Conditions: Influenza A
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 334
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the clinical and virologic benefit of pimodivir in combination with Standard-of-Care (SOC) treatment compared to placebo in combination with SOC treatment.

Detailed description:
This double-blind (neither researchers nor participants know what treatment participant is receiving) study will evaluate efficacