs need to be administered no later than 24 to 
48 hours after infection, and therefore many patients are not eligible for therapy when they 
present for treatment. Further, none of these antiviral agents have been able to demonstrate a 
clinical benefit to those with the greatest unmet medical need, specifically those patients who are 
hospitalized or at high risk of complications due to influenza. Given these considerations, there 
remains a need for better therapeutic options for the treatment of influenza. 
A desired profile of a novel influenza antiviral includes: (1) rapid onset of protective effects 
leading to an expanded treatment window; (2) better activity in patients with high viral load; 
(3) inhibition of both production and release of virus; (4) maintenance of potency against 
neuraminidase and M2 inhibitor resistant viral strains; (5) safe and well tolerated. Pimodivir, an 
inhibitor of the viral replication complex, potentially meets all of these criteria.
Clinical Studies
At the time of protocol writing, data were available from 12 completed clinical studies: 
nine Phase 1 studies and three Phase 2 studies (note: for one Phase 2 study, the clinical study 

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report is not final yet). In addition, two Phase 1 studies were still ongoing. Refer to the IB for 
more details.9
Human Pharmacokinetics
After oral administration of pimodivir as a capsule or tablet formulation in healthy adult subjects, 
pimodivir was absorbed with a median time to reach the maximum plasma concentration (tmax) of 
2 to 4 hours, with some subjects exhibiting multiple peaks suggestive of enterohepatic recycling. 
Concomitant food (a high-fat meal) has no effect on the oral bioavailability (based on area under 
the plasma concentration-time curve from time of dosing extrapolated to infinity [AUC∞]) of 
pimodivir when administered as either capsule or tablet. However, the Cmax was decreased by 
9% for the capsule formulation and increased by 53% for the tablet formulation when compared 
to fasted conditions. The absolute bioavailability of the tablet was approximately 46%.
Results from a 14C-pimodivir human mass balance study (Study 63623872FLZ1007) showed that 
unchanged pimodivir is the major circulating entity (about 86%) in plasma with an 
acylglucuronide (J4) as a minor metabolite (about 3%). Fecal elimination was the main excretion 
pathway for pimodivir (83% to 89% of the administered dose); renal elimination is a minor 
excretion pathway.
Pimodivir plasma concentrations exhibit biphasic kinetics, eliminated from plasma initially at a 
more rapid rate, followed by a slower terminal elimination phase. The mean terminal phase 
elimination half-life (t1/2term) ranged from approximately 13 to 28 hours following single doses of 
pimodivir.
Study 63623872FLZ2001 was a Phase 2b, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study of 2 dose levels of pimodivir administered as monotherapy and 
as 1 dose level of pimodivir in combination with OST for the treatment of acute uncomplicated 
seasonal influenza A in adult subjects. Pimodivir concentrations appeared to reach steady-state 
between Days 3 and 4, with no evidence of a pharmacokinetic (PK) drug interaction between 
pimodivir and OST.
Study 63623872FLZ2002 was a randomized, double-blind, placebo-controlled, parallel-group, 
multicenter Phase 2b study to evaluate the effect of pimodivir 600 mg twice daily (bid) vs 
placebo, both in combination with OST 75 mg bid in adult (aged 18 to ≤64 years) and elderly 
(aged 65 to ≤85 years) hospitalized subjects with influenza A infection. The geometric mean 
ratios (95% confidence interval [CI]) of the pimodivir PK parameters at Day 3 of elderly adults 
(65 to ≤85 years) vs non-elderly adults (18 to ≤64 years) showed that PK of pimodivir was 
comparable between elderly and non-elderly adults. 
Drug-drug Interactions With Pimodivir 
Pimodivir has a low potential to reversibly inhibit cytochrome P450 (CYP)1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1, or 3A4. Its potential to inactivate CYP3A4 in a time dependent manner also 
was assessed and determined to be low. In human hepatocytes, pimodivir did not induce 

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CYP1A2 or 3A4 enzyme expression or activity. Taken together, these data suggest a low 
potential for drug-drug interactions (DDIs) with coadministered CYP substrates.
Pimodivir was evaluated as a potential substrate and inhibitor of organic anion transporting 
polypeptide
(OATP)
1B1
in stably transfected human embryonic kidney-293 cells 
overexpressing OATP1B1. Pimodivir was found to inhibit OATP1B1 with a 50% inhibitory 
concentration (IC50) of 0.6 μM. Pimodivir was also determined to be a substrate of OATP1B1. In 
vitro, pimodivir is an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT) 1 and 
OAT3. 
A clinical DDI study with pitavastatin (OATP1B1 and OATP1B3 substrate) was completed 
(Study 63623872FLZ1004). Based on the ratios of the least squares (LS) means, Cmax and AUC 
from time of dosing to time of last observation (AUClast) of pitavastatin were 1.20-fold and 
1.44-fold higher, respectively, after coadministration of pitavastatin with pimodivir compared to 
the administration of pitavastatin alone. These changes are not considered clinically relevant 
interactions and no dose adjustment is necessary.
Pimodivir 600 mg bid administered alone or in combination with OST 75 mg bid for 5 days in 
healthy volunteers (Study 63623872FLZ1001) resulted in generally comparable values for 
pimodivir predose analyte concentrations (C0h) on Days 3, 4, and 5, indicating that near 
steady-state conditions had been achieved between Day 3 and 4. For pimodivir administered 
alone vs in combination with OST, Cmin, and AUC from time of dosing to 12 hours postdose
(AUC12h) of pimodivir were comparable, while mean pimodivir Cmax was 30% higher when 
administered in combination with OST, compared with administration of pimodivir alone. The 
median tmax of pimodivir was 3.0 hours when pimodivir was administered alone and 1.5 hours 
when administered in combination with OST. For OST administered alone vs in combination 
with pimodivir, OST AUC12h and OST carboxylate (also referred to as OST acid) Cmin, Cmax, and 
AUC12h were comparable. Oseltamivir mean Cmin was 10% higher and Cmax was 5% lower when 
administered in combination with pimodivir, compared with OST administered alone. Following 
doses of 600 mg of pimodivir bid for 10 days, mean Cmax and AUC12h of pimodivir were, 
respectively, 1.2-fold and 1.8-fold higher on Day 10 compared with Day 1.
A clinical DDI study with ethinylestradiol and norethindrone, provided as the commercially 
available oral contraceptive (OC) tablet Ovysmen®, was completed (Study 63623872FLZ1009). 
The coadministration of ethinylestradiol and norethindrone with pimodivir did not result in a PK 
DDI, and therefore pimodivir may be dosed with OCs without special considerations.
In Study 63623872FLZ1006, the influence of food intake on the bioavailability of pimodivir was 
investigated. Single administration of 600 mg of pimodivir taken under fasted or under fed 
conditions resulted in a similar AUClast and AUC∞, as the 90% CIs of the LS means were 
completely within the 80% to 125% boundaries. Cmax was 45% higher under fed conditions 
compared to fasted conditions. The 90% CI of the LS means ratio of Cmax fell outside the 80% to 
125% boundaries (112.97% to 185.18%).

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Clinical Efficacy 
Refer to the IB for detailed info on the Phase 2a challenge study (Study VX11-787-101).9
In Study 63623872FLZ2001 (community study), subjects received one of the 4 treatments for a 
total of 5 days: (1) pimodivir placebo bid + OST placebo bid, (2) pimodivir 300 mg bid + OST 
placebo bid, (3) pimodivir 600 mg bid + OST placebo bid, or (4) pimodivir 600 mg bid + OST 
75 mg bid. Results from Study 63623872FLZ2001 showed that pimodivir was effective in 
decreasing viral loads (by quantitative real time polymerase chain reaction [qRT-PCR]) in
subjects with a confirmed influenza A infection.

The results showed an average change of AUC viral load (95% CI) (by qRT-PCR) vs 
placebo treatment of -3.6 (-7.1; -0.1), -4.5 (-8.0; -1.0), and -8.6 (-12; -5.1) 
day*log10 copies/mL for the pimodivir 300 mg bid, pimodivir 600 mg bid, and pimodivir 
600 mg bid + OST 75 mg bid treatment groups, respectively. The average change in AUC 
viral load of pimodivir 600 mg bid + OST 75 mg bid vs pimodivir 600 mg bid treatment 
was -4.1 (-7.4; -0.7) day*log10 copies/mL. The primary analysis showed a statistically 
significant dose-response relationship of reduction in AUC viral load vs pimodivir dose.

The results showed an average change on the AUC of viral load (95% CI) (by viral culture) 
vs placebo treatment of -2.1 (-2.9; -1.3), -2.1 (-2.8; -1.3), and -2.0 (-2.8; -1.2) log10 50% 
tissue culture infective dose (TCID50)/mL for the pimodivir 300 mg bid, pimodivir 
600 mg bid, and pimodivir 600 mg bid + OST 75 mg bid treatment groups, respectively. The 
AUC viral load of pimodivir 600 mg bid + OST 75 mg bid and pimodivir 600 mg bid 
treatment was similar (0.1 [-0.7; 0.8]).

There was a reduction of time to viral negativity vs placebo treatment of 13%, 18%, and 
31% for the pimodivir 300 mg bid, pimodivir 600 mg bid, and pimodivir 600 mg bid + OST
75 mg bid treatment groups, respectively. The time to viral negativity was statistically 
significantly shorter for the pimodivir 600 mg bid and pimodivir 600 mg bid + OST
75 mg bid treatment groups compared to placebo treatment.

There was an estimated reduction in time to resolution of the 7 primary influenza symptoms 
vs placebo of 13% and 17% for the pimodivir 600 mg bid and pimodivir 600 mg bid + OST
75 mg bid treatment groups, respectively, and an estimated increase in time to resolution of 
the influenza symptoms vs placebo of 7% for the pimodivir 300 mg bid treatment group. 
The differences in time to resolution compared to placebo treatment were not statistically 
significant for active treatment groups. However, given that the study was finalized at the 
interim analysis for early success on virologic response, the sample sizes per arm were 
relatively small, and clinical outcome comparisons had reduced power to show differences.
In Study 63623872FLZ2002 (hospital study), adult (aged 18 to ≤64 years) and elderly (aged 
65 to ≤85 years) hospitalized subjects with influenza A infection received pimodivir 600 mg bid 
+ OST 75 mg bid or pimodivir placebo bid + OST 75 mg bid, for a total of 7 days. The following 
results were observed:
Viral Kinetics

The difference (95% CI) in viral titer (by culture) AUC of pimodivir 600 mg bid + OST
75
mg
bid 
treatment 
vs 
placebo
bid
+ 
OST 
75 
mg 
bid 
treatment 

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was -0.5 (-2.0, 1.0) log10 TCID50/mL*day. For subjects that were treated within 
72 hours 
from 
onset 
of 
symptoms, 
the 
difference 
(95% 
CI) 
in 
AUC 
was -1.2 (-4.2, 1.8) log10 TCID50/mL*day. For subjects that were treated within 
96 hours 
from 
onset 
of 
symptoms, 
the 
difference 
(95% 
CI) 
in 
AUC 
was -0.9 (-3.0, 1.3) log10 TCID50/mL*day.

Based on viral titer (by culture), the median time to viral negativity was 1.1 and 
1.3 days for the pimodivir 600 mg bid + OST 75 mg bid and placebo bid + OST 75 mg
bid treatment groups, respectively, as estimated from an accelerated failure time model. 
For subjects that were treated within 72 hours from onset of symptoms, the median time 
to viral negativity was 1.2 and 1.8 days for the pimodivir 600 mg bid + OST 75 mg bid 
and placebo bid + OST 75 mg bid treatment groups, respectively, as estimated via the 
accelerated failure time analysis. For subjects that were treated within 96 hours from 
onset of symptoms, the median time to viral negativity was 1.2 and 1.6 days for the 
pimodivir 600 mg bid + OST 75 mg bid and placebo bid + OST 75 mg bid treatment 
groups, respectively, as estimated via the accelerated failure time analysis.

The difference (95% CI) in viral load (by qRT-PCR) AUC of pimodivir 600 mg bid 
+ OST 75 mg bid treatment vs placebo bid + OST 75 mg bid treatment was 
0.7 (-3.0, 4.3) log10 viral particles (vp)/mL*day. For subjects that were treated within 
72 hours 
from 
onset 
of 
symptoms, 
the 
difference 
(95% 
CI) 
in 
AUC 
was -2.2 (-8.0, 3.7) log10 vp/mL*day. For subjects that were treated within 96 hours 
from 
onset 
of 
symptoms, 
the 
difference 
(95% 
CI) 
in 
AUC 
was -0.9 (-5.4, 3.6) log10 vp/mL*day.

Ordinal Scale at Day 8
Overall, treatment with either placebo bid + OST 75 mg bid or pimodivir 600 mg bid + OST 
75 mg bid resulted in a similar improvement in clinical status at Day 8, as expressed by a 
common odds ratio (95% CI) of 1.03 (0.43; 2.47). For subjects treated within 72 hours from 
onset of influenza symptoms, the estimated reduction of 0.60 in the odds, as expressed by a 
common odds ratio (95% CI) of 0.40 (0.09; 1.71), reflects an improvement in clinical 
outcome of 60%, with pimodivir 600 mg bid + OST 75 mg bid treatment compared to 
placebo bid + OST 75 mg bid treatment at Day 8. For subjects treated within 96 hours from 
onset of influenza symptoms, the estimated reduction of 0.50 in the odds, as expressed by a 
common odds ratio (95% CI) of 0.50 (0.16; 1.56), reflects an improvement in clinical 
outcome of 50%, with pimodivir 600 mg bid + OST 75 mg bid treatment compared to 
placebo bid + OST 75 mg bid treatment at Day 8.

Influenza-related Complications
Overall, the incidence of influenza-related complications was 7.9% (5/63) and 15.6% (5/32) 
in the pimodivir 600 mg bid + OST 75 mg bid and placebo bid + OST 75 mg bid treatment 
groups, respectively. For subjects treated within 72 hours from onset of influenza symptoms, 
the incidence of influenza-related complications was 4.8% (1/21) and 26.7% (4/15) in the 
pimodivir 600 mg bid + OST 75 mg bid and placebo bid + OST 75 mg bid treatment groups, 
respectively. For subjects treated within 96 hours from onset of influenza symptoms, the 
incidence of influenza-related complications was 5.9% (2/34) and 23.8% (5/21) in the 
pimodivir 600 mg bid + OST 75 mg bid and placebo bid + OST 75 mg bid treatment groups, 
respectively.

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
Time to Clinical Endpoints

Median times to clinical endpoints were shorter for treatment with pimodivir
600 mg bid + OST 75 mg bid compared to placebo bid + OST 75 mg bid for resolution 
of 7 primary influenza symptoms (cough, sore throat, headache, nasal stuffiness, 
feverishness or chills, muscle or joint pain, and fatigue) (22%), return to usual activity 
(24%) and return to usual health (22%). A 13% longer time to hospital discharge was 
estimated for the pimodivir 600 mg bid + OST 75 mg bid treatment group compared to 
the placebo bid + OST 75 mg bid treatment group. 

For subjects treated within 72 hours from onset of symptoms, results for resolution of 
7 primary influenza symptoms, return to usual health results and hospital discharge 
were similar to the overall study population, whereas the median time to return to usual 
activity was estimated to be 61% shorter for pimodivir 600 mg bid + OST 75 mg bid
treatment compared to placebo bid + OST 75 mg bid treatment.

For subjects treated within 96 hours from onset of symptoms, results for resolution of 
7 primary influenza symptoms, return to usual health results and hospital discharge 
showed relatively minimal differences between the pimodivir 600 mg bid + OST 
75 mg bid compared to placebo bid + OST 75 mg bid, whereas the median time to 
return to usual activity was estimated to be 26% shorter for the pimodivir 600 mg bid + 
OST 75 mg bid treatment.
Resistance 
Population sequence analyses of the PB2 segment in subjects in Study VX11-787-101 identified 
a variant (PB2 M431I) that was observed in multiple subjects (N=4). This amino acid change 
confers a 57-fold decrease in sensitivity to pimodivir in in vitro studies but the virus had reduced 
replication capacity compared to wild type strains. Additional variants at 3 PB2 positions that 
had previously been associated with mutations that cause a decrease in sensitivity to pimodivir in 
vitro (S324C, K376R, and M431L/R/V) were also observed in single pimodivir treated subjects. 
Emergence of variants was not coincident with viral rebound, and all subjects subsequently 
cleared virus after treatment.
In the Phase 2b study 63623872FLZ2001, genotypic and phenotypic changes in the influenza A 
viral variants obtained from the nasal swab samples of subjects were investigated. This first 
exploratory analysis was focused on the baseline and the last virus-positive post-baseline 
samples, which were analyzed using population sequencing of the PB2 and neuraminidase genes 
as well as phenotypic susceptibility testing in cell culture. The Full Analysis Set consisted of 
223 subjects that were randomized, treated, and had a confirmed influenza A infection. 
Sequencing of the baseline samples was successful in 206/223 (92%) subjects and did not show 
any mutation at PB2 positions of interest. In addition, baseline phenotypic resistance to 
pimodivir, defined as a fold change in EC50 >4.0, was not observed (data available for 
180/223 [81%] subjects). 
Emergence of mutations at positions of interest occurred in 9 subjects, of which only 1 subject in 
the pimodivir + OST combination treatment group. These mutations included S324K, S324N, 
S324R, F325L, S337P, K376N, K376R, and N510K. Emergence of phenotypic resistance to 

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pimodivir was observed in 9 subjects. Seven of these 9 subjects also had emerging known PB2 
position mutations, one subject had no genotypic data available, and one subject harbored 
T378S, a newly identified resistance mutation in PB2. No emergent-phenotypic resistance was 
observed in the combination arm. Virologic breakthrough was not observed in any of these 
subjects. Overall, a high correlation between the presence of PB2 mutations at positions of 
interest and the emergence of phenotypic resistance to pimodivir was observed. The PB2 
mutation T378S was associated with high-level phenotypic resistance to pimodivir and 
represented a newly identified position of interest. The list of PB2 positions of interest was
updated for subsequent analyses to contain the following 13 amino acid substitutions: Q306, 
F323, S324, F325, S337, H357, F363, K376, T378, F404, Q406, M431, and N510.
Resistance data from Study 63623872FLZ2002 are not yet available. 
Clinical Safety
Up to 15 June 2017, 634 subjects had been exposed to pimodivir, which included 277 healthy 
subjects, 72 subjects inoculated with influenza, and 285 subjects naturally infected with 
influenza, in the Phase 1, Phase 2a, and Phase 2b studies, respectively. Administration of 
pimodivir was generally safe and well tolerated. In these studies, 1 serious adverse event (SAE) 
of hypersensitivity was reported and considered to be at least possibly related to pimodivir by the 
investigator. Refer to the IB for more details.9
Based on the data available up to 15 June 2017, only headache and diarrhea were seen 
consistently in healthy subjects. In the pooled analysis of the Phase 1 and Phase 2a studies, on 
the list of events that occurred in at least 10% of subjects, the overall incidence of headache was 
comparable following single doses of pimodivir (9.1%) and placebo (8.7%); the overall 
incidence was also comparable following multiple doses of pimodivir (12.8%) and placebo 
(11.9%). The overall incidence of diarrhea was higher following single doses of pimodivir 
(9.8%) than following single doses of placebo (2.9%) and was increased following multiple 
doses of pimodivir (18.1%) compared with multiple doses of placebo (2.4%). The investigator 
reported term for the diarrhea cases were “loose stools”, “diarrhea” and “acute diarrhea”. The 
severity was recorded as mild, with 1 exception of a case reported as “diarrhea” of moderate 
severity in a subject receiving pimodivir 600 mg bid.
In accordance with the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E14 guideline, the thorough QT (TQT) study 
(Study 63623872FLZ1005) was negative and study sensitivity was shown by moxifloxacin 
control, demonstrating that pimodivir induces no corrected QT (QTc) interval prolongation of 
regulatory concern.
Results from Phase 2b Study 63623872FLZ2001 (community study) showed that pimodivir was 
generally safe and well tolerated:

The most common treatment-emergent adverse event (TEAE) was diarrhea: 5.6%, 6.8%, 
27.0%, and 17.8% of subjects in the placebo, pimodivir 300 mg bid, pimodivir 600 mg bid, 
and pimodivir 600 mg bid + OST 75 mg bid treatment groups, respectively. The majority of 

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the diarrhea cases were mild, with 1 case of diarrhea indicated as severe (in the pimodivir 
600 mg bid treatment group).

No subjects died and for 2 subjects 1 treatment-emergent SAE was reported: an SAE of 
moderate increased alanine aminotransferase (ALT) in the pimodivir 600 mg bid treatment 
group (doubtfully related according to the investigator, started on Day 14 and was reported 
resolved 21 weeks later), and an SAE of severe thrombocytopenia in the placebo group 
(possibly related according to the investigator, started on Day 63 and was reported resolved 
5 weeks later).
Results from Phase 2b Study 63623872FLZ2002 (hospital study) showed that overall safety was 
similar for the pimodivir 600 mg bid + OST 75 mg bid treatment group compared with placebo
bid + OST 75 mg bid treatment group. Overall, TEAEs were reported in 75.0% of subjects in the 
pimodivir 600 mg bid + OST 75 mg bid treatment group compared with 71.4% of subjects in the 
placebo bid + OST 75 mg bid treatment group. The most common TEAE was diarrhea, reported 
in 20.3% and 11.4% of subjects in the pimodivir 600 mg bid + OST 75 mg bid treatment group 
and placebo bid + OST 75 mg bid treatment group, respectively. The diarrhea cases were 
transient in nature and of mild to moderate severity. 

One subject in the pimodivir 600 mg bid + OST 75 mg bid treatment group died at Day 8 
after experiencing multiple SAEs, all reported to be doubtfully or not related to treatment. 
Serious AEs were reported in 17.2% and 11.4% of subjects in the pimodivir 600 mg bid + 
OST 75 mg bid treatment group and placebo bid + OST 75 mg bid treatment group, 
respectively. One SAE of hypersensitivity was reported to be possibly related to pimodivir 
600 mg bid + OST 75 mg bid treatment.
1.2.
Standard-of-care
Currently available influenza antiviral therapies used as standard-of-care (SOC) treatment 
include NAIs and, less commonly, adamantanes. The NAIs OST (oral), zanamivir (inhaled), and 
peramivir (IV) are not indicated for influenza treatment in hospitalized patients, although there 
are some data indicating the potential benefit of OST and NAIs in general in the hospital setting. 
Based on this and in the absence of approved treatments for hospitalized patients, the Centers for 
Disease Control and prevention and the European Center for Disease prevention and Control 
recommend the use of OST or NAIs in the hospital setting. Adamantanes, such as rimantadine, 
are no longer recommended for antiviral treatment of currently circulating influenza A virus 
strains due to widespread resistance.2 Reports of ribavirin (RBV) use have been published 
although this drug has not been approved for influenza treatment. Worldwide treatment of 
influenza is diverse and not standardized. As such, local SOC treatment may include any of the 
above antivirals as well as supportive care.
1.3.
Overall Rationale for the Study
Although generally a self-limited disease, infection with influenza A can cause significant 
morbidity and mortality and may result in hospitalization, especially in certain patient 
populations such as those at the extremes of age. 

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Pimodivir is being developed for the treatment of patients who are hospitalized due to or at high 
risk of complications from influenza A, and who have the highest unmet medical need. As a 
therapeutic option intended for global use, studying pimodivir in combination with the SOC 
accounts for worldwide differences in the treatment of this population. In the instances where 
pimodivir is administered with a NAI SOC option, an additive effect of pimodivir over NAI 
administration alone will be explored in high-risk and hospitalized subjects. Further, the 
FLZ3001 study design is based on a recognition that local SOC approaches, particularly NAI, 
may have some benefit to patients even if used off label, as was noted above. Accordingly, the 
study design allows subjects to gain any potential benefits of the current SOC therapies, while 
also assessing the benefit of pimodivir.
The purpose of the current study is therefore to evaluate the additional benefit of pimodivir in 
combination with SOC treatment over placebo in combination with SOC treatment in adolescent 
(13 to 17 years), adult (18 to 65 years), and elderly (>65 to ≤85 years) hospitalized subjects with 
influenza A infection following a 5-day 600 mg bid therapy course.
1.4.
Benefits and Risks Management
Known Benefits of Pimodivir
1.4.1.
The clinical benefit of pimodivir remains to be established.
Potential Benefits of Pimodivir
1.4.2.
Results from pimodivir clinical studies may be useful in developing a new therapy for 
influenza A infection. 
The dose regimen of 600 mg bid is expected to result in antiviral activity and subjects may 
benefit from participating in this study.
Known Risks of Pimodivir
1.4.3.
At the time of protocol writing, 634 subjects had been exposed to pimodivir, with 277 healthy 
subjects, 72 subjects inoculated with influenza, and 285 subjects naturally infected with 
influenza, in the Phase 1, Phase 2a, and Phase 2b studies, respectively. In these studies, 1 SAE of 
hypersensitivity was reported and considered to be at least possibly related to pimodivir by the 
investigator.
Adverse drug reactions:
A formal adverse drug reaction (ADR) identification process was conducted on the clinical 
safety data of Study 63623872FLZ2001 and Study 63623872FLZ2002. No serious ADRs have 
been identified to date. Diarrhea is considered a non-serious ADR because most cases were mild 
or moderate.
Adverse events in healthy subjects:
Based on the data available at the time of protocol writing, only headache and diarrhea were seen 
consistently in healthy subjects. In the pooled analysis of the Phase 1 and Phase 2a studies, the 

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occurrences of headache were equally distributed among pimodivir and placebo, while diarrhea 
occurred more often after treatment with 
pimodivir
compared to placebo.
The 
investigator-reported term for the diarrhea cases were “loose stools”, “diarrhea” and “acute 
diarrhea”. The severity was recorded as mild, with 1 exception of a case reported as “diarrhea” of 
moderate severity in a subject receiving pimodivir 600 mg bid.
Adverse events in subjects naturally infected with influenza A:
In subjects naturally infected with influenza A, pimodivir was generally safe and well tolerated 
and 
a 
favorable 
safety 
profile 
was 
established. 
In 
the 
community 
study 
(Study 63623872FLZ2001), the overall incidence of diarrhea was comparable in subjects treated 
with pimodivir or pimodivir + OST, but higher than in those treated with placebo. Increased 
incidence of diarrhea was reported and was more common with pimodivir 600 mg (as mono- or 
combination 
therapy) 
than 
with 
pimodivir 
300 
mg. 
In 
hospitalized 
subjects 
(Study63623872FLZ2002), the overall incidences of headache and diarrhea were higher in 
subjects treated with pimodivir + OST than in those treated with placebo + OST.
Potential Risks of Pimodivir
1.4.4.
Reproductive Risk and Pregnancy
Based on preclinical studies, no reproductive (embryo-fetal, fertility and early embryonic 
development) liabilities have been identified for pimodivir.
In the current study, subjects who are heterosexually active must follow the contraception 
requirements detailed in Section 4.1. Subjects’ study treatment will be discontinued if they 
become pregnant (see Section 10.2).
Increased Transaminases
In the Phase 2a Proof-of-concept study (VX12-787-101), conducted in healthy volunteers 
inoculated with influenza A and treated for 5 days with placebo (N=32) or pimodivir (N=72; 
from 100 mg qd to 1,200 mg (loading dose)/600 mg qd doses), liver function test (ALT and 
AST) elevations were observed in both placebo and pimodivir groups (ALT: placebo, 15.6%; 
pimodivir, 13.9%; AST: placebo, 3.1%; pimodivir 5.6%). The pimodivir group had a higher 
incidence of subjects with ALT increases of >2x upper limit of normal (ULN; among the 
6 subjects with increases of >2x ULN, all had complete resolution on follow-up: 1 subject in the 
placebo group, 1 subject in the pimodivir 400-mg qd group, and 4 subjects in the pimodivir 
1,200/600-mg qd group). The majority of adverse events (AEs) due to liver function test
elevations were observed in subjects who had evidence of a successful influenza A inoculation; 
similarly, for the majority of subjects with ALT elevation AEs, the event occurred on or after the 
date that the first dose of OST (≥ Day 7) was administered. ALT elevation has been previously 
described in influenza and upper respiratory infections and following administration of OST. 
Conclusions could not be drawn about the relationship between viral inoculation, pimodivir 
administration, and OST administration with ALT AEs.

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In the Phase 2b study 63623872FLZ2001 conducted in acute uncomplicated seasonal influenza 
A-infected adults, among the 147 patients treated with pimodivir 600 mg bid (with or without 
OST) for 5 days, 3 had TEAEs corresponding to transaminase elevations ≥grade 3. These 
3 events were considered of moderate severity by the investigators. Among them, there was one 
SAE (moderate severity) of increased ALT in the pimodivir 600 mg bid treatment group 
(doubtfully related to study drugs according to the investigator), which started on Day 14 and 
was reported resolved 21 weeks later. In 2 of these cases, potential confounding factors were 
observed (use of OST, likely presence of NASH). No transaminase TEAE was reported in the 
placebo group (N=71).
In the Phase 2b study 63623872FLZ2002 conducted in acute seasonal influenza A-infected 
hospitalized adults, among the 64 patients treated with pimodivir 600 mg bid + OST 75 mg bid
for 7 days, one had a TEAE corresponding to a grade 3 ALT elevation. The event was 
considered of mild severity by the investigator, and possibly related to pimodivir and OST. The 
following confounding factors were noted: OST, paracetamol and clarithromycin use. One 
patient in the placebo + OST treatment group had a moderate TEAE (grade 2 ALT and grade 3 
AST elevation), considered possibly related to placebo by the investigator.
No Hy’s law case (>3x ULN ALT + >2x ULN total bilirubin) was reported in the Phase 1 or 2 
pimodivir clinical studies.
To date, transaminases elevations remain a potential risk, hence, due to the limited amount of 
data available, this study will exclude subjects with chronic hepatitis C undergoing hepatitis C 
treatment and subjects with known severe hepatic impairment (Child Pugh C cirrhosis) (see 
Section 4.2),
and include study treatment hepatic-related discontinuation criteria
(see 
Section 10.2).
Potential Toxicity
No genotoxicity (mutagenicity, in vitro chromosomal aberration, or mammalian erythrocyte), 
phototoxicity (in vitro), or safety pharmacology (battery of in vitro studies designed to evaluate 
effects of pimodivir against multiple cellular targets and a battery of in vivo cardiovascular, 
central nervous system, and respiratory systems) liabilities have been identified for pimodivir. 
There were no toxicological effects in acute studies in mice and rats at doses up to 1,000 mg/kg. 
The no observed adverse effect level (NOAEL) in 14-day, repeat-dose toxicology studies was 
100 mg/kg/day in rats and 150 mg/kg/day in monkeys. These doses correspond to animal to 
human exposure multiples (AUC from time 0 to 24 hours after dosing [AUC24h] basis) of 41-fold 
and 24-fold in male and female rats, respectively, and 2-fold and 4-fold in male and female 
monkeys, respectively, based on a clinical dose of 600 mg bid for 5 days. When using the 
exposures measured in the 63623872FLZ2002 study (600 mg pimodivir bid in subjects at 
steady-state), these doses correspond to animal to human exposure multiples (AUC24h basis) of 
17-fold and 10-fold in male and female rats, respectively, and 0.7-fold and 1.6-fold in male and 
female monkeys, respectively. Although exposure ratios vs the NOAEL in monkeys are small, 
all adverse effects seen at the medium dose of 250 mg/kg/day show recovery after dosing and are 
monitorable in the clinic. At oral doses of 250 mg/kg/day and above, specific organ toxicity 

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(liver, kidney, bone marrow, spleen, and lymph nodes) and other toxicological findings were 
noted in rats and monkeys. When rats were dosed at 50, 100, or 250 mg/kg/day for 3 months, the 
NOAEL was set at 100 mg/kg/day, which corresponds to animal to human exposure multiples of 
12-fold in males and 15-fold in females (multiple vs Study 63623872FLZ2002). At 
250 mg/kg/day, body weight gain was decreased in both sexes. Additionally, minor alterations 
were seen in red blood cell (RBC) parameters. Full recovery of the adverse effects was noted at 
the end of the 1-month recovery period. The NOAEL in 14-day continuous IV infusion studies 
was 180 mg/kg/day in rats and 40 mg/kg/day in monkeys. Pimodivir exposure at the NOAEL in 
the IV studies was in the same range (AUC) or lower (Cmax) than at the NOAEL in the oral 
toxicity studies.
Based on human experience to date at high doses (up to 3,000 mg) no toxicology findings were 
observed, however this study will include study treatment discontinuation and study withdrawal 
criteria for individual subjects as a precaution (see Section 10.2 and Section 10.3). 
Overall Benefit/Risk Assessment
1.4.5.
Based on the available data and proposed safety measures, the overall benefit/risk assessment for 
this study is acceptable for the following reasons:

Pimodivir has been studied in healthy subjects receiving single oral doses of pimodivir up to 
3,000 mg (Studies VX11-787-001, VX12-787-002, 63623872FLZ1001, 63623872FLZ1005, 
63623872FLZ1006, 63623872FLZ1007 [administration of a single dose of 14C-pimodivir], 
and 63623872FLZ1008), multiple oral doses of pimodivir as monotherapy up to 800 mg 
once 
daily 
for 
10 
days
(Studies 
VX11-787-001, 
63623872FLZ1001, 
and 
63623872FLZ1009), multiple oral doses of pimodivir of 600 mg bid for 5 days 
coadministered with OST (Study 63623872FLZ1001), and single IV doses up to 300 mg 
pimodivir (Study VX12-787-002). In addition, pimodivir has been studied in multiple oral 
doses in subjects infected with a challenge dose of influenza A (up to 1,200 mg loading dose 
on the first day followed
by 600 mg once daily for an additional 4 days; 
Study VX11-787-101). Pimodivir has also been studied in multiple oral doses in subjects 
naturally infected with influenza either as monotherapy up to 600 mg bid for 5 days or 
coadministered with OST 600 mg bid for 7 days (Studies 63623872FLZ2001 and 
63623872FLZ2002). Pimodivir was generally safe and well tolerated.

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.

Safety will be closely monitored by the investigator throughout the study. Safety and 
tolerability assessments (including vital signs, peripheral capillary oxygen saturation, ECG, 
physical examination, clinical laboratory tests, and assessment of AEs or SAEs) will be 
performed at scheduled visits throughout the study.

Several safety measures have been proposed to minimize potential risks to subjects, 
including:

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
The safety margins for the projected exposures calculated from non-clinical toxicology 
studies in monkeys warrant close laboratory monitoring during the study, thus samples 
for clinical laboratory tests will be collected throughout the study. 

Utilization of treatment discontinuation and withdrawal criteria (see Section 10.2 and 
Section 10.3).

Pregnancy and breastfeeding are exclusion criteria for all clinical studies conducted to 
date. All subjects are required to use contraceptive methods as detailed in the protocol.

An independent data monitoring committee (IDMC) will be established to monitor 
safety and efficacy data on a regular basis.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives and Endpoints
Objectives
2.1.1.
Primary Objective
The primary objective is to evaluate superiority of pimodivir in combination with SOC treatment 
compared to placebo in combination with SOC treatment on Day 6, with respect to the clinical 
outcome on the hospital recovery scale.
Secondary Objectives
The secondary objectives are: 

To investigate the safety and tolerability of pimodivir in combination with SOC treatment 
compared to placebo in combination with SOC treatment.

To evaluate superiority with respect to the time from start of study drug to hospital discharge
in subjects treated with pimodivir in combination with SOC treatment compared to placebo 
in combination with SOC treatment.

To evaluate superiority with respect to the time from intensive care unit (ICU) admission to 
ICU discharge in subjects treated with pimodivir in combination with SOC treatment 
compared to placebo in combination with SOC treatment.

To evaluate superiority with respect to the time from start to end of mechanical ventilation 
in subjects treated with pimodivir in combination with SOC treatment compared to placebo 
in combination with SOC treatment.

To evaluate superiority of pimodivir in combination with SOC treatment compared to 
placebo in combination with SOC treatment each separated day from Days 2 to 14
(excluding the primary time point), with respect to the clinical outcome on the hospital 
recovery scale.

To evaluate superiority with respect to the time to return to daily activities in subjects treated 
with pimodivir in combination with SOC treatment compared to placebo in combination 
with SOC treatment.

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
To evaluate superiority with respect to the incidence of complications associated with 
influenza after the start of study treatment in subjects treated with pimodivir in combination 
with SOC treatment compared to placebo in combination with SOC treatment.

To investigate all-cause mortality in the pimodivir in combination with SOC treatment arm, 
compared to the placebo in combination with SOC treatment arm.

To investigate the incidence and duration of antibiotic treatment in the pimodivir in 
combination with SOC treatment arm, compared to the placebo in combination with SOC 
treatment arm.

To investigate the number (proportion) of subjects needing extended treatment in the 
pimodivir in combination with SOC treatment arm, compared to the placebo in combination 
with SOC treatment arm. 

To investigate the number (proportion) of subjects requiring re-hospitalization in the 
pimodivir in combination with SOC treatment arm, compared to the placebo in combination 
with SOC treatment arm.

To investigate the number (proportion) of subjects not hospitalized at Day 6 in the pimodivir 
in combination with SOC treatment arm, compared to the placebo in combination with SOC 
treatment arm.

To investigate the time to clinical response in the pimodivir in combination with SOC 
treatment arm, compared to the placebo in combination with SOC treatment arm.

To investigate the time to improvement of respiratory status in the pimodivir in combination 
with SOC treatment arm, compared to the placebo in combination with SOC treatment arm.

To assess the PK of pimodivir and to explore the PK/PD relationships of pimodivir for 
efficacy and safety. 

To investigate the acceptability (taste and swallowability) of the pimodivir formulation in 
adolescents.

To evaluate superiority with respect to the following influenza A viral parameters in the 
pimodivir treatment arm compared to the control arm by qRT-PCR and viral culture:

Time to viral negativity.

Viral load over time. 

To investigate the emergence of viral resistance against pimodivir detected by genotyping 
and/or phenotyping.
Exploratory Objective

To evaluate the measurement performance of the influenza symptom diary for hospitalized 
influenza subjects.
Endpoints
2.1.2.
Primary Endpoint
The primary endpoint is the hospital recovery scale as assessed on Day 6.

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Secondary Endpoints
The secondary endpoints are:

Safety and tolerability based on assessment of AEs, clinical laboratory assessments, 12-lead 
electrocardiograms (ECGs), vital signs, and peripheral capillary oxygen saturation.

Time from start of study drug to hospital discharge and total length of hospital stay.

Time from ICU admission to ICU discharge and total time in ICU. Time in ICU before start 
of study drug is discarded.

Time from start to end of mechanical ventilation and total time on mechanical ventilation.
Time on mechanical ventilation before start of study drug is discarded.

The hospital recovery scale as assessed each separated day from Days 2 to 14 (excluding the 
primary time point).

Time to return to daily activities.

Incidence of complications associated with influenza after the start of study treatment:

Pulmonary complications:
The pulmonary complications of influenza include respiratory failure, primary viral 
pneumonia, secondary bacterial pneumonia (including pneumonia attributable to unusual 
pathogens), exacerbations of chronic underlying pulmonary diseases such as COPD, asthma, 
and bronchitis.
o
Respiratory failure: defined as either hypoxemic respiratory failure characterized 
by an arterial oxygen tension (PaO2) lower than 60 mmHg with a normal or low 
arterial carbon dioxide tension (PaCO2), or hypercapnic respiratory failure 
characterized by a PaCO2 higher than 50 mmHg.
o
Primary viral pneumonia: a progressive event involving the lower respiratory tract 
with bilateral and/or diffuse radiological findings. No bacterial agent is identified 
using sputum cultures. 
o
Secondary bacterial pneumonia (including pneumonia attributable to unusual 
pathogens): a clinical event compatible with lower respiratory tract involvement, 
with lobar infiltrates on radiological studies and/or microbiological isolate of a 
bacterial pathogen, including unusual pathogens.
o
Exacerbations of chronic underlying pulmonary diseases such as COPD and 
asthma: subjects with documented medical history of COPD or asthma with a 
sudden worsening of symptoms and deteriorating respiratory function (the latter as 
evidenced by worsening hypoxia, tachypnea, etc.) The event must start before a full 
recovery from the influenza infection occurred.
o
Bronchitis

Extrapulmonary complications: 
o
Cardiovascular and cerebrovascular disease (eg, myocardial infarction, congestive 
heart failure, arrhythmia, stroke)
o
Muscular disorders (eg, myositis, rhabdomyolysis)

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o
Central nervous system [CNS] involvement
o
Acute exacerbation of chronic kidney disease
o
Decompensation of previously controlled diabetes mellitus
o
Other infections (eg, sinusitis, otitis)

All-cause mortality.

Incidence and duration of antibiotic treatment.

The number (proportion) of subjects needing extended treatment.

The number (proportion) of subjects requiring re-hospitalization.

The number (proportion) of subjects not hospitalized at Day 6.

Time to clinical response. Clinical response is defined as achieving 4 of the 5 following vital 
sign resolution criteria, including at least the fever and oxygen saturation criteria, 
maintained for at least 24 hours: 

having no fever (without the use of antipyretics within 8 hours), 

oxygen saturation of at least 94% without oxygen supplementation or return to 
pre-influenza infection oxygen saturation (in patients with a known pre-influenza 
oxygen saturation level <94%), 

improved respiratory status
(a respiratory rate ≤24 breaths per min without 
supplemental oxygen or return to pre-influenza infection supplemental oxygen 
requirement in patients with chronic oxygen use), 

heart rate 100 beats per minute or lower, 

systolic blood pressure of 90 mmHg or higher without inotropic support given within 
2 hours of assessment.

Time to respiratory response. Respiratory response is defined as achieving the following 
2 criteria for at least 24 hours:

improved oxygen saturation of at least 94% without oxygen supplementation (return to 
pre-influenza infection oxygen saturation in patients with a known pre-influenza oxygen 
saturation level <94%) and 

improved respiratory status characterized by a respiratory rate ≤24 breaths per min 
without supplemental oxygen or return to pre-influenza infection supplemental oxygen 
requirement in patients with chronic oxygen use.

PK parameters of pimodivir (ie, plasma concentration just prior to the beginning or at the 
end of a dosing interval [Ctrough], Cmax, tmax, and AUC12h), as determined by population PK 
analysis. 

Time to viral negativity by qRT-PCR and viral culture.

Viral load over time by qRT-PCR and viral culture.

The emergence of viral resistance against pimodivir detected by genotyping and/or 
phenotyping.

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
The acceptability of the pimodivir formulation in adolescents, as measured by a taste and 
swallowability questionnaire.
Exploratory Endpoint

A patient-reported outcome (PRO) based on subjects’ ratings on the influenza symptom 
diary will be formulated.
Refer to Section 9, Study Evaluations, for evaluations related to endpoints.
2.2.
Hypothesis
The outcome on the hospital recovery scale with pimodivir in combination with SOC treatment 
is statistically superior to treatment with placebo in combination with SOC treatment on Day 6 in 
hospitalized subjects with influenza A infection.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a Phase 3 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of pimodivir in combination with SOC treatment vs placebo in combination 
with SOC treatment in adolescent (13 to 17 years), adult (18 to 65 years), and elderly (>65 to 
≤85 years) hospitalized subjects with influenza A infection. A target of 600 hospitalized 
influenza-infected subjects will be randomly enrolled in this study with 300 subjects planned per 
treatment arm. The aim is to enroll a minimum of 60 adolescent subjects in this study in selected 
countries and study sites consistent with local regulations. The randomization will be stratified 
for baseline NEWS2 (4-5 or >5), type of baseline SOC (including or not including influenza 
antiviral treatment), and time since onset of influenza symptoms (first administration of study 
drug within 72 hours or between 72 and 96 hours since onset of influenza symptoms). The study 
population should consist of at least 75% of subjects (75% of the total planned sample size of 
600 subjects) with first administration of study drug ≤72 hours since onset of influenza 
symptoms. 
Subjects who meet all eligibility criteria will be randomized in a 1:1 ratio to receive 1 of the 
following treatments. 

Treatment Arm 1: pimodivir 600 mg bid for 5 days + SOC treatment*

Treatment Arm 2: pimodivir placebo bid for 5 days + SOC treatment*
*SOC treatment is determined by the investigator based on local practice, and may include 
influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of
the SOC should be made before randomization. The influenza antiviral should be started no later 
than the day of first study drug intake. An influenza antiviral as part of the SOC cannot be 
changed (eg, switching one influenza antiviral for another) during either the treatment period or 
extension phase, with the exception that an influenza antiviral may be discontinued in the case of 
a suspected AE.

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Study drugs will be taken orally. During hospitalization, in case of medical need, study drug 
tablets may be dispersed in water before intake (in case of administration via a nasogastric tube 
or if the subject has difficulties swallowing the tablets). Refer to the pharmacy manual/study site 
investigational product manual for additional guidance on study drug preparation, handling, and 
storage.
Subjects (1) who complete the 5-day treatment, (2) who are still hospitalized upon treatment 
completion, (3) who are on invasive mechanical ventilation or who have an ongoing respiratory 
deficiency as evidenced by having a peripheral capillary oxygen saturation (SpO2) <94% on 
room air, or in case of known pre-influenza SpO2 <94% (eg, due to COPD), the current blood 
oxygen saturation on room air is lower than pre-influenza infection levels by at least 3%, (4) 
who, in the opinion of the investigator, are expected to derive clinical benefit from extending the 
treatment period, and (5) for whom the investigator agrees to extend treatment with the same 
SOC will be given the option for treatment extension. In the second blinded course of treatment, 
subjects will continue treatment with pimodivir or placebo for another 5 days in combination 
with continued SOC treatment. If the SOC contained no influenza antiviral during the first 
treatment period, no influenza antiviral can be started in the treatment extension as part of the 
SOC
The study will consist of a screening/baseline visit, a double-blind treatment period of 5 days 
(with the possibility to extend the treatment period), and a follow-up period of 23 days after the 
last dosing day. The entire study duration for each subject will be 28 days, except for subjects 
receiving extended treatment, for whom the study will last 33 days. The study is considered 
complete with the completion of the last study assessment for the last subject participating in the 
study.
The impact of influenza infection and its treatment on patient-reported symptoms will be 
evaluated throughout the study using a variety of tools. Sparse blood samples for the 
measurement of plasma concentrations of pimodivir will be taken on Days 1, 3 and 5 during 
hospitalization. In case subjects are discharged during the treatment period, a blood sample will 
be taken on the on-site or at-home visit on Day 6. The acceptability of the pimodivir formulation
in adolescents will be assessed using a taste and swallowability questionnaire. Safety and 
tolerability will be assessed throughout the study from signing of the informed consent form 
(ICF)/assent form until the subject’s last study-related activity. Safety evaluations will include 
the monitoring of AEs, clinical laboratory tests, 12-lead ECGs, vital signs, peripheral capillary
oxygen saturation measurements, and (symptom-directed) physical examinations.
Nasal 
mid-turbinate (MT) swabs for viral quantification and resistance testing will be collected.
A diagram of the study design is provided in Figure 1.

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Figure 1:
Schematic Overview of the Study
Abbreviations: bid: twice daily; MT: mid-turbinate; RT-PCR: reverse transcriptase polymerase chain reaction; 
SOC: standard-of-care.
*SOC treatment is determined by the investigator based on local practice, and may include influenza antivirals 
and/or supportive care only. The choice to use influenza antivirals as part of the SOC should be made before 
randomization. The influenza antiviral should be started no later than the day of first study drug intake. An influenza 
antiviral as part of the SOC cannot be changed (eg, switching one influenza antiviral for another) during either the 
treatment period or extension phase, with the exception that an influenza antiviral may be discontinued in the case of 
a suspected adverse event.
Subjects (1) who complete the 5-day treatment, (2) who are still hospitalized upon treatment completion, (3) who are 
on invasive mechanical ventilation or who have an ongoing respiratory deficiency as evidenced by having a 
peripheral capillary oxygen saturation (SpO2) <94% on room air, or in case of known pre-influenza SpO2 <94% (eg, 
due to COPD), the current blood oxygen saturation on room air is lower than pre-influenza infection levels by at 
least 3%, (4) who, in the opinion of the investigator, are expected to derive clinical benefit from extending the 
treatment period, and (5) for whom the investigator agrees to extend treatment with the same SOC will be given the 
option for treatment extension. In the second blinded course of treatment, subjects will continue treatment with 
pimodivir or placebo for another 5 days in combination with continued SOC treatment. If the SOC contained no 
influenza antiviral during the first treatment period, no influenza antiviral can be started in the treatment extension 
as part of the SOC.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to 
monitor efficacy and safety data on a regular basis. Refer to Section 11.13, for details.

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3.2.
Study Design Rationale
Blinding, Control, Randomization, Treatment Arms
A placebo control will be used to establish the frequency and magnitude of changes in clinical 
endpoints that may occur in the absence of active treatment and to minimize bias. Randomization 
will be used to minimize bias in the assignment of subjects to treatment arms, to increase the 
likelihood that known and unknown subject attributes (eg, demographic and baseline 
characteristics) are evenly balanced across treatment arms, and to enhance the validity of 
statistical comparisons across treatment arms. Blinding will be used to reduce potential bias 
during data collection and evaluation of clinical endpoints.
Stratification Factors
Stratification will be used to ensure equal allocation of treatment to subjects over the 
(combination of) prognostic factors, thereby minimizing bias when comparing treatment effects. 
Subjects will be stratified at enrollment by baseline NEWS2, type of SOC used, and time since 
onset of influenza symptoms.

Baseline disease severity and subject condition tend to be the most predictive factors of 
disease outcome. The variable that is considered to be the best measure of baseline status is 
the NEWS2 (4-5 versus ≥6). The NEWS2 is a measure for acute-illness severity, based on 
the following 6 physiological parameters: respiratory rate, oxygen saturations, temperature, 
systolic blood pressure, heart rate, and level of consciousness. It will be derived based on 
vital signs, peripheral capillary oxygen saturation, and ACVPU (alert, new confusion, voice,
pain, unresponsive) scale at baseline and during hospitalization (Attachment 5).13,17

The type of SOC, ie, supportive care including influenza antiviral treatment or supportive 
care excluding influenza antiviral treatment is a factor that could impact virologic and 
clinical outcome results. 

The time since onset of influenza symptoms (first administration of study drug ≤72 hours or 
between 72 and 96 hours since onset of influenza symptoms) may influence the 
effectiveness of antiviral treatment. The earlier treatment can start, the more the antiviral 
medication can be effective by limiting the overall exposure to the virus. To limit study drug 
exposure to subjects with longer times since onset of influenza symptoms, the study will be 
set up such that the subgroup of subjects with first administration of study drug between 
72 and 96 hours (72-to-96-hoursubgroup) since onset of influenza symptoms may be 
stopped during the study in case treatment appears not to be effective in this subgroup 
(futility) (see Section 11.12).
Study Population
Patients hospitalized with influenza are more severely ill and are reported to shed virus longer 
compared to patients with uncomplicated disease with no need for hospitalization.18 In 
prospective studies, none of the commercially available agents have been shown to be 
efficacious in hospitalized patients, who have the greatest unmet medical need. However, they 
are used as de-facto SOC as recommended by the CDC, the European Center for Disease 
prevention and Control, and the World Health Organization (WHO) for this patient population.3

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A number of prospective and retrospective studies of NAIs in severe influenza in the hospital 
setting have been conducted.11 In retrospective studies, early treatment with the orally 
administered NAI OST had a favorable effect on outcome.18
Given the limitations of the currently available anti-influenza therapies, such as a short window 
for initiation of study treatment, concerns about drug resistance, and the lack of any 
demonstrated clinical benefit in the most fragile population of hospitalized patients, there is a 
clear high unmet medical need for better influenza therapies.
Dose Regimen Selection
The dose of pimodivir (600 mg bid for 5 days) was selected based on efficacy and PK/PD
modeling data, as well as safety and viral resistance data from the completed Phase 2 studies
(FLZ2001 and FLZ2002). 
The SOC treatment is determined by the investigator based on local practice, and may include 
influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of
the SOC should be made before randomization. The influenza antiviral should be started no later 
than the day of first study drug intake. An influenza antiviral as part of the SOC cannot be 
changed (eg, switching one influenza antiviral for another) during either the treatment period or 
extension phase, with the exception that an influenza antiviral may be discontinued in the case of 
a suspected AE.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed during the screening/baseline visit, before 
administration of the study drug.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.3, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female, 13 to 85 years of age, inclusive. Note: Adolescent subjects (13 to 
17 years) will be enrolled in selected countries and study sites consistent with local 
regulations.
2.
Tested positive for influenza A infection after the onset of symptoms using a 
polymerase chain reaction (PCR)-based or other rapid molecular diagnostic assay.

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3.
Requires hospitalization to treat influenza infection and/or to treat complications of 
influenza infection (eg, radiological signs of lower respiratory tract disease, septic 
shock, central nervous system [CNS] involvement, myositis, rhabdomyolysis, acute 
exacerbation of chronic kidney disease, severe dehydration, myocarditis, pericarditis, 
ischemic heart disease, exacerbation of underlying chronic pulmonary disease, including 
asthma, chronic obstructive pulmonary disease [COPD], decompensation of previously 
controlled diabetes mellitus), including subjects admitted to the ICU. Note: For the 
purpose of the protocol, subjects admitted under “observation” status with an 
anticipated length of stay beyond 24 hours are eligible for enrollment.
4.
Enrollment and initiation of study drug treatment ≤96 hours after onset of influenza
symptoms.
5.
Being on invasive mechanical ventilation or having a peripheral capillary oxygen 
saturation (SpO2) <94% on room air during screening. Subjects with known 
pre-influenza SpO2 <94% must have an SpO2 decline ≥3% from pre-influenza SpO2
during screening.
6.
Having a screening/baseline NEWS2 of ≥4.
7.
Must sign an ICF (or their legally acceptable representative (LAR) must sign on behalf 
of the subject to participate in the study for minors and incapacitated subjects, as 
permitted by local regulatory authorities, IRB/IECs, and local laws) indicating that he or 
she understands the purpose of, and procedures required for, the study and is willing to 
participate in the study. Assent is also required of adolescents capable of understanding 
the nature of the study.
Note: A number of subjects eligible for this study may be acutely incapacitated and not 
able to consent due to their medical condition (eg, too weak or debilitated, unconscious, 
experiencing severe shortness of breath, or mechanically ventilated). These subjects can 
be included as permitted by local regulatory authorities, IRB/IEC, and local laws. 
Subjects enrolled in the study, based on consent by a LAR, will be required to provide 
written confirmatory consent/assent to continue, as soon as they become capable to do so. 
In case the subject does not consent/assent to continue participation in the study, the 
subject will be withdrawn from the study and the optional withdrawal Safety Follow-up 
Visit will be offered (refer to Section 10.3).
Subject or LAR must sign a separate ICF/assent form if he or she agrees to provide an 
optional DNA sample for research (where local regulations permit). Refusal to give 
consent for the optional DNA research sample does not exclude a subject from 
participation in the study.
8.
Before randomization, a woman must be either:
a.
Not of childbearing potential defined as:

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o
Premenarchal
A premenarchal state is one in which menarche has not yet occurred.
o
Postmenopausal
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level 
(>40 IU/L or mIU/mL) in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy, however in the absence 
of 12 months of amenorrhea, a single FSH measurement is insufficient.
o
Permanently sterile
Permanent 
sterilization 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy.
b.
Of childbearing potential and
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 (IUD); intrauterine 
hormone-releasing system (IUS); 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.)
- User-dependent methods:
combined 
(estrogen-
and 
progestogen-containing) 
hormonal 
contraception associated with inhibition of ovulation: oral, 
intravaginal, 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. Use should be consistent with local regulations regarding the 
use of contraceptive methods for subjects participating in clinical studies.
o
Agrees to remain on a highly effective method throughout the study and 
for at least 30 days after the last dose of study drug. 
Note: If the childbearing potential changes after start of the study (eg, a premenarchal 
woman experiences menarche) 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.
9.
A woman of childbearing potential must have a negative urine or serum pregnancy test 

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at screening.
10.
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for a period of at least 30 days after the last dose of 
study drug.
11.
During the study and for a minimum of 1 spermatogenesis cycle (defined as 
approximately 90 days) after receiving the last dose of study drug, in addition to the 
highly effective method of contraception being used by the female partner, a man 
regardless of having been vasectomized

Who is sexually active with a woman of childbearing potential must agree to use a 
barrier method of contraception (eg, condom preferably with spermicidal 
foam/gel/film/cream/suppository).

Who is sexually active with a woman who is pregnant must use a condom.

Must agree not to donate sperm.
Note: If the female sexual partner is postmenopausal (defined as no menses for 
12 months without an alternative medical cause), is permanently sterilized (eg, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or otherwise incapable 
of becoming pregnant, the birth control methods mentioned are not applicable.
12.
Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
Received more than 3 doses of influenza antiviral medication (eg, OST or zanamivir), or
any dose of RBV within 2 weeks, prior to first study drug intake. Received IV peramivir 
more than one day prior to screening.
2.
Unwilling to undergo regular nasal MT swabs or has any physical abnormality which 
limits the ability to collect regular nasal MT specimens.
3.
Unstable angina pectoris or myocardial infarction within 30 days prior to screening 
(inclusive).
4.
Presence of clinically significant heart arrhythmias, uncontrolled, unstable atrial 
arrhythmia, or sustained ventricular arrhythmia, or risk factors for Torsade de Pointes 
syndrome.
5.
Known severe hepatic impairment (Child Pugh C cirrhosis) or chronic hepatitis C 
infection undergoing hepatitis C antiviral therapy.

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6.
Severely immunocompromised in the opinion of the investigator (eg, known cluster of 
differentiation 4+ [CD4+] count <200 cells/mm3, absolute neutrophil count <750/mm3, 
first course of chemotherapy completed within 2 weeks prior to screening, history of 
stem cell transplant within 1 year prior to screening, any history of a lung transplant).
7.
Known allergies, hypersensitivity, or intolerance to pimodivir or its excipients (refer to 
IB).9
8.
Received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 30 days or has received an 
investigational biological product within 3 months or 5 half-lives (whichever is longer) 
before the planned first dose of study drug or is currently enrolled in an investigational 
study.
9.
Taken any disallowed therapies as noted in Section 8, Pre-study and Concomitant 
Therapy before the planned first dose of study drug. 
10.
A woman who is pregnant, or breast-feeding, or planning to become pregnant while 
enrolled in this study or a woman of childbearing potential who is unwilling to use an 
acceptable method of contraception as outlined in the inclusion criteria. 
11.
A man who plans to father a child while enrolled in this study.
12.
Subject has 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 (eg, subjects unable 
to swallow study medication tablets outside the hospital setting), with the exception of 
ePRO completion (see Section 9.2.1.3), ie, if a subject is not able to complete ePRO, the 
subject is still allowed to be enrolled in the study.
13.
Subject has presence of any pre-existing illness, clinically significant laboratory 
abnormalities, ECG findings, or physical examination findings that, in the opinion of the 
investigator, would place the subject at an unreasonably increased risk through 
participation in this study. The investigator should consider the laboratory parameter 
criteria for study drug discontinuation (see Section 10.2) when screening a subject for 
enrollment.
14.
An employee of the investigator or study site, with direct involvement in the study or 
other studies under the direction of that investigator or study site, as well as family 
members of the employees or the investigator, or an employee of the sponsor.
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 

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participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
4.3.
Treatment Extension Criteria
Subjects will be given the option for treatment extension in case all of the following conditions 
are met:
1.
The subject completed the 5-day treatment period.
2.
The subject is still hospitalized.
3. 
The subject is on invasive mechanical ventilation or has an ongoing respiratory 
deficiency as evidenced by having an SpO2 <94% on room air, or in case of known 
pre-influenza SpO2 <94% (eg, due to COPD), the current blood oxygen saturation on 
room air is lower than pre-influenza infection levels by at least 3%.
4.
The subject is expected to derive clinical benefit from extending the treatment period, in 
the opinion of the investigator.
5.
The investigator agrees to extend treatment with the same SOC. If the SOC contained 
no influenza antiviral during the first treatment period, no influenza antiviral can be 
started in the treatment extension as part of the SOC.
4.4.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Section 8, Prestudy and concomitant therapy for details regarding prohibited 
and restricted therapy during the study.
2.
Agree to follow the contraceptive requirements as noted in the inclusion criteria.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation: Procedures for Randomization
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment arms in a 1:1 ratio based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified for baseline NEWS2 (4-5 or 
>5), type of baseline SOC (including or not including antiviral treatment), and time since onset 
of influenza symptoms (first administration of study drug ≤72 hours or between 72 and 96 hours
since onset of influenza symptoms). 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 

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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 plasma 
concentrations) 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 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 documents. The documentation received 
from the IWRS indicating the code break must be retained with the subject's source documents in 
a secure manner.
6.
DOSAGE AND ADMINISTRATION
During the treatment period, all subjects will receive study drug in a 1:1 ratio in 1 of the 
2 treatment arms shown in the table below. Depending on the time of screening/enrollment, 
subjects will receive 1 dose (evening) or 2 doses (morning and evening) of study drug on Day 1. 
Subjects may delay or bring forward administration of the second dose (by no more than 4 hours) 
only if the nominal timing for this second dose falls in the middle of the night. For subjects who 
receive only 1 dose of pimodivir or placebo on Day 1 (evening), dosing should continue until the 
morning of Day 6 so that all subjects receive 10 doses in total.
Subjects who are eligible for the blinded extension arm will receive study drug as described in 
the table below. Subjects will receive 1 dose (evening) or 2 doses (morning and evening) of 
study drug on Day 6. For subjects who receive the first dose of study drug in the second
treatment course in the evening of Day 6, dosing should continue until the morning of Day 11 so 
that the subject receives 10 doses in total during the second treatment course.
Study-site personnel will instruct subjects on how to store study drug for at-home use as 
indicated for this protocol. 

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No post-study medication is provided as part of this protocol.

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Treatment Arm 1
Treatment Arm 2
Treatment Extension Arm 1a
Treatment Extension Arm 2a
Test Article(s) Pimodivir (Day 1 through Day 5)
+ SOC treatmentb,c
Placebo (Day 1 through Day 5)
+ SOC treatmentb,c
Pimodivir (Day 6 through Day 10)
+ SOC treatmentb,c
Placebo (Day 6 through Day 10)
+ SOC treatmentb,c
Description
300 mg tablet
Placebo tablet
300 mg tablet
Placebo tablet
Dose per 
Delivery
Day 1 to Day 5
600 mg pimodivir (2 tablets)
Day 1 to Day 5
Placebo (2 tablets)
Day 6 to Day 10
600 mg pimodivir (2 tablets)
Day 6 to Day 10
Placebo (2 tablets)
Frequency
Bid
Bid
Bid
Bid
Total Daily 
Dose
1,200 mg 
NAP
1,200 mg 
NAP
Delivery 
Methodd
Oral
Oral
Oral
Oral
Food/Fasting 
Requirement
No food requirements
No food requirements
No food requirements
No food requirements
Abbreviations: bid: twice daily; NAP: not applicable; SOC: standard-of-care.
a
Subjects (1) who complete the 5-day treatment, (2) who are still hospitalized upon treatment completion, (3) who are on invasive mechanical ventilation or who have 
an ongoing respiratory deficiency as evidenced by having a peripheral capillary oxygen saturation (SpO2) <94% on room air, or in case of known pre-influenza SpO2
<94% (eg, due to COPD), the current blood oxygen saturation on room air is lower than pre-influenza infection levels by at least 3%, (4) who, in the opinion of the 
investigator, are expected to derive clinical benefit from extending the treatment period, and (5) for whom the investigator agrees to extend treatment with the same 
SOC will be given the option for treatment extension. In the second blinded course of treatment, subjects will continue treatment with pimodivir or placebo for 
another 5 days in combination with continued SOC treatment. If the SOC contained no influenza antiviral during the first treatment period, no influenza antiviral can 
be started in the treatment extension as part of the SOC.
b
Depending on the time of screening/enrollment, subjects will receive 1 dose (evening) or 2 doses (morning and evening) of study drug on Day 1. For subjects who 
receive only 1 dose of pimodivir or placebo on Day 1 (evening), dosing should continue until the morning of Day 6 so that all subjects receive 10 doses in total.
c
SOC treatment is determined by the investigator based on local practice, and may include influenza antivirals and/or supportive care only. The choice to use 
influenza antivirals as part of the SOC should be made before randomization. The influenza antiviral should be started no later than the day of first study drug intake.
An influenza antiviral as part of the SOC cannot be changed (eg, switching one influenza antiviral for another) during either the treatment period or extension phase, 
with the exception that an influenza antiviral may be discontinued in the case of a suspected adverse event.
d
During hospitalization, in case of medical need, study drug tablets may be dispersed in water before intake (in case of administration via a nasogastric tube or if the 
subject has difficulties swallowing the tablets). Refer to the pharmacy manual/study site investigational product manual for additional guidance on study drug 
preparation, handling, and storage.

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7.
TREATMENT COMPLIANCE
Missed doses of pimodivir or placebo will be recorded in the source documents and the eCRF, 
and re-dosed if the missed dose is discovered <6 hours past the scheduled dosing time. If the 
missed dose is discovered >6 hours past the scheduled dosing time, the missed dose should be 
skipped, and the next dose should be taken as scheduled. In case of vomiting within 6 hours after 
dosing and visual confirmation of tablet(s) in the vomit, the subject should be re-dosed (2x 300-
mg tablets). In case of vomiting >6 hours after dosing or in case of no visual confirmation of 
tablet(s) in the vomit, the subject should not be re-dosed.
A dosing time memory aid will be available in the ePRO device for patients in order to document 
date and time of intakes. Subjects who are discharged during the treatment period, will receive 
study drug for at-home use. Compliance will be assessed at each visit by counting study drug 
dispensed and study drug returned. Discrepancies will be discussed with the subject and date and 
time of study drug intakes recorded in the source documents and the eCRF.
If a subject’s study drug intake (pimodivir or placebo) is not according to the protocol, the 
investigator will take the necessary measures to ensure future adherence to the protocol.
8.
PRESTUDY AND CONCOMITANT THERAPY
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study drug through the Final Study Visit/Safety Follow-up Visit. Medications that are 
part of the SOC should be recorded as concomitant medications throughout the study. 
Concomitant therapies should also be recorded beyond Final Study Visit/Safety Follow-up Visit
if in conjunction with SAEs that meet the criteria outlined in Section 12.3.2. Serious Adverse 
Events.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study drug must be recorded in the eCRF. Recorded 
information will include a description of the type of the drug, treatment period, dosing regimen, 
route of administration, and its indication.
The following pre-study and concomitant therapies are disallowed:
More than 3 doses of influenza antiviral medication (eg, OST, zanamivir), or ribavirin

within 2 weeks, prior to first study drug intake.
IV peramivir more than 1 day prior to screening.

An investigational drug (including investigational vaccines) or an invasive investigational 

medical device within 30 days, or an investigational biological product within 3 months or 
5 half-lives (whichever is longer) prior to the first dose of study drug until the end of the 
study.
Use of a live attenuated intranasal spray influenza vaccine within 3 weeks before study 

entry.

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Substrates of OATP1B1 and/or OATP1B3, including atrasentan, bosentan, ezetimibe, glyburide, 
irinotecan, repaglinide, rifampin, telmisartan, valsartan, and olmesartan may be continued. 
Statins (ie, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) may also be 
continued, but subjects should be cautioned and observed for potential statin-related toxicity.
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
Overview
9.1.1.
The TIME AND EVENTS SCHEDULES summarize the frequency and timing of efficacy, PK, 
PD, biomarker (if not restricted by local regulations), and safety measurements applicable to this 
study during hospitalization (up to discharge), after discharge from hospital and during the 
optional blinded extension treatment arm.
If multiple assessments are scheduled for the same time point, it is recommended that procedures 
be performed in the following sequence: ECG, vital signs, peripheral capillary oxygen saturation, 
blood sampling. Blood collections for PK and PD 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. At the time points where both nasal MT swabs and PK samples are obtained, these 
samples should be obtained as close together in time as possible. If subjects are intubated, 
endotracheal samples should be taken in addition to the MT swabs.
Additional urine or serum pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
The total blood volume to be collected from each subject is considered to be within the acceptable
range allowed for this subject population over this time frame.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Screening Phase
9.1.2.
At the screening visit, after signing of the ICF/assent form (see Section 16.2.3, Informed Consent 
for more details), the overall eligibility of the subject to participate in the study will be assessed 
and documented in the eCRF. First study drug intake should take place immediately after all 
screening/baseline procedures have taken place and eligibility has been established. 
Screening/baseline assessments start at signing of the ICF/assent form and occur before 
randomization and the first administration of study drug. Note: It is recommended that the 
screening/baseline assessments are completed as quickly as possible, in order to start study drug 

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treatment as soon as possible. However, if needed, and depending on the time of hospital 
admission, screening/baseline assessments and establishment of eligibility can continue the next 
calendar day, in which case the first study drug intake will be on that day, immediately after 
establishing eligibility. For analysis purposes, the day of first study drug intake will be 
considered Day 1. Subjects who successfully meet all inclusion criteria and none of the exclusion 
criteria will be eligible for participation in the study.
The subject’s characteristics, demographic data, medical and surgical history, and prestudy and 
concomitant medication, including influenza vaccination status, will be recorded. A local
virology test, capable of distinguishing between influenza types A and B, will be carried out as 
part of the screening procedures. MT swabs are recommended for local virology testing, 
although nasopharyngeal (NP) swabs are allowed if required by local procedures. Nasal swabs 
(either for local or central virology testing) should be obtained from the left and right nostrils 
(from both nostrils if feasible, but from only one nostril otherwise) and pooled into the same 
collection tube. The results of an earlier sample collected and tested positive for influenza A 
infection after the onset of symptoms can be used in lieu of the local virology testing at screening 
(this sample is used to determine eligibility). If available, leftovers from the local virology
sample (with the exception of “an earlier sample”) will be shipped to and stored at the central lab 
for further testing, regardless of local influenza test result. If subjects are intubated, an 
endotracheal sample should be collected at the same time points as the nasal MT swab. Only 
those subjects testing positive for influenza A will be considered for enrollment.
In case a subject does not remember the exact hour of onset of symptoms, a granular imputation 
method for the missing onset time will be applied by the investigator at screening.
A physical examination (including height and [recent] body weight measurements, if not already 
available and if practically feasible) will be conducted. A urine or serum pregnancy test will be 
performed for all female subjects of childbearing potential. The result of a prior urine or serum 
pregnancy test that occurred within 1 calendar day before signing of the ICF/assent form can be 
used in lieu of the baseline requirement.
Subjects will be requested to complete PRO assessments at sites where appropriate translations 
are available and approved to assess influenza-related signs and symptoms (see Section 9.2.1.3
for more details). The baseline PRO assessments should be completed prior to first study drug 
intake.
Blood samples (for hematology, chemistry, and biomarker [if not restricted by local regulations]
analysis) and a urine sample (for urinalysis) will be taken. A nasal MT swab will be obtained for 
central virology testing. Vital signs (systolic blood pressure [SBP], diastolic blood pressure 
[DBP], pulse rate, respiratory rate, body temperature), peripheral capillary oxygen saturation, 
and level of consciousness (ACVPU) will be measured, and a 12-lead ECG will be performed.
An ECG recorded within 1 calendar day before signing of the ICF/assent form can be used in 
lieu of the baseline ECG requirement. The level of consciousness will be measured according to 
the ACVPU scale (see Section 9.6.4).

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Subjects will be observed/interviewed for any AEs, concomitant medication will be reviewed 
and AEs and concomitant medication will be recorded.
Double-blind Treatment Phase
9.1.3.
Subjects who meet all eligibility criteria will be randomized in a 1:1 ratio to receive 1 of the 
following 2 treatments:

Pimodivir 600 mg bid on Days 1 through 5 + SOC treatment; OR

Pimodivir placebo bid on Days 1 through 5 + SOC treatment. 
For subjects who receive only 1 dose of pimodivir or placebo on Day 1 (evening), dosing should 
continue until the morning of Day 6 so that all subjects receive 10 doses in total.
The SOC treatment is determined by the investigator based on local practice, and may include 
influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of
the SOC should be made before randomization. The influenza antiviral should be started no later 
than the day of first study drug intake. An influenza antiviral as part of the SOC cannot be 
changed (eg, switching one influenza antiviral for another) during either the treatment period or 
extension phase, with the exception that an influenza antiviral may be discontinued in the case of 
a suspected AE.
Subjects will undergo sparse PK sampling for the measurement of plasma concentrations of 
pimodivir at the time points specified in the TIME AND EVENTS SCHEDULES.
Throughout the treatment period, PRO assessments will be completed before any other 
assessments for a specific visit. At the time points specified in the TIME AND EVENTS 
SCHEDULES, a symptom-directed physical examination, blood sampling (for hematology, 
chemistry, drug concentrations, and biomarker [if not restricted by local regulations] analysis), 
urine sampling (for urinalysis), and a pregnancy test (urine or serum for females of childbearing 
potential) will be performed; nasal MT swabs will be obtained for central virology testing; and 
vital signs, peripheral capillary oxygen saturation, and level of consciousness (ACVPU) will be 
measured. If subjects are intubated, an endotracheal sample should be collected at the same time 
points as the nasal MT swab. A taste and swallowability questionnaire will be completed by 
adolescent subjects, within approximately 15 minutes after the first and last intake of the 
pimodivir or placebo tablet (not applicable when tablets are administered via nasogastric tube).
Subjects will be observed/interviewed for any AEs, concomitant medication will be reviewed, 
and AEs and concomitant medication will be recorded. 
Once daily, an assessment of readiness for discharge and ICU level of care requirement will be 
performed.
Subjects, who are discharged during the treatment phase, will receive study drug for at-home 
use.

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End of Treatment
A subject will be considered to have completed treatment after 5-day therapy of pimodivir or 
placebo (ie, 10 doses). 
Subjects (1) who complete the 5-day treatment, (2) who are still hospitalized upon treatment 
completion, (3) who are on invasive mechanical ventilation or who have an ongoing respiratory 
deficiency as evidenced by having an SpO2 <94% on room air, or in case of known pre-influenza 
SpO2 <94% (eg, due to COPD), the current blood oxygen saturation on room air is lower than 
pre-influenza infection levels by at least 3%, (4) who, in the opinion of the investigator, are 
expected to derive clinical benefit from extending the treatment period, and (5) for whom the 
investigator agrees to extend treatment with the same SOC will be given the option for treatment 
extension. In the second blinded course of treatment, subjects will continue treatment with 
pimodivir or placebo for another 5 days in combination with continued SOC treatment. If the 
SOC contained no influenza antiviral during the first treatment period, no influenza antiviral can 
be started in the treatment extension as part of the SOC (see Section 9.1.4).
Early Withdrawal
Subjects who prematurely discontinue study drug treatment for any reason (except withdrawal of 
consent) will be asked to continue with their remaining study visits and assessment schedule. 
Subjects who withdraw consent during the treatment phase will be offered an optional Safety 
Follow-up Visit. The optional Safety Follow-up Visit will occur the day of consent withdrawal 
or the day after and will consist of the same assessments as at the Final Study Visit (Day 28 or 
Day 33), with optional PRO completion. If the subject discontinues treatment due to an AE or 
other medical reason, efforts will be made by the investigator to continue following up with the 
subject at regular intervals until the AE normalizes or returns to the subject’s baseline condition. 
The sponsor and the investigator will agree on an acceptable individual follow-up schedule for 
these subjects.
Double-blind Extension Phase
9.1.4.
Subjects (1) who complete the 5-day treatment, (2) who are still hospitalized upon treatment 
completion, (3) who are on invasive mechanical ventilation or who have an ongoing respiratory 
deficiency as evidenced by having an SpO2 <94% on room air, or in case of known pre-influenza 
SpO2 <94% (eg, due to COPD), the current blood oxygen saturation on room air is lower than 
pre-influenza infection levels by at least 3%, (4) who, in the opinion of the investigator, are 
expected to derive clinical benefit from extending the treatment period, and (5) for whom the 
investigator agrees to extend treatment with the same SOC will be given the option for treatment 
extension. In the second blinded course of treatment, subjects will continue treatment with 
pimodivir or placebo for another 5 days in combination with continued SOC treatment. If the 
SOC contained no influenza antiviral during the first treatment period, no influenza antiviral can 
be started in the treatment extension as part of the SOC (see Section 4.3).
Upon completion of the 5-day treatment, the eligibility of the subject to participate in the blinded
extension treatment arm will be assessed and documented in the eCRF. The procedures to be 
completed during the blinded extension treatment phase are listed in the 3. TIME AND EVENTS 

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SCHEDULE – DURING HOSPITALIZATION (UP TO DISCHARGE), FOR PATIENTS 
WHO ENTERED THE OPTIONAL DOUBLE-BLIND EXTENSION TREATMENT ARM.
Post-treatment Phase (Follow-up)
9.1.5.
The procedures to be completed during the follow-up phase are listed in the TIME AND 
EVENTS SCHEDULES.
Subjects who withdraw consent during the follow-up phase will be offered an optional Safety 
Follow-up Visit. The optional Safety Follow-up Visit will consist of the same assessments as at 
the Final Study Visit (Day 28 or Day 33), with optional PRO completion. In case of ongoing 
AEs, efforts will be made by the investigator to continue following up with the subject at regular 
intervals until the AE normalizes or returns to the subject’s baseline condition.
After Discharge From the Hospital
9.1.6.
In case subjects are discharged from the hospital during the study, the remainder of the study 
visits should be carried out as outpatient visits (preferably on-site or, if not feasible, at the 
subject’s home) or by telephone follow-up, as indicated in the 2. TIME AND EVENTS 
SCHEDULE – AFTER DISCHARGE FROM HOSPITAL and 4. TIME AND EVENTS 
SCHEDULE – AFTER DISCHARGE FROM HOSPITAL, FOR PATIENTS WHO HAD 
ENTERED THE OPTIONAL DOUBLE-BLIND EXTENSION TREATMENT ARM. Every 
effort should be made to perform all of the assessments (either on-site or at the subject’s home) if 
practically feasible. If the subject has died, the date and cause of death will be collected and 
documented on the eCRF.
9.2.
Efficacy
Evaluations
9.2.1.
9.2.1.1.
Hospital Recovery Scale Assessment
The hospital recovery scale assesses a subject’s clinical status and will be assessed as the 
subject’s condition on Day 6 as the primary endpoint. The hospital recovery scale will be 
assessed on Days 2 to 14 (excluding the primary time point) as secondary endpoints. 
The hospital recovery scale provides 6 mutually exclusive conditions ordered from best to worst,
and the score reflects the subject’s worst situation on the day of assessment:

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1. Not Hospitalized
2. Non-ICU Hospitalization, Not Requiring Supplemental Oxygen
3. Non-ICU Hospitalization, Requiring Supplemental Oxygen
4. Admitted to the ICU, Not Requiring Invasive Mechanical Ventilation
5. Requiring Invasive Mechanical Ventilation 
6. Death
The hospital recovery scale categories are defined below. For ease of categorization, the 
categories are defined from worst to best.
Hospital Recovery Scale: Definitionsa
6. Death

Subject died at any time on the day of assessment or earlier (all-cause mortality).
5. Requiring invasive mechanical ventilation

Any oxygen support requiring intubation or extracorporeal oxygenation

Invasive mechanical ventilation is used at any time on the day of assessment.
4. Admitted to the ICU, not requiring invasive mechanical ventilation
Subject met either of the 2 following criteria:

In the ICU (and ICU level of care is required during the day of assessment)

On the hospital ward, with or without supplemental oxygen, but deemed to require ICU 
level of care at any time during the day of assessment (eg, not transferred to ICU due to 
bed availability)
Requiring ICU level of care is defined by:

Some specific conditions:
o
Treatment of acute unstable arrhythmias
o
Treatment of complicated acid-base or electrolyte imbalances
o
Large volume resuscitation
o
Utilization of intravenous vasoactive medications
                                                
a If a subject was discharged from the hospital “Against Medical Advice” on the day prior to the day of assessment, 
the subject will be categorized per the definitions above in the category the subject was in at the moment of 
discharge “Against Medical Advice”. The hospital recovery scale category will be considered missing on 
subsequent days. 
If a subject declines medically-indicated mechanical ventilation or care that requires an ICU level of intervention, 
the subject will be categorized according to the care they would otherwise have received on that day.

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o
S/P cardiac arrest
o
Cardiogenic Shock
o
Acute myocardial infarct with complications
o
Cardiac tamponade 
o
Acute congestive heart failure
o
Acute or imminent respiratory failure
o
Hemodynamic instability 
o
Diabetic ketoacidosis complicated by hemodynamic instability, altered mental 
status, respiratory insufficiency, or severe acidosis

Other conditions requiring specialized equipment and/or staff competencies only 
available in the ICU
3. Non-ICU hospitalization, requiring supplemental oxygen
Subject met either of the 2 following criteria:

Non-ICU hospitalized on the day of assessment (including readmittance), not ready for 
discharge during the whole day of assessment, as judged by the investigator and 
supplemental oxygen is required by the subject

In the ICU but there is no medical reason to be in the ICU during the day of assessment, 
and supplemental oxygen is required by the subject
Requiring supplemental oxygen is defined by:

Receiving supplemental oxygen through a face mask or nasal cannula and not being 
able to sustain a blood oxygen saturation of ≥94% when breathing room air for 
15 minutes at any time on the day of assessment.  

If supplemental oxygen was provided chronically pre-influenza infection (based on 
medical history), that amount of supplemental oxygen is exceeded to prevent hypoxia, 
tachypnea or dyspnea at some point on the day of assessment.

Not receiving supplemental oxygen and either:
o
Having a blood oxygen saturation of <94% when breathing room air for 15 minutes
at any measurement on the day of assessment, or 
o
In case of known pre-influenza SpO2 <94% (eg, due to COPD), the current blood 
oxygen saturation on room air is lower than pre-influenza infection levels by at 
least 3%.
2. Non-ICU hospitalization, not requiring supplemental oxygen
Subject met either of the 2 following criteria:

Non-ICU hospitalized on the day of assessment (including readmittance) and not ready 
for discharge during the whole day of assessment, as judged by the investigator 

In the ICU but there is no medical reason to be in the ICU during the day of assessment

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1. Not hospitalized
Any of the following:

Discharged from the hospital before the day of assessment 

Hospitalized at the day of assessment but ready for discharge on both the day of 
assessment and the day prior, as judged by the investigator (eg, in case of lack of bed 
availability in a skilled nursing facility, lack of social support at home).
9.2.1.2.
Complications of Influenza
From the moment subjects signing the informed consent form, any untoward event occurring 
with the subject is reported by investigators as AEs, refer to Section 12. For each reported event, 
investigators will be asked if they consider the event to be a complication of influenza. When 
answered yes, additional data related to that event is collected when available. A blinded 
Adjudication Committee (AC) will be established to adjudicate AEs as complications based on 
predefined criteria, refer to Section 11.14.
Based on the collected data, event identified as complications by investigators will be 
categorized into pulmonary versus extrapulmonary, major versus minor, as well as infectious 
versus noninfectious complications of influenza.
Pulmonary complications

Respiratory failure: defined as either hypoxemic respiratory failure characterized by an 
arterial oxygen tension (PaO2) lower than 60 mmHg with a normal or low arterial carbon 
dioxide tension (PaCO2), or hypercapnic respiratory failure characterized by a PaCO2 higher 
than 50 mmHg.

Primary viral pneumonia: a progressive event involving the lower respiratory tract with 
bilateral and/or diffuse radiological findings. No bacterial agent is identified using sputum 
cultures. 

Secondary bacterial pneumonia (including pneumonia attributable to unusual pathogens): a 
clinical event compatible with lower respiratory tract involvement, with lobar infiltrates on 
radiological studies and/or microbiological isolate of a bacterial pathogen, including unusual 
pathogens.

Exacerbations of chronic underlying pulmonary diseases such as COPD and asthma: 
subjects with documented medical history of COPD or asthma with a sudden worsening of 
symptoms and deteriorating respiratory function (the latter as evidenced by worsening 
hypoxia, tachypnea, etc.) The event must start before a full recovery from the influenza 
infection occurred.

Bronchitis
Extrapulmonary complications

Cardiovascular and cerebrovascular disease (eg, myocardial infarction, congestive heart 
failure, arrhythmia, stroke)

Muscular disorders (eg, myositis, rhabdomyolysis)

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
Central nervous system [CNS] involvement

Acute exacerbation of chronic kidney disease

Decompensation of previously controlled diabetes mellitus

Other infections (eg, sinusitis, otitis)
9.2.1.3.
Patient-reported Outcomes
Influenza Symptom Diary
This diary is an 11-item PRO measure designed to capture influenza symptom burden from the
subject’s perspective (see Attachment 6). Subjects will report the severity of symptoms (cough, 
trouble breathing, body aches, fatigue (tiredness, weariness), headache, sweating, nasal 
congestion, sore throat, chills, runny nose, and nausea) at their worst in the past 12 hours using 
an 11-point numerical rating scale (NRS), where the descriptor on the zero anchor is ‘No 
[symptom]’ and the descriptor on the ten anchor is ‘[Symptom] as bad as you can imagine’. 
Subjects will complete the influenza symptom diary at screening/baseline (prior to the first dose) 
and then twice daily onto the ePRO device (morning upon waking for the day and in the evening 
prior to retiring for bed).
The influenza symptom diary should be completed first of PROs except when the PGIC is 
administered (the PGIC should be administered BEFORE the influenza symptom diary).
Patient Global Impression of Severity (PGIS)
The PGIS is a single item PRO that captures daily influenza symptom severity from the subjects’ 
perspective. Subjects rate their perception of overall influenza symptoms for the day using the 
following response scale: "Mild", "Moderate", "Severe", “Very Severe”, or "No flu symptoms 
today". Study participants will complete the PGIS once daily from screening/baseline throughout 
Final Study Visit/Safety Follow-up Visit.
Patient Global Impression of Change (PGIC)
The PGIC is a single item PRO aimed to capture the subject’s perceptions of improvement or 
deterioration in the severity of influenza symptoms compared to when the subject arrived to the 
hospital for influenza treatment.8 Response options include: “Much better”, “Somewhat better”, 
“A little better”, “About the same”, “A little worse”, “Somewhat worse”, and “Much worse”. 
Study participants will complete the PGIC on Days 6, 14, and 28, and on Days 6, 14, 19, and 33 
in case of treatment extension.6
EQ-5D
The EQ-5D is a standardized measure of health status designed for self-completion and 
developed in order to provide a simple, generic measure of health for clinical and economic 
appraisal. The EQ-5D includes 5 levels of severity (EQ-5D-5L) in each of the existing 5 EQ-5D 
dimensions (no problems, slight problems, moderate problems, severe problems, and extreme 
problems). The EQ-5D questionnaire consists of the EQ-5D descriptive system and the EQ-5D 
visual analogue scale. The descriptive system comprises the following 5 dimensions: mobility, 

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self-care, usual activities, pain/discomfort, and anxiety/depression. The subject is asked to 
indicate his/her health state by ticking the box against the most appropriate statement in each of 
the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that 
dimension. The digits for 5 dimensions can be combined in a 5-digit number describing the 
respondent’s health state. It should be noted that the numerals 1-5 have no arithmetic properties 
and should not be used as a cardinal score. The EQ-5D visual analogue scale records the 
subject’s self-rated health on a vertical, visual analogue scale with endpoints labelled ‘the best 
health you can imagine’ and ‘the worst health you can imagine’. This information can be used as 
a quantitative measure of health as judged by the individual subjects. Study participants will 
complete the EQ-5D at screening/baseline and on Days 6, 14, and 28 in this study. In case of 
treatment extension, study participants will complete the EQ-5D at screening/baseline and on 
Days 6, 14, 19, and 33.4
Assessment of Daily Activities Resumption
Return to daily activities will be assessed once daily from screening through the Final Study 
Visit/Safety Follow-up Visit by means of the subject’s response to the question 'Over the past 
24 hours, how much has influenza (flu) interfered with your ability to carry out your daily 
activities?'.
Subjects will respond to the above by means of the following response scale:
Not at all

A little bit

Somewhat

Quite a bit

Very much

Administration of Patient-reported Outcomes
The PRO assessments will be completed by all subjects at sites where appropriate PROs and 
translations are available and approved. Subjects should complete the PRO assessments in a 
language in which the subject is fluent and literate. Study personnel will instruct subjects how to 
self-complete the PRO assessment. Incapacitated subjects and subjects who develop a decreased 
level of consciousness or are intubated will not complete PROs. 
Site personnel can enter responses on the ePRO device on behalf of subjects only when subjects 
are too ill to hold devices in their hands but are able to respond to questions. If these criteria are 
met, site personnel will log into the ePRO device under the Site ID module, will read the 
instructions, questions, and potential responses aloud and in entirety to subjects, and enter their 
responses into the ePRO device. If the subjects cannot provide verbal responses, site personnel 
should document that the reason for missing data is due to illness. Site personnel will not allow 
caregivers or family members of subjects to complete the PROs. Site staff will complete specific 
training on these study procedures.      

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Subjects will complete the PRO assessments electronically on a touch screen computer (ePRO 
device) provided for this study. The subject should be provided a quiet place to complete the 
PRO assessments. When deciding which answer to report, subjects should not be influenced by 
anyone accompanying them (such as family members and friends) or study personnel; the 
responses should reflect the subject’s interpretation and response.
Subjects’ responses to the PRO questionnaires will not be reported as AEs or SAEs.
PRO completion compliance should be assessed daily by the site staff via the ePRO web 
platform. Reasons for missing assessments should be documented on the web platform by the 
site after discussion with the subject.
9.2.1.4.
Viral Kinetics
Influenza viral load will be quantified in nasal MT swab samples (and endotracheal aspirates in 
subjects who are intubated) taken at scheduled times throughout the study as indicated in the 
TIME AND EVENTS SCHEDULES. Nasal MT swabs and endotracheal samples will be 
analyzed centrally using qRT-PCR and viral culture. The presence of viral (other than influenza) 
and/or bacterial pathogens can be analyzed in selected samples. Influenza A subtype will be 
determined from the baseline sample.
Details about the nasal MT and endotracheal swab sample collection, processing, and shipping 
will be provided in the laboratory manual or other instruction documents.
Nasal swab sampling should be done at approximately the same (±4 hours) time when required. 
The investigator should designate a limited number of trained study site personnel to collect the 
nasal MT swabs for the sake of consistency.
Efficacy Endpoints
9.2.2.
Refer to Section 2.1.2, Endpoints for an overview of efficacy endpoints.
9.3.
Resistance Evaluations
Viral Sequencing
9.3.1.
Nasal MT swab and endotracheal samples will be collected as described in Section 9.2.1.4 at the 
time points specified in the TIME AND EVENTS SCHEDULES and will be used for sequence 
analysis of the PB2 region of the influenza polymerase gene, and of neuraminidase (and HA, if 
applicable) gene for subjects using an NAI as part of their SOC. For subjects who meet criteria 
for reduced virologic response or viral rebound, the PA and PB1 regions of the influenza 
polymerase will be sequenced as well. Gene sequencing will be performed on all baseline
samples and on the last evaluable post-baseline sample (on-treatment), including time points of 
viral rebound. Additional samples might be selected for analysis if required. Exploratory 
sequencing of other regions of the influenza virus genome may also be performed.

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Phenotyping
9.3.2.
Nasal MT swabs and endotracheal samples collected as described in Section 9.2.1.4 at the time 
points specified in the TIME AND EVENTS SCHEDULES will be used for the analysis of 
phenotypic resistance against pimodivir, and other antivirals if applicable. Phenotypic analysis 
will be performed on all baseline and the last evaluable post-baseline sample (on-treatment), 
including time points of viral rebound. Additional samples might be selected for analysis if 
required.
Details about sample collection, processing, and shipping will be provided in the laboratory 
manual.
9.4.
Pharmacokinetics 
Sparse PK sampling will be performed at the time points specified in the TIME AND EVENTS 
SCHEDULES. 
Evaluations
9.4.1.
Venous blood samples of approximately 1-2 mL per sample will be collected for measurement of 
plasma concentrations of pimodivir. Samples are processed, handled and identified per the 
laboratory manual, which will be provided before the start of the study. The exact dates and 
times of blood sampling and the preceding study drug intake must be recorded in the eCRF 
and/or laboratory requisition form. 
Analytical Procedures
9.4.2.
Plasma samples will be analyzed to determine concentrations of pimodivir using a validated, 
specific, and sensitive liquid chromatography-mass spectrometry/mass spectrometry method by 
or under the supervision of the sponsor.
If required, some plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method. In addition, plasma PK samples may be stored for 
future analysis of protein binding.
Pharmacokinetic Endpoints
9.4.3.
Refer to Section 2.1.2, Endpoints for an overview of study endpoints.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic 
9.4.4.
Evaluations 
The plasma concentration-time data of pimodivir will be analyzed using population PK 
modeling. Typical population values of basic PK parameters (eg, clearance and distribution 
volume) will be estimated together with the inter‑individual variability. Effects of subject 
demographics, laboratory parameter values, and other covariates on the PK of pimodivir will be 
evaluated. The relationship between the PK and PD (clinical outcomes, safety parameters, and 
antiviral activity) after repeated oral administration of pimodivir will be explored. If there is any 

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visual trend in graphical analysis, suitable models will be applied to describe the PK/PD
relationships. The results of the population PK/PD analysis will be reported in a separate report. 
9.5.
Taste and Swallowability
A taste and swallowability questionnaire will be completed by adolescent subjects, within 
approximately 15 minutes after the first and last intake of the pimodivir or placebo tablet to 
evaluate the taste and swallowability (see Attachment 3; not applicable when tablets are 
administered via nasogastric tube). The results of the taste and swallowability questionnaire will 
be filled out on paper and will be transcribed into the eCRF by a member of the study site 
personnel.
9.6.
Safety Evaluations
Details regarding the IDMC are provided in Section 11.13.
Safety and tolerability will be evaluated throughout the study from signing of the ICF/assent 
form onwards until the last study-related activity.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event 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. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the TIME AND EVENTS SCHEDULES.
Adverse Events
9.6.1.
Adverse events (including influenza complications) will be reported by the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's LAR) for the duration of the study. 
Adverse events will be followed by the investigator as specified in Section 12, Adverse Event 
Reporting. Any events 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.
Special attention will be paid to those subjects who discontinue the study or study drug for an 
AE, or who experience an AE of at least grade 3, or an SAE.
Clinical Laboratory Tests
9.6.2.
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis 
will be collected at the time points provided in the TIME AND EVENTS SCHEDULES. The 
investigator must review the laboratory results, document this review, and record any clinically 
relevant changes occurring during the study in the Adverse Event section of the eCRF. The 
laboratory reports must be filed with the source documents.
If feasible, safety blood samples will be collected after fasting for at least 10 hours.

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In case a grade 3 or grade 4 laboratory abnormality occurs (defined in Attachment 1), a 
confirmatory test may be performed, preferably within 48 hours but no later than 72 hours after 
the results have become available.
The following tests will be performed by the central laboratory:

Hematology Panel
-hemoglobin
-WBC differential
-hematocrit
*neutrophils
-RBC count
*lymphocytes
-RBC parameters
*monocytes
*mean corpuscular hemoglobin (MCH)
*eosinophils
*MCH concentration
*basophils
*mean corpuscular volume
-platelet count
-white blood cell (WBC) count 
A WBC evaluation may include any abnormal cells, which will then be reported by the
laboratory. A RBC evaluation may include abnormalities in the RBC count, RBC 
parameters, or RBC morphology, which will then be reported by the laboratory.

Serum Chemistry Panel
-sodium
-uric acid
-potassium
-estimated glomerular filtration rate
-chloride
-calcium
-bicarbonate
-calcium (corrected for albumin)
-blood urea nitrogen (BUN)
-phosphate
-creatinine
-serum albumin
-glucose
-total protein
-aspartate aminotransferase (AST)
-total cholesterol
-ALT
-high-density lipoprotein cholesterol
-gamma-glutamyltransferase
-low-density lipoprotein cholesterol
-total, direct, and indirect bilirubin
-triglycerides
-alkaline phosphatase (ALP)
-magnesium
-creatine phosphokinase (CPK)
-lipase
-lactate dehydrogenase 
-pancreatic amylase

Urinalysis
Dipstick
Sediment (if dipstick result is
-specific gravity
abnormal)
-pH
-RBCs
-glucose
-WBCs
-protein
-epithelial cells
-blood
-crystals
-ketones
-casts
-bilirubin
-bacteria
-urobilinogen
-nitrite

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-leukocyte esterase
In case the dipstick shows 4+ (or >1.0%) proteinuria, a confirmatory test must be performed 
preferably within 48 hours but no later than 72 hours after the results have become available. If 
dipstick result is abnormal, microscopy will be used to measure sediment. Dipstick and 
microscopic testing will be performed by the central lab.

At screening/baseline, Day 3, Day 8 (only in optional treatment extension arm), and at the 
Final Study Visit/Safety Follow-up Visit (Day 28 or Day 33), a urine or serum pregnancy 
test will be performed for female subjects of childbearing potential. The result of a prior 
urine or serum pregnancy test that occurred within 1 calendar day before signing of the 
ICF/assent form can be used in lieu of the baseline requirement.

At screening/baseline, FSH will be tested for female subjects who are amenorrheic for 
12 months or less.
Electrocardiogram (ECG)
9.6.3.
12-lead ECGs will be performed at the time points provided in the TIME AND EVENTS 
SCHEDULES. 
During the collection of ECGs, subjects should be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital signs measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECGs, vital signs, blood draw. An ECG recorded 
within 1 calendar day before signing of the ICF/assent form can be used in lieu of the baseline 
ECG requirement.
Twelve-lead ECGs will be recorded so that the different ECG intervals (PR, QRS, and QT) and 
heart rate will be measured. The QT intervals will be corrected for heart rate according to 
Bazett’s (QTcB) and Fridericia’s (QTcF) QT correction.1,5,14
Clinically relevant abnormalities (as defined in Attachment 4) occurring during the study should 
be recorded in the Adverse Event section of the eCRF.
Vital Signs
9.6.4.
Vital signs (including temperature, pulse rate, respiratory rate, and blood pressure), peripheral 
capillary oxygen saturation, and level of consciousness (ACVPU) will be assessed once at 
screening (before the first dose) and once at the Final Study Visit/Safety Follow-up Visit (Day 
28 or Day 33, if the subject is still hospitalized). During the treatment period, vital signs,
peripheral capillary oxygen saturation, and level of consciousness will be assessed 3 times daily 
until the subject is discharged from the hospital or until Day 14 (or Day 19 if the subject 
participates in the treatment extension phase), whichever comes first: in the morning (prior to 
study drug intake if applicable), approximately half-way in the middle of the day, and in the 
evening (prior to study drug intake if applicable). If the subject is discharged from the hospital, 
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provided in the TIME AND EVENTS SCHEDULES. In case, per standard practice, vital signs 
are measured more frequently than required per protocol, these additional measurements will 
also be recorded in the eCRF. 
During hospitalization and after discharge, temperature will be measured using the local, 
standardized method. The method will also be recorded in the eCRF. Dedicated thermometers 
will be sourced for oral temperature measurement and can be used optionally. 
Blood oxygen saturation will be measured using a standard pulse oximeter. If possible, the same 
type of probe should be used for all subjects enrolled at the site while they are hospitalized. The 
SpO2 should be measured either in a sitting or supine position after 5 minutes of rest in a quiet 
environment. Subjects should be encouraged to sit still during the measurements. Pulse oximetry 
measurements using finger, toe, earlobe or frontal sensors are considered acceptable. If using the 
digits, nail polish should be removed, and warmth and capillary refill should be assessed, since 
adequate arterial pulse strength is necessary for obtaining accurate SpO2 measurements. The 
sensor should not be placed on sites distal to indwelling arterial catheters, blood pressure cuffs, 
or venous engorgement (eg, arteriovenous fistulas, blood transfusions). If supplemental oxygen 
is provided to the subject by either nasal cannula, face mask, or a reservoir system, remove 
supplemental oxygen while the subject is appropriately monitored. Wait for either 5 minutes to 
elapse with oxygen saturation maintained at or above 94%, or until saturation declines to less 
than 94%. (For subjects with known pre-influenza illness SpO2 levels of <94%, the pre-influenza 
SpO2 level should be used as target level instead of 94%). Document those findings, then either 
return to previous level of supplemental oxygen therapy or discontinue therapy. For subjects 
receiving invasive or non-invasive mechanical ventilation, peripheral oxygen saturation should 
be measured with the ventilatory support in place, and it should be recorded that the 
measurement was with supplemental oxygen.
Blood pressure, pulse rate, and respiratory rate measurements should be preceded by at least 
5 minutes of rest in the supine position in a quiet setting without distractions (eg, television, cell 
phones). These measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
The level of consciousness will be measured according to the ACVPU scale (alert, new 
confusion, voice, pain, unresponsive).10

Alert: The subject is fully awake. This subject will have spontaneously opening of the eyes, 
will respond to voice, and will have motor function. 

New confusion: A subject may be alert but confused or disorientated. It is not always 
possible to determine whether the confusion is ‘new’ when a subject presents acutely ill. 
Such a presentation should always be considered to be ‘new’ until confirmed to be 
otherwise. 

Voice: The subject makes some kind of response when you talk to them, which could be in 
any of the 3 component measures of eyes, voice, or motor. The response could be as little as 
a grunt, moan, or slight move of a limb. 

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
Pain: The subject makes a response on any of the 3 component measures on the application 
of pain stimulus, such as a central pain stimulus (sternal rub) or a peripheral stimulus 
(squeezing the fingers). 

Unresponsive: Sometimes seen noted as 'Unconscious'; this outcome is recorded if the 
subject does not give any eye, voice or motor response to voice or pain. 
The NEWS2 will be derived based on vital signs, peripheral capillary oxygen saturation, and 
ACVPU scale at baseline and during hospitalization (Attachment 5).13,17 At baseline, these 
parameters need to be assessed by the investigator in order to calculate the NEWS2 required for 
determination of eligibility. 
Clinically relevant abnormalities (as defined in Attachment 4) occurring during the study should 
be recorded in the Adverse Event section of the eCRF.
Physical Examination 
9.6.5.
To evaluate the subject’s eligibility, a physical examination (including height and [recent] body 
weight measurement, if not already available and if practically feasible) will be performed at 
screening and at the Final Study Visit/Safety Follow-up Visit (Day 28 or Day 33). In addition, a 
symptom-directed physical examination will be performed at the time points provided in the 
TIME AND EVENTS SCHEDULES. 
A physical examination includes a review of the following systems: head/neck/thyroid; eyes; 
ears/nose/throat; respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and 
neurological. Breast, anorectal, and genital examinations will be performed when medically 
indicated.
To obtain the actual body weight, subjects must be weighed lightly clothed. The height should be 
measured barefoot.
Any clinically relevant changes occurring during the study must be recorded in the Adverse 
Event section of the eCRF.
Specific Toxicities
9.6.6.
Diarrhea
Loperamide can be administered.
AST and ALT Elevation 
Subjects should be followed until resolution (return to baseline). A subject's study treatment 
must be discontinued if the subject experiences specific hepatic-related laboratory abnormalities
(refer to Section 10.2).
Clinical Hepatitis 
Subjects taking the study drugs should be monitored for the development of signs and symptoms 
of hepatitis, which include fatigue, malaise, anorexia, nausea, dark urine and clay-colored stools, 

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bilirubinuria, jaundice, liver tenderness, or hepatomegaly, with or without initially abnormal 
serum transaminase levels. 
Subjects with these signs and symptoms must seek medical attention immediately and have 
hepatic parameters assessed. Relevant markers of viral hepatitis should also be assessed.
Subjects reporting AST/ALT elevations or clinical hepatitis should be followed until resolution 
of the AE or toxicity and necessary standard management should be undertaken. 
9.7.
Biomarker Evaluations
Samples for biomarker analysis will only be obtained and used if not restricted by local 
regulations. At the time points specified in the TIME AND EVENTS SCHEDULES, a blood 
sample will be collected for exploratory analyses of biomarkers (host RNA). In addition, 
leftovers from MT nasal swabs or blood samples may be used for other biomarker analyses (eg, 
proteins including cytokines). 
Samples can only be used for research related to safety, PK, and efficacy of the influenza 
treatment, or influenza disease. They may also be used to develop tests/assays related to 
influenza treatment, or influenza disease.
Analyses of biomarkers may be conducted at the sponsor’s discretion and may be reported 
separately from this study.
9.8.
Pharmacogenomics Evaluations
A pharmacogenomic blood sample may be collected for future exploratory pharmacogenomic 
analyses (where local regulations permit). This pharmacogenomic sample collection is optional. 
The sample will be collected only from subjects who consent separately to this component of the 
study. Pharmacogenomic samples will be analyzed if it is hypothesized that this may help 
understand the clinical outcomes. Samples can only be used for research related to safety, PK,
and efficacy of the influenza treatment, or influenza disease. They may also be used to develop 
tests/assays related to influenza treatment, or influenza disease.
Pharmacogenomics analyses may be conducted at the sponsor’s discretion and may be reported 
separately from this study.
9.9.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form. 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) sodium heparin of 10 U/mL and charged with a volume equal to 
the dead space volume of the lock.

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Refer to the TIME AND EVENTS SCHEDULES for the timing and frequency of all sample 
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed treatment 
and has completed the assessments at the Safety Follow-up Visit/Final Study Visit (Day 28 or 
Day 33).
10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. 
A subject's study treatment must be discontinued if:

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 experiences the following laboratory abnormalities:

If baseline AST or ALT within normal range: enzyme activity increases >10x ULN  

If baseline AST or ALT not within normal range: enzyme activity increases 
>10x baseline or >500 U/L (whichever occurs first)

Total bilirubin increases >5x ULN

ALT or AST enzyme activity increases >3x ULN and total bilirubin >2x ULN
If a subject prematurely discontinues study drug treatment, the subject will be asked to continue 
with their remaining study visits and assessment schedule. Subjects who withdraw consent 
during the treatment phase, will be offered an optional Safety Follow-up Visit. The optional 
Safety Follow-up Visit will occur the day of consent withdrawal or the day after and will consist 
of the same assessments as at the Final Study Visit (Day 28 or Day 33), with optional PRO 
completion.
10.3.
Withdrawal From the Study
A subject will be automatically withdrawn from the study for any of the following reasons:

Lost to follow-up.

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
Withdrawal of consent/assent.

Death.
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. No additional subjects will be enrolled for 
subjects who withdraw early. If a subject withdraws from the study before the end of the 
treatment or the follow-up phase, he or she will be offered an optional Safety Follow-up Visit.
The optional Safety Follow-up Visit will occur on the day of withdrawal or on the day after and 
will consist of the same assessments as at the Final Study Visit (Day 28), with optional PRO 
completion.
10.4.
Withdrawal From the Use of Research Samples
A subject who withdraws from the study will have the following options regarding the optional 
pharmacogenomics sample:

The collected sample will be retained and used in accordance with the subject's original 
separate ICF/assent form for optional pharmacogenomic samples.

The subject may withdraw consent/assent for the optional pharmacogenomics sample, in 
which case the sample 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/assent for the optional pharmacogenomics 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/assent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF/assent form.
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, PK and safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan.
The primary analysis will be performed when all randomized subjects have completed the final 
study visit or discontinued earlier.

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11.1.
Analysis Sets
The efficacy endpoints will be analyzed on the Intent-to-Treat-infected (ITT-i) and by 
randomized treatment. The ITT-i set consists of all subjects who were randomized and treated 
and had a confirmed influenza A infection. 
The primary endpoint will also be analyzed on the Per Protocol set, consisting of all subjects in 
the ITT-i set without major protocol deviations that have an effect on efficacy and who were not 
prematurely unblinded during the study.
All safety endpoints will be evaluated on the Safety population, consisting of all subjects who 
received at least one dose of study drug and will be analyzed by treatment arm as treated.
Pharmacokinetic data will be evaluated on subjects in the ITT-i set who received pimodivir. 
Subjects will be excluded from the population PK analysis if their data do not allow for accurate 
assessment of the PK parameters (eg, incomplete administration of the study drug; missing 
information of dosing and sampling times).
11.2.
Subject Information
For all subjects who receive at least 1 dose of study drug descriptive statistics will be provided. 
All demographic characteristics (eg, age, race, ethnicity [if allowed per local regulations], height, 
body weight, body mass index) and other initial subject characteristics (eg, physical examination, 
medical and surgical history, concomitant diseases) will be tabulated and analyzed descriptively
or listed.
11.3.
Sample Size Determination
The study will enroll 600 subjects between the ages of 13 and 85 years, inclusive. Subjects will 
be randomized 1:1 to one of the treatment arms.
The sample size is based on the primary endpoint of the hospital recovery scale at Day 6. Based 
on the proportional odds model and assuming a benefit of approximately 38% reduction of the 
common odds ratio, a total sample size of 600 subjects (randomized 1:1) is required to obtain a 
power of 90%.19 Inclusion of stratification factors would provide some improvement on the 
derived power.
In the sample size calculation, it is assumed that the distribution of subjects treated with placebo
in combination with SOC treatment will be as follows on Day 6:
Not hospitalized: 30%

Non-ICU hospitalization, not requiring supplemental oxygen: 30%

Non-ICU hospitalization, requiring supplemental oxygen: 25%

Admitted to the ICU, not requiring invasive mechanical ventilation: 5%

Requiring invasive mechanical ventilation: 5%

Death: 5%


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This sample size is robust to mild to moderate changes in this distribution.
11.4.
Efficacy Analyses
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment 
arm and stratification factors (baseline NEWS2, type of baseline SOC, and time since onset of 
influenza symptoms). Subgroup analyses will be performed by, but might not be limited to, 
treatment extension, region and age group.
As a confirmatory strategy, to account for multiplicity in the statistical evaluation of the most 
important efficacy endpoints, a combination of hierarchical testing and the Bonferroni-Holm 
testing procedure will be applied to control for the overall Type I error rate at the 5% level
(2-sided). The following endpoints are included in the confirmatory strategy: 
1. Hospital recovery scale at Day 6, ie, primary endpoint
2. Incidence in post-baseline complications
3. Time from start of study drug to hospital discharge
4. Time from ICU admission to ICU discharge
5. Time to return to daily activities
6. Time from start to end of mechanical ventilation
7. Rate of re-hospitalization
First, the primary endpoint will be tested for superiority of pimodivir in combination with SOC 
over placebo in combination with SOC at the 2-sided 5% significance level. If superiority is 
shown on the primary endpoint, then the 2 secondary endpoints indicated by 2. and 3. in the 
sequence above will be tested for superiority using the Bonferroni-Holm testing procedure: the 
smallest p-value from the analysis of these 2 secondary endpoints will be compared to a 
significance level of 0.025 and, if statistically significant (ie, 2-sided p<0.025), then the 2-sided 
p-value for the second endpoint will be compared to a significance level of 0.05. If both 
endpoints show superiority, the same Bonferroni-Holm testing procedure will be applied to the 2 
secondary endpoints indicated by 4. and 5. in the sequence above. If both these endpoints show 
superiority, the secondary endpoint indicated by 6. in the sequence above will be tested at the 2-
sided 5% significance level. If superiority of this sixth endpoint is shown, the seventh and last 
endpoint in the sequence above will be tested at the 2-sided 5% significance level.
For the primary endpoint, the results from the proportional odds model will be used in the 
hypothesis testing. For the secondary endpoints time from start of study drug to hospital 
discharge, time from ICU admission to ICU discharge, time to return to daily activities, and time 
from start to end of mechanical ventilation, the results of the Gehan-Wilcoxon test will be used 
in the hypothesis testing. For incidence in post-baseline complications and rate of 
re-hospitalization the results of the logistic regression will be used.

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Primary Endpoint
The primary efficacy analysis will be based on the ITT-i analysis set and consists of the analysis 
of the hospital recovery scale outcome on Day 6. 
A proportional odds model will be used to analyze the hospital recovery scale, including at a 
minimum treatment and the stratification factors (baseline NEWS2, type of baseline SOC, and 
time since onset of influenza symptoms).
Model assumptions will be assessed by the score test for parallel slopes. In addition, each of 
5 dichotomizations of the hospital recovery scale, ie,

Not hospitalized, vs worse (ie, hospitalized)

Non-ICU hospitalized without supplemental oxygen (or better), vs worse

Non-ICU hospitalized with supplemental oxygen (or better), vs worse

In the ICU without invasive mechanical ventilation (or better), vs worse

Invasive mechanical ventilation (or better), vs worse (ie, died)
will be analyzed using a logistic regression model, including at a minimum treatment, hospital 
recovery scale category at baseline, and strata. The hospital recovery scale will also be analyzed 
using the Van Elteren test with strata defined by the stratification factors.
In case of more than 10% missing data on Day 6, multiple imputation will be employed as 
sensitivity analyses, under the missing-at-random (MAR) assumption and missing-not-at-random 
(NMAR) assumption. For the NMAR assumption, imputation under the MAR assumption will 
be applied, but with a structural shift in hospital recovery scale category of the imputed values, to 
introduce non-ignorable missing patterns:

To reflect missingness patterns as a result of study discontinuation due to a dissatisfying 
treatment effect or safety issues in the placebo treatment group, the following shifts will be 
applied in the placebo treatment group only: 

1 category down, eg, from ‘1. Not hospitalized’ to ‘2. Non-ICU hospitalization, not 
requiring supplemental oxygen’

2 categories down, eg, from ‘1. Not hospitalized’ to ‘3. Non-ICU hospitalization, 
requiring supplemental oxygen’

To reflect missingness patterns as a result of study discontinuation due to a dissatisfying 
treatment effect or safety issues in the pimodivir treatment group, the following shifts will 
be applied in the pimodivir treatment group only: 

1 category down, eg, from ‘1. Not hospitalized’ to ‘2. Non-ICU hospitalization, not 
requiring supplemental oxygen’

2 categories down, eg, from ‘1. Not hospitalized’ to ‘3. Non-ICU hospitalization, 
requiring supplemental oxygen’

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In all cases, ‘6. Death’ will be the worst hospital recovery scale category after imputation and 
structural shift.
Secondary Endpoints
Time from start of study drug to hospital discharge will be analyzed by a stratified Gehan-
Wilcoxon test (using the stratification factors, ie, type of baseline SOC, time of onset of 
symptoms and baseline NEWS2). Kaplan‑Meier curves, overall and by stratum, and a stratified 
log-rank test for time to symptom resolution will also be provided. Additionally, the data will be 
analyzed using an accelerated failure time model. Also, a Cox proportional hazards model will 
be applied. Both models will be adjusted for stratification factors. Time from ICU admission to 
ICU discharge and time from start to end of mechanical ventilation will be analyzed analogously
to that of time from start of study drug to hospital discharge. Time from start of study drug to 
hospital discharge and time from ICU admission to ICU discharge will also be derived based on 
investigator's evaluation of the subjects' clinical status and analyzed analogously.
Total length of hospitalization, total time in ICU, and total time on mechanical ventilation will be 
analyzed by the stratified Wilcoxon Rank-Sum test and using the stratification factors. 
Corresponding 95% CIs will be derived using the Hodges-Lehman approach.
Time to return to daily activities will be assessed once daily by means of the question 'Over the 
past 24 hours, how much has influenza (flu) interfered with your ability to carry out your daily 
activities?' The responses will be dichotomized: 'Not at all' and 'A little bit' will be considered as 
returned to daily activities and 'Somewhat', 'Quite a Bit' and 'Very much' will be considered as 
not having returned to daily activities. The time to return to daily activities will be analyzed 
analogously to that of time from start of study drug to hospital discharge.
To compare the incidence of treatment-emergent complications a logistic regression model will 
be used. Stratification factors will be added to the model. A similar model will be applied for 
all-cause mortality, the incidence of antibiotic treatment, number (proportion) of subjects 
needing extended treatment, number (proportion) of subjects requiring re-hospitalization, and 
number (proportion) of subjects not hospitalized at Day 6. The duration of antibiotic treatment 
will be analyzed analogously to the total length of hospitalization.
Time to viral negativity by qRT-PCR and viral culture will be analyzed analogously to that of 
time from start of study drug to hospital discharge. The viral load over time will be analyzed 
using mixed-effects modeling. Stratification factors will be added to the model and additional 
predictive baseline factors, including but not limited to baseline viral load, baseline resistance 
parameters and influenza A subtype, may be added.
The hospital recovery scale outcome on each separate day from Days 2 to 14 (excluding the 
primary time point) will be analyzed similarly to the primary endpoint. The day with 30% of 
subjects not hospitalized will be identified, and the results on that numeric day (eg, Day 5 or 
Day 6, etc.) will be reported.

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Time to clinical response and time to respiratory response will be analyzed analogously to time 
from start of study drug to hospital discharge. Clinical response is defined as achieving 4 of the 5 
following vital signs resolution criteria, including at least the fever and oxygen saturation 
criteria, maintained for at least 24 hours: 

having no fever (without the use of antipyretics within 8 hours), 

oxygen saturation of at least 94% without oxygen supplementation or return to pre-influenza 
infection oxygen saturation (in patients with a known pre-influenza oxygen saturation level 
<94%), 

improved respiratory status (a respiratory rate ≤24 breaths per min without supplemental 
oxygen or return to pre-influenza infection supplemental oxygen requirement in patients 
with chronic oxygen use), 

heart rate 100 beats per min or lower, 

systolic blood pressure of 90 mmHg or higher without inotropic support given within 2 
hours of assessment.
Respiratory response is defined as achieving the following 2 criteria for at least 24 hours:

improved oxygen saturation of at least 94% without oxygen supplementation (return to 
pre-influenza infection oxygen saturation in patients with a known pre-influenza oxygen 
saturation level <94%) and 

improved respiratory status characterized by a respiratory rate ≤24 breaths per min without 
supplemental oxygen or return to pre-influenza infection supplemental oxygen requirement 
in patients with chronic oxygen use.
Exploratory Endpoint
Data analysis, validation and anchor-based analysis of the influenza symptom diary will be 
defined, analyzed and reported in a separate report.
Other Analyses
Descriptive statistics by day of assessment will be provided for PGIS and PGIC questionnaires. 
The EQ-5D total scores and EQ-5D visual analog scale (VAS) ‘thermometer’ scores will be 
evaluated at each time point.
The PGIS and PGIC questionnaire responses will be used as anchors to perform responder 
analyses for selected PROs.
For the EQ-5D questionnaire a post-hoc analysis plan will be developed when the economic 
model structure is finalized, and results of this analysis will be reported separately.
11.5.
Resistance Analyses
Development of resistance against pimodivir (and other antivirals in the SOC if applicable) will 
be determined by viral sequencing and phenotypic testing. All baseline samples as well as the 

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last evaluable post-baseline samples will be analyzed. Additional genotypic and phenotypic 
testing might be requested by the sponsor virologist.
The presence of baseline polymorphisms potentially affecting virologic response will be 
analyzed. The incidence of emerging mutations as well as changes in drug susceptibility (fold 
change in EC50 value) will be described and compared between treatment arms. Results of 
resistance analysis may be reported in a separate report.
11.6.
Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers 
vary and depend on the different data types of the applied technology platforms, as well as on the 
extent of observed differences between subjects. Analyses will be conducted at the sponsor’s 
discretion and may be reported separately from this study.
11.7.
Pharmacogenomic Analyses
Pharmacogenomic samples may be used for research related to pimodivir or influenza A. They 
may also be used to develop tests/assays related to pimodivir or influenza A. Pharmacogenomic 
research may consist of the analysis of one or more candidate genes or of the analysis of genetic 
markers throughout the genome or analysis of the entire genome (as appropriate) in relation to 
pimodivir clinical endpoints. Results of pharmacogenomic analysis will be reported in a separate 
report.
11.8.
Pharmacokinetic Analyses
Population PK analysis of plasma concentration-time data of pimodivir will be performed using 
nonlinear mixed-effects modeling. Data may be combined with those of other selected studies
(ie, Phase 1 and 2 studies) to support a relevant structural model. Available baseline subject 
characteristics (eg, demographics, body weight, laboratory variables, race, etc.) will be tested as 
potential covariates affecting PK parameters. The results of the population PK analysis will be 
reported in a separate report. 
Data will be listed for all subjects with available plasma concentrations per treatment arm. 
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 dosing and 
sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All subjects and samples excluded from the analysis will be 
clearly documented.
Descriptive statistics, including arithmetic mean, standard deviation (SD), coefficient of 
variation, median, minimum, and maximum will be calculated for all individual derived PK 
parameters (ie, Ctrough, Cmax, tmax, and AUC12h) including exposure information of pimodivir.

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11.9.
Pharmacokinetic/Pharmacodynamic Analyses
The PK/PD relationship of pimodivir exposure (AUC12h, Cmax, or Ctrough) with selected efficacy 
(eg, time from start of study drug to hospital discharge, actual values and change in viral load 
from baseline and in other virologic response parameters) and safety (including AEs and 
laboratory abnormalities) parameters will be explored. If there is any visual trend in graphical 
analysis, suitable models will be applied to describe the exposure-effect relationships. Results of 
PK/PD analyses will be reported in a separate report.
11.10. Taste and Swallowability
Taste and swallowability questionnaire results (collected for adolescents who take pimodivir or 
placebo tablets; not applicable when tablets are administered via nasogastric tube) will be 
summarized per tablet intake (first and last intake of the study drug) by means of frequency 
tabulations. For overall taste, a dichotomization will be made for the overall question, 
categorizing ‘bad’ and ‘almost acceptable’ vs ‘acceptable’ and ‘good’. For swallowability, a 
dichotomization will be made of ‘slightly difficult’ or worse vs ‘neither difficult nor easy’ or 
better. The number of subjects (%) will be presented by category.
11.11. Safety Analyses
Safety will be evaluated by means of AEs, clinical laboratory tests, ECGs, vital signs, peripheral 
capillary oxygen saturation, and (symptom-directed) physical examinations. The safety analysis 
will be performed for each study phase separately (treatment, extended treatment, follow-up, and 
combined).
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are AEs 
with onset after start of study medication or that are a consequence of a pre-existing condition 
that has worsened since baseline. All reported AEs will be included in the analysis. For each AE, 
the percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment. 
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or a 
serious AE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) 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- vs post-treatment 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 

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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 
WHO grading table (see Attachment 1) and in accordance with the normal ranges of the clinical 
laboratory if no gradings are available. Laboratory abnormalities will be tabulated by scheduled 
time point.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline 
values (the predose ECG will be used as baseline) to allow detection of clinically relevant 
changes in individuals.
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be 
calculated at baseline and for observed values and changes from baseline at each scheduled time 
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and QTc interval using the following correction methods: QTcB and QTcF.1,5,7,14
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of subjects with QTc interval >450 milliseconds, 
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of subjects 
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline 
readings will be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
The percentage of subjects with abnormalities will be tabulated by treatment arm as received. 
Vital Signs
Descriptive statistics of temperature, pulse rate, respiratory rate, blood pressure (systolic and 
diastolic) (supine) values, oxygen saturation values, and changes from baseline will be 
summarized at each scheduled time point by treatment group. For oxygen saturation, an 
overview will be presented for the number of subjects that require supplemental oxygen. The 
percentage of subjects with values beyond clinically important limits for pulse and systolic and 
diastolic blood pressure will be summarized (Attachment 4).
For each subject, the NEWS2 will be derived based on the vital signs data, peripheral blood 
oxygen saturation, and ACVPU scale (Attachment 5).13,17 The NEWS2 will be summarized by 
time point and treatment group. Frequency tabulations of the ACVPU score, by time point and 
treatment group will be provided.

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Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be listed.
11.12. Interim Analysis
All interim analyses will be performed by an independent Statistical Support Group (SSG) and 
will be reviewed by the Independent Data Monitoring Committee (IDMC; see Section 11.13). 
Only the IDMC and the SSG will be unblinded to the data. The IDMC will provide 
recommendations to a Sponsor Committee.
An interim analysis will be implemented to assess lack of efficacy in the subgroup with time 
since onset of influenza symptoms between 72 and 96 hours.

In case lack of efficacy is concluded for the subgroup with time since onset of influenza 
symptoms between 72 and 96 hours:

Enrollment in this subgroup will be stopped

Sample size re-estimation will be performed based on the subgroup with time since 
onset of influenza symptoms ≤72 hours and consequently, the sample size of this 
subgroup may be increased. The maximum number of subjects that may be enrolled in 
this subgroup will be approximately 900.

Futility will be assessed in the subgroup with time since onset of influenza symptoms 
≤72 hours based on re-estimated sample size. 

At the final analysis, hypotheses will be evaluated in the subgroup with time since onset 
of influenza symptoms ≤72 hours.

In case no lack of efficacy is concluded for the subgroup with time since onset of influenza 
symptoms between 72 and 96 hours:

The subgroup with time since onset of influenza symptoms between 72 and 96 hours
will be continued in the study.

Sample size re-estimation will be performed based on all subjects. The sample size may 
be increased. The maximum total number of subjects that may be enrolled in the study 
will be approximately 900. The study population should consist of at least 75% of 
subjects with first administration of study drug ≤72 hours since onset of influenza 
symptoms.

Futility will be assessed in all subjects based on re-estimated sample size. 

At the final analysis,  hypotheses will be evaluated in all subjects.
Details on the statistical decision rules will be provided in a separate Modeling and Simulation 
Report. The interim analysis will be conducted at the end of the first influenza season when 
between 300 and 450 subjects have been enrolled or during the season when 450 subjects have 
been enrolled. Further details will be specified in the IDMC charter.

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11.13. Independent Data Monitoring Committee
An IDMC will be established to monitor data on a regular basis. The committee will meet 
periodically to review interim data. After the review, the IDMC will make recommendations 
regarding the continuation of the study. The details will be provided in a separate IDMC charter.
The IDMC will consist of at least 3 members, including one medical expert in the relevant 
therapeutic area and at least one statistician knowledgeable about statistical methods for clinical 
studies and sequential analysis of study data. One of these individuals will chair the Committee. 
The IDMC responsibilities, authorities, and procedures will be documented in its charter.
11.14. Adjudication Committee
A blinded Adjudication Committee (AC) will be established to adjudicate AEs as complications 
based on predefined criteria (pulmonary versus extrapulmonary, major versus minor, as well as 
infectious versus noninfectious complications). The AC will receive data on AEs, including 
medical assessments (eg, chest X-ray results, lab results) and concomitant therapy of cases 
selected from the AEs. Details will be provided in an AC 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.
12.1.
Definitions
Adverse Event Definitions and Classifications
12.1.1.
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/assent form (refer to 
Section 12.3.1, All Adverse Events, for time of last AE recording).

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Serious Adverse Event
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Is a suspected transmission of any infectious agent via a medicinal product.

Is Medically Important*.
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For pimodivir, since no serious ADRs are currently 
identified in the IB, all related SAEs are considered unexpected for reporting purposes. For 
medications part of the SOC treatment, the expectedness of an AE will be determined by whether 
or not it is listed in the manufacturer’s prescribing information.
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, Attribution Definitions.
Attribution Definitions
12.1.2.
Not Related
An AE that is not related to the use of the drug.

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Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
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).
Severity Criteria
12.1.3.
An assessment of severity grade will be made using the general categorical descriptors outlined 
in the WHO Toxicity Grading Scale in Attachment 1.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug.

Suspected abuse/misuse of a sponsor study drug.

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).
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the Serious Adverse Event section of the 
eCRF.

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12.3.
Procedures
All Adverse Events
12.3.1.
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF/assent form is obtained until completion of the subject's last 
study-related procedure, which may include contact for follow-up of safety. Serious AEs, 
including those spontaneously reported to the investigator within 30 days after the last dose of 
study drug, must be reported using the Serious Adverse Event Form. The sponsor will evaluate 
any safety information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol.
All events, including influenza complications, that meet the definition of an SAE will be reported 
as SAEs, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 2.
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. Whenever diarrhea is reported, 
the site will be asked to capture detailed information (eg, frequency, consistency) on the specific 
eCRF diarrhea form.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). The investigator 
(or sponsor where required) must report SUSARs to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB. 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.

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
Subject number.

Any other information that is required to do an emergency breaking of the blind.
Serious Adverse Events
12.3.2.
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor (or designee) through the eCRF, 
which must be completed and confirmed 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 in the 
eCRF. In case eDC is inaccessible, SAE reports (paper form) should be submitted via fax or 
email.
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 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/assent form, 
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.

For convenience, the investigator may choose to hospitalize the subject for the duration of 
the treatment period.
Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms 
of clinical sequelae resulting from disease progression/lack of efficacy will be reported if they 

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fulfill the SAE
definition (refer to
Section 12.1.1, Adverse Event Definitions and 
Classifications).
Pregnancy
12.3.3.
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs 
and must be reported using the Serious Adverse Event Form. Any subject who becomes pregnant 
during the study must discontinue further study treatment. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor.

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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 pimodivir supplied for this study is formulated as: 300-mg tablets for oral administration, 
containing pimodivir, hypromellose, polysorbate 20, crospovidone, silica colloidal anhydrous, 
silicified microcrystalline cellulose, microcrystalline cellulose, pregelatinized starch, sodium 
stearyl fumarate, Opadry II yellow. It will be manufactured and provided under the responsibility 
of the sponsor.
Matching pimodivir placebo tablets will be provided for subjects randomized to the placebo arm.
Placebo tablets will be manufactured and provided under the responsibility of the sponsor.
SOC treatment is determined by the investigator based on local practice, and may include 
influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of
the SOC should be made before randomization. The influenza antiviral should be started no later 
than the day of first study drug intake. An influenza antiviral as part of the SOC cannot be 
changed (eg, switching one influenza antiviral for another) during either the treatment period or 
extension phase, with the exception that an influenza antiviral may be discontinued in the case of 
a suspected AE.
14.2.
Packaging
The investigational supplies will be uniquely packaged in child-resistant blisters to assure that 
they are appropriately managed throughout the supply chain process.
No study drugs can be repacked without prior approval from the sponsor.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.
No study drugs can be relabeled without prior approval of the sponsor.
14.4.
Preparation, Handling, and Storage
All study drug must be stored as specified on the label.
Refer to the pharmacy manual/study site investigational product manual for additional guidance on 
study drug preparation, handling, and storage.

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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 study drug administered to the subject must be 
documented on the drug accountability form. In case subjects are discharged from the hospital 
during the treatment period, 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 LAR where applicable, must be instructed to return all original containers, 
whether empty or containing study drug. All study drug will be stored and disposed of according 
to the sponsor's instructions. Study-site personnel must not combine contents of the study drug 
containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug (and study drug returned by the subject, where 
applicable) 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.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Whenever a subject brings his or her study drug to the study site for pill count, 
this is not seen as a return of supplies. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure of pimodivir.

Pharmacy manual/study site investigational product and procedures manual.

Laboratory manual (including procedures for nasal swabs).

Contact information pages.

ePRO device and user manual.

IWRS Manual.

Electronic data capture (eDC) Manual.

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
Sample ICF/assent form.
16.
ETHICAL ASPECTS
16.1.
Study-specific Design Considerations
Potential subjects or their LAR 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/assent 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. It is anticipated that a number of subjects who 
will be eligible for this study will not be able to give consent due to their medical condition. In 
such cases, and if allowed by local regulatory authorities, IRB/IEC and local laws, consent may be 
obtained from a LAR. 
When referring to the signing of the ICF/assent form, the term LAR refers to the legal 
representative for those incapable of consenting due to their medical condition, or the legally 
appointed guardian of the child with authority to authorize participation in research. For each 
minor subject, his or her parent(s) (preferably both parents, if available) or LAR, as required by 
local regulations, must give written consent/assent (permission) according to local requirements 
after the nature of the study has been fully explained and before the performance of any study-
related assessments. Assent must be obtained from children (minors) capable of understanding the 
nature of the study, depending on the institutional policies. For the purposes of this study, all 
references to subjects who have provided consent/assent (and assent as applicable) refers to the 
subjects and his or her parent(s) or the subject's legal guardian(s) or LAR who have provided 
consent/assent according to this process. Minors who assent to a study and later withdraw that 
assent should not be maintained in the study against their will, even if their parents still want them 
to participate.
The total blood volume to be collected is considered to be within the normal range allowed for this 
subject population over this time frame. 
16.2.
Regulatory Ethics Compliance
Investigator Responsibilities
16.2.1.
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.

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Independent Ethics Committee or Institutional Review Board
16.2.2.
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments.

Sponsor-approved ICFs/assent forms (and any other written materials to be provided to the 
subjects or LAR).

Investigator's Brochure (or equivalent information) and amendments/addenda.

Sponsor-approved subject recruiting materials.

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable.

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB).

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects.

Any other documents that the IEC/IRB requests to fulfill its obligation.
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF/assent form, 
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.
Approval for the collection of optional samples for research and for the corresponding 
ICF/assent form must be obtained from the IEC/IRB. Approval for the protocol can be obtained 
independent of this optional research component. 
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/assent form and any other written materials to be provided to subjects.

If applicable, new or revised subject recruiting materials approved by the sponsor.

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable.

New edition(s) of the IB and amendments/addenda.

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually).

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
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/assent 
form revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion. 
Informed Consent and Assent Form
16.2.3.
Each subject (or a LAR) must give written consent/assent according to local requirements after 
the nature of the study has been fully explained. The ICF(s)/assent form(s) must be signed before 
performance of any study-related activity. The ICF(s) and assent form that is/are used must be 
approved by both the sponsor and by the reviewing IEC/IRB and be in a language that the 
subject can read and understand. The informed consent/assent 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 LAR 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/assent 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/assent form the subject or LAR is authorizing such 
access, which includes permission to obtain information about his or her survival status and 

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agrees to allow his or her study physician to recontact the subject for the purpose of obtaining 
consent/assent for additional safety evaluations, and subsequent disease-related treatments, if 
needed. The physician may also recontact the subject for the purpose of obtaining consent/assent 
to collect information about his or her survival status.
The subject or LAR will be given sufficient time to read the ICF/assent form and the opportunity 
to ask questions. After this explanation and before entry into the study, consent/assent should be 
appropriately recorded by means of either the subject's or his or her LAR's personally dated 
signature. After having obtained the consent/assent, a copy of the ICF must be given to the 
subject.
Subjects will be asked for consent/assent to provide optional samples for research. After 
informed consent/assent for the study is appropriately obtained, the subject or his or her LAR
will be asked to sign and personally date a separate ICF/assent form indicating agreement to 
participate in the optional research component. Refusal to participate in the optional research will 
not result in ineligibility for the study. A copy of this signed ICF/assent form will be given to the 
subject.
If the subject or LAR is unable to read or write, an impartial witness should be present for the 
entire informed consent/assent process (which includes reading and explaining all written 
information) and should personally date and sign the ICF/assent form after the oral 
consent/assent of the subject or LAR is obtained.
Children (minors), subjects who are unable to comprehend the information provided, and 
incapacitated, can be enrolled only after obtaining consent of a LAR. Subjects enrolled in the 
study, based on consent by a LAR, will be required to provide written confirmatory consent/assent 
to continue in the study, as soon as they become capable to do so. In case the subject does not 
consent/assent to continue participation in the study, the subject will be withdrawn from the study 
and the optional withdrawal Safety Follow-up Visit will be offered (refer to Section 10.3). Assent 
must be obtained from children (minors) capable of understanding the nature of the study, 
depending on the institutional policies. Written assent should be obtained from subjects who are 
able to write. A separate assent form written in language the subject can understand should be 
developed for adolescents. After having obtained the assent, a copy of the assent form must be 
given to the subject, and to the subject's parent or if applicable LAR.
Privacy of Personal Data
16.2.4.
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.

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The informed consent/assent obtained from the subject (or his or her LAR) includes explicit 
consent/assent 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/assent 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 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.
Long-term Retention of Samples for Additional Future Research
16.2.5.
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research, if not restricted by local regulations. Samples will only be 
used to understand pimodivir, to understand influenza A infection, to understand differential 
drug responders, and to develop tests/assays related to pimodivir and influenza A infection. The 
research may begin at any time during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent/assent for their samples to 
be stored for research (refer to Section 10.4, Withdrawal From the Use of Samples in Future 
Research.
Country Selection
16.2.6.
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, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 

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amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
Regulatory Approval/Notification
17.2.1.
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.
Required Prestudy Documentation
17.2.2.
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/assent form, 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 Food and Drug Administration 1572), 
if applicable.

Documentation of investigator qualifications (eg, curriculum vitae).

Completed investigator financial disclosure form from the principal investigator, where 
required.

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
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
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent/assent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all AEs and follow-up of AEs; concomitant medication; drug 
receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The following data will be recorded directly into the eCRF and will be considered source data: 

Race.

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
History of smoking.

Blood pressure and pulse/heart rate.

Height and weight.

Details of physical examination.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria (that specify a need for a fully documented medical history) are 
as follows:

Complete history of medical notes at the site.

Discharge summaries.
In case the documented medical history at site is incomplete, medical history must be verified at 
a minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format.
Electronic data capture will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, if applicable. Study-specific data 
will be transmitted in a secure manner within the timeframe agreed upon between the sponsor 
and the study site. The electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. All data relating to the 
study must be recorded in the eCRFs prepared by the sponsor. 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. The investigator must verify that all data entries in the eCRF are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
eCRF must be adjusted (if applicable) and a response provided to the query (complete, sign, and 
date the data clarification form).
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

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
Study-site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel. 
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base, and 
direct transmission of PRO data to the ePRO vendor database and then into the sponsor’s 
database. Written instructions will be provided for collection, handling, storage, and shipment of 
samples. 
Site investigators will receive training on the importance of subjects completing the PROs during 
the study. Subjects will receive a training guide outlining the importance of completing the PROs
on the electronic device. Site investigators will train subjects on how to complete the PROs using 
the subject guide. The ePRO devices will include programmed alarms to remind the subjects to 
complete the PROs within the allowable windows of completion.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Monitoring
The sponsor will use a combination of monitoring techniques 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 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by 
the sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel at the study initiation visit. 
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 study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.

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In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
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, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.9.
Study Completion/Termination
Study Completion/End of Study
17.9.1.
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.
Study Termination
17.9.2.
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.

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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines.

Inadequate recruitment of subjects by the investigator.

Discontinuation of further study drug development.
17.10. On-site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding pimodivir 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/assent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of pimodivir, 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 

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study will be used to determine a coordinating investigator. 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 identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.

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REFERENCES
Available on request
1.
Bazett HC. An analysis of the time-relationship of electrocardiograms. Heart. 1920;7:353-380.
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Centers of Disease Control and Prevention. Antiviral Agents for the Treatment and Chemoprophylaxis of 
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de Jong MD, et al. Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin 
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4.
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, Badia X. Development and 
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5.
Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for 
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Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome 
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International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
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and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
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Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important 
difference. Control Clin Trials. 1989;10(4):407-415.
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JNJ-63623872 Investigator’s Brochure Edition 6.0 (28 July 2017). Janssen Research & Development, a 
division of Janssen Pharmaceutica NV
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McNarry AF, Bateman DN. Simple bedside assessment of level of consciousness: comparison of two simple 
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Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in 
patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual 
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Robinson LD and Jewell NP. Some surprising results about covariate adjustment in logistic regression models. 
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Royal College of Physicians. National Early Warning Score (NEWS2): Standardizing the assessment of acute
illness severity in NHS. Updated Report of a working Party. London: RCP, 2017. 
https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2. Accessed 03 June 2019.
14.
Sagie A, Larson MG, Goldberg RJ, Bengston JR, Levy D. An improved method for adjusting the QT interval 
for heart rate (the Framingham Heart Study). Am J Cardiol. 1992;70:797-801.
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Selecting the Viruses in the Seasonal Influenza (Flu) Vaccine.
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Shrestha SS, Swerdlow DL, Borse RH, et al. Estimating the Burden of 2009 Pandemic Influenza A (H1N1) in 
the United States (April 2009–April 2010). Clin Infect Dis. 2011;52 (Suppl 1):S75-82.
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Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. "The ability of the National Early 
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Webster R, Monto A, Bracaile T, et al. Textbook of influenza. Second Edition. 2013. 
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Whitehead J. Sample size calculations for ordered categorical data, 1993. Statistics in medicine; 12:2257-2271.

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ATTACHMENTS
Attachment 1:
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (Feb 2003)
ABBREVIATIONS (used in the table)
ULN = Upper Limit of Normal
Rx = Therapy
FEV1 = forced expiratory volume in 1 second
LLN = Lower Limit of Normal
IV = Intravenous
ESTIMATING SEVERITY GRADE
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate grade of 
severity:
GRADE 1
Mild
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required.
GRADE 2
Moderate
Mild to moderate limitation in activity; some assistance may be needed; 
no or minimal medical intervention/ therapy required.
GRADE 3
Severe
Marked limitation in activity; some assistance usually required; medical 
intervention/therapy required; hospitalizations possible.
GRADE 4
Potentially life-
threateninga
Extreme limitation in activity; significant assistance required; 
significant medical intervention/therapy required; hospitalization or 
hospice care probable.
a
Revised by the sponsor
COMMENTS REGARDING THE USE OF THESE TABLES

For parameters not included in the following Toxicity Tables, sites should refer to the “Guide For 
Estimating Severity Grade” located above.

Criteria are generally grouped by body system. Some protocols may have additional protocol-
specific grading criteria, which will supersede the use of these tables for specified criteria.


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Item
Grade 1
Grade 2
Grade 3
Grade 4
Hematology
Hemoglobin
9.5-10.5 gm/dL
8.0-9.4 gm/dL
6.5-7.9 gm/dL
<6.5 gm/dL
Absolute Neutrophil 
Count
1,000-1,500/mm³
750-999/mm³
500-749/mm³
<500/mm³
Platelets
75,000-99,000/mm³
50,000-74,999/mm³
20,000-49,999/mm³
<20,000/mm³
Prothrombin Time 
(PT)
≥1.01 to ≤1.25 x 
ULN
>1.25 to ≤1.50 x 
ULN
>1.50 to ≤3.00 x 
ULN
>3.00 x ULN
Activated Partial 
Thromboplastin 
Time (aPTT)
≥1.01 to ≤1.66 x 
ULN
>1.66 to ≤2.33 x 
ULN
>2.33 to ≤3.00 x 
ULN
>3.00 x ULN
Fibrinogen
≥0.75 to ≤0.99 x 
LLN
≥0.50 to <0.75 x LLN
≥0.25 to <0.50 x 
LLN
<0.25 x LLN
Fibrin Split Product
20-40 mcg/mL
41-50 mcg/mL
51-60 mcg/mL
>60 mcg/mL
Methemoglobin
5.0-9.9%
10.0-14.9%
15.0-19.9%
>20.0%
Liver Enzymes
AST (SGOT)
≥1.25 to ≤2.50 x 
ULN
>2.50 to ≤5.00 x 
ULN
>5.00 to ≤10.00 x 
ULN
>10.00 x ULN
ALT (SGPT)
≥1.25 to ≤2.50 x 
ULN
>2.50 to ≤5.00 x 
ULN
>5.00 to ≤10.00 x 
ULN
>10.00 x ULN
GGT
≥1.25 to ≤2.50 x 
ULN
>2.50 to ≤5.00 x 
ULN
>5.00 to ≤10.00 x 
ULN
>10.00 x ULN
Alkaline 
Phosphatase
≥1.25 to ≤2.50 x 
ULN
>2.50 to ≤5.00 x 
ULN
>5.00 to ≤10.00 x 
ULN
>10.00 x ULN
Amylase
≥1.1 to ≤1.5 x ULN
>1.5 to ≤2.0 x ULN
>2.0 to ≤5.0 x ULN
>5.0 x ULN
Chemistries
Hyponatremia
130-135 mEq/L
123-129 mEq/L
116-122 mEq/L
<116 mEq/L or 
mental status 
changes or 
seizures
Hypernatremia
146-150 mEq/L
151-157 mEq/L
158-165 mEq/L
>165 mEq/L or 
mental status 
changes or 
seizures
Hypokalemia
3.0-3.4 mEq/L
2.5-2.9 mEq/L
2.0-2.4 mEq/L or 
intensive 
replacement Rx 
required or 
hospitalization 
required
<2.0 mEq/L or 
paresis or ileus or 
life-threatening 
arrhythmia
Hyperkalemia
5.6-6.0 mEq/L
6.1-6.5 mEq/L
6.6-7.0 mEq/L
>7.0 mEq/L or 
life-threatening 
arrhythmia
Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
<30 mg/dL or 
mental status 
changes or coma
Hyperglycemia 
(note if fasting)
116-160 mg/dL
161-250 mg/dL
251-500 mg/dL
>500 mg/dL or 
ketoacidosis or 
seizures
Hypocalcemia 
(corrected for 
albumin)
8.4-7.8 mg/dL
7.7-7.0 mg/dL
6.9-6.1 mg/dL
<6.1 mg/dL or 
life-threatening 
arrhythmia or 
tetany

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Item
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia 
(corrected for 
albumin)
10.6-11.5 mg/dL
11.6-12.5 mg/dL
12.6-13.5 mg/dL
>13.5 mg/dL or 
life-threatening 
arrhythmia
Hypomagnesemia
1.4-1.2 mEq/L
1.1-0.9 mEq/L
0.8-0.6 mEq/L
<0.6 mEq/L or 
life-threatening 
arrhythmia
Hypophosphatemia
2.0-2.4 mg/dL
1.5-1.9 mg/dL or 
replacement Rx 
required
1.0-1.4 mg/dL 
intensive Rx or 
hospitalization 
required
<1.0 mg/dL or 
life-threatening 
arrhythmia
Hyperbilirubinemia
≥1.1 to ≤1.5 x ULN
>1.5 to ≤2.5 x ULN
>2.5 to ≤5.0 x ULN
>5.0 x ULN
BUN
≥1.25 to ≤2.50 x 
ULN
>2.50 to ≤5.00 x 
ULN
>5.00 to ≤10.00 x 
ULN
>10.00 x ULN
CPK*
3 to <6 x ULN
6 to <10 x ULN
10 to <20 x ULN
≥20 x ULN
Creatinine
≥1.1 to ≤1.5 x ULN
>1.5 to ≤3.0 x ULN
>3.0 to ≤6.0 x ULN
>6.0 x ULN or 
required dialysis
Lipase*
1.1 to <1.5 x ULN 
1.5 to <3.0 x ULN
3.0 to <5.0 x ULN
≥5.0 x ULN
Urinalysis
Proteinuria
1+ or <0.3% or 
<3g/L or 
200 mg – 1 gm 
loss/day
2-3+ or 0.3-1.0% or 
3-10 g/L or 
1-2 gm loss/day
4+ or >1.0% or 
>10 g/L or 
2-3.5 gm loss/day
nephrotic 
syndrome or 
>3.5 gm loss/day
Hematuria
microscopic only
gross, no clots
gross + clots
obstructive or 
required 
transfusion
Cardiac Dysfunction
Cardiac Rhythm
-
asymptomatic, 
transient signs, no 
Rx required
recurrent/persistent; 
no Rx required
requires Rx
Hypertension
transient inc. 
>20 mm; no Rx
recurrent, chronic, 
>20 mm, Rx 
required
requires acute Rx; no 
hospitalization
requires 
hospitalization
Hypotension
transient orthostatic 
hypotension, no Rx
symptoms 
correctable with oral 
fluids Rx
requires IV fluids; no 
hospitalization 
required
requires 
hospitalization
Pericarditis
minimal effusion
mild/moderate 
asymptomatic 
effusion, no Rx
symptomatic 
effusion; pain; ECG 
changes
tamponade; 
pericardiocentesis 
or surgery 
required
Hemorrhage, Blood 
Loss
microscopic/occult
mild, no transfusion
gross blood loss; 
1-2 units transfused
massive blood 
loss; >3 units 
transfused
* Grading based on Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, version 2.0, November 2014.

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Item
Grade 1
Grade 2
Grade 3
Grade 4
Respiratory
Cough
transient; no Rx
treatment associated 
cough; local Rx
uncontrolled
-
Bronchospasm, 
Acute
transient; no Rx 
<80-70% FEV1
(or peak flow)
requires Rx 
normalizes with 
bronchodilator; 
FEV1 50-70% (or 
peak flow)
no normalization 
with bronchodilator; 
FEV1 25-50% (or 
peak flow 
retractions)
cyanosis: FEV1
<25% (or peak 
flow) or intubated
Gastrointestinal
Stomatitis
mild discomfort; no 
limits on activity
some limits on 
eating/drinking
eating/talking very 
limited
requires IV fluids
Nausea
mild discomfort; 
maintains 
reasonable intake
moderate discomfort; 
intake decreased 
significantly; some 
activity limited
severe discomfort; 
no significant intake; 
activities limited
minimal fluid 
intake
Vomiting
transient emesis
occasional/moderate 
vomiting
orthostatic 
hypotension or IV 
fluids required
hypotensive 
shock or 
hospitalization 
required for IV 
fluid therapy
Constipation
mild
moderate
severe
distensions 
w/vomiting
Diarrhea
transient 3-4 loose 
stools/day
5-7 loose stools/day
orthostatic 
hypotension or 
>7 loose stools/day 
or required IV fluids
hypotensive 
shock or 
hospitalization 
for IV fluid 
therapy required
Neuro & Neuromuscular
Neuro-Cerebellar
slight incoordination 
dysdiadochokinesis
intention tremor, 
dysmetria, slurred 
speech; nystagmus
locomotor ataxia
incapacitated
Mood
mild anxiety or 
depression
moderate anxiety or 
depression and Rx 
required
severe anxiety or 
depression or mania; 
needs assistance
acute psychosis; 
incapacitated, 
requires 
hospitalization
Neuro Control 
(ADL = activities of 
daily living)
mild difficulty 
concentrating; no 
Rx; mild 
confusion/agitation; 
ADL unaffected
moderate 
confusion/agitation 
some limitation of 
ADL; minimal Rx
severe 
confusion/agitation 
needs assistance for 
ADL; Rx required
toxic psychosis; 
hospitalization
Muscle Strength
subjective weakness 
no objective 
symptoms/ signs
mild objective 
signs/symptoms no 
decrease in function
objective weakness 
function limited
paralysis

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Item
Grade 1
Grade 2
Grade 3
Grade 4
Other Parameters
Fever: oral, 
>12 hours
37.7-38.5 °C or 
100.0-101.5 °F
38.6-39.5 °C or 
101.6-102.9 °F
39.6-40.5 °C or 
103-105 °F
>40 °C or 
>105 °F
Headache
mild, no Rx 
transient, moderate; 
Rx required
severe; responds to 
initial narcotic 
therapy
intractable; 
required repeated 
narcotic therapy
Fatigue
no decrease in ADL
normal activity 
decreased 25-50%
normal activity 
decreased >50% 
can’t work
unable to care for 
self
Allergic Reaction
pruritus without 
rash
localized urticaria
generalized urticaria; 
angioedema
anaphylaxis
Local Reaction
tenderness or 
erythema
induration <10 cm or 
phlebitis or 
inflammation
induration >10 cm or 
ulceration
necrosis
Mucocutaneous
Erythema; pruritus
diffuse, 
maculopapular rash, 
dry desquamation
vesiculation, moist 
desquamation, or 
ulceration
exfoliative 
dermatitis, 
mucous 
membrane 
involvement, or 
erythema 
multiforme or 
suspected 
Stevens-Johnson 
or necrosis 
requiring surgery

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Attachment 2:
Anticipated Events
Anticipated Event
An anticipated event is an AE (serious or non-serious) that commonly occurs as a consequence of the 
underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events: 

Pneumonia

Bronchitis

Sinus infection

Ear infection

Worsening of asthma, asthma attack

Chronic obstructive pulmonary disease exacerbation

Complications of sickle cell disease, sickle cell crisis

Complications of diabetes mellitus, diabetic ketoacidosis

Acute respiratory distress syndrome 
Reporting of Anticipated Events
These events will be captured on the eCRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All Adverse Events. Any event that meets SAE criteria will be reported to the 
sponsor within the appropriate timeline as described in Section 12.3.2, Serious Adverse Events. These 
anticipated events are exempt from expedited reporting as individual single cases to Health Authorities. 
However, if based on an aggregate review, it is determined that an anticipated event is possibly related to 
study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
In this study, the IDMC will perform the role of an Anticipated Event Review Committee (ARC) and will 
conduct reviews of pre-specified anticipated events at an aggregate level. The IDMC will provide the 
recommendation to the Sponsor Committee as to whether there is a reasonable possibility that an 
anticipated event is related to the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan.

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Attachment 3:
Taste/Swallowability Questionnaire
The taste and swallowability questionnaire should be completed within approximately 15 minutes after 
the first and last intake of the study drug (consequently, the questionnaire should be completed 2 times 
in total by the subject).
Date (DD/MM/YYYY): ___________________
Subject Clinical Trial ID number: _________________
Questionnaire completion time (24-hours formatinsert a time between 00:00 and 23:59): 
______:_____
Questions:
1.
How did you take the study drug? (Put a cross in the box beneath your appreciation)
A. I swallowed the tablets whole
B. The tablets were dispersed in water (only 
applicable at the hospital)
If you have answered A, please answer the following questions:
2.
Taste (Put a cross in the box beneath your appreciation)
Sweetness
None
Weak
Moderate
Strong
Bitterness
None
Weak
Moderate
Strong
Flavour
None
Weak
Moderate
Strong

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Overall
None
Weak
Moderate
Strong
3.
Swallowability: 
On a scale of 1-7, how difficult/easy was it to swallow the tablet? (Circle the number corresponding to 
your appreciation)  
1. Very difficult
2. Moderately difficult
3. Slightly difficult
4. Neither difficult nor easy
5. Slightly easy
6. Moderately easy
7. Very easy

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Attachment 4:
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 (see also Attachment 1).

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Attachment 5:
National Early Warning Score (NEWS) 2: Scoring System
Level of consciousness is assessed using the Alert New confusion Voice Pain Unresponsive (ACVPU) 
scale, which assesses five possible outcomes to measure and record a patient’s level of consciousness. 
The assessment is done in sequence and only one outcome is recorded. For example, if the patient 
responds to voice, it is not necessary to assess the response to pain.

Alert (A): a fully awake patient. Such patients will have spontaneous opening of the eyes, will 
respond to voice and will have motor function.

New confusion (C): A patient may be alert but confused or disorientated. It is not always possible to 
determine whether the confusion is ‘new’ when a patient presents acutely ill. Such a presentation 
should always be considered to be ‘new’ until confirmed to be otherwise. New-onset or worsening 
confusion, delirium or any other altered mentation should always prompt concern about potentially 
serious underlying causes and warrants urgent clinical evaluation.

Voice (V): the patient makes some kind of response when you talk to them, which could be in any of 
the three component measures of eyes, voice or motor – eg patient’s eyes open on being asked, ‘Are 
you okay?’. The response could be as little as a grunt, moan, or slight movement of a limb when 
prompted by voice.

Pain (P): the patient makes a response to a pain stimulus. A patient who is not alert and who has not 
responded to voice (hence having the test performed on them) is likely to exhibit only withdrawal 
from pain, or even involuntary flexion or extension of the limbs from the pain stimulus. The person 
undertaking the assessment should always exercise care and be suitably trained when using a pain 
stimulus as a method of assessing levels of consciousness.

Unresponsive (U): this is also commonly referred to as ‘unconscious’. This outcome is recorded if 
the patient does not give any eye, voice or motor response to voice or pain.

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Each of the physiological parameters and the supplemental use of oxygen should be allocated a score 
reflecting the magnitude of disturbance/use of supplemental oxygen. The individual scores should then be 
combined to derive the aggregate NEWS2 for the patient.
For more information, see reference13.

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Attachment 6:
Influenza Symptom Diary
1.
Please select the number that describes your cough at its worst in the past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
       No                                                                                                                                                                         
Cough as bad as
    Cough                                                                                                   
                                    you can imagine
2.
Please select the number that describes your trouble breathing at its worst in the past 
12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
        No                                                                                                                                                                          Trouble breathing as bad
Trouble Breathing                                                                                                   
                  as you can imagine
3.
Please select the number that describes your body aches at their worst in the past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8             9            10
        No                                                                                                                                                                                  Body aches as bad
Body Aches                                                                                                   
                               as you can imagine

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4.
Please select the number that describes your fatigue (tiredness, weariness) at its worst in the 
past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
        No                                                                                                                                                                                  Fatigue as bad
Fatigue                                                                                                   
                               as you can imagine
5.
Please select the number that describes your headache at its worst in the past 12 hours.
|______|______|______|______|______|______|______|______|______|______|
0             1             2             3             4             5             6             7             8            9            10
No                                                                                                                                                                                  Headache as bad
Headache                                                                                                   
                         as you can imagine
6.
Please select the number that describes your sweating at its worst in the past 12 hours.
           
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
No                                                                                                                                                                                  Sweating as bad
Sweating                                                                                                  
                        as you can imagine
7.
Please select the number that describes your nasal congestion at its worst in the past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8             9            10
No                                                                                                                                                                                   Nasal congestion as bad
Nasal Congestion                                                                                                   
         as you can imagine

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8.
Please select the number that describes your sore throat at its worst in the past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
No                                                                                                                                                                                  Sore throat as bad
Sore Throat                                                                                                  
                         as you can imagine
9.
Please select the number that describes your chills at their worst in the past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
No                                                                                                                                                                                  Chills as bad
Chills                                                                                                   
                        as you can imagine
10.
Please select the number that describes your runny nose at its worst in the past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
No                                                                                                                                                                                  Runny nose as bad
Runny Nose                                                                                                   
       as you can imagine
11.
Please select the number that describes your nausea at its worst in the past 12 hours.
        |______|______|______|______|______|______|______|______|______|______|
        0             1             2             3             4             5             6             7             8            9            10
No                                                                                                                                                                                  Nausea as bad
Nausea                                                                                                   
                        as you can imagine

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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Lorant Leopold, MD
Institution:
Janssen Research & Development
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.

 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lorant Leopold
11Jun2019, 20:25:45 PM, UTC
Document Approval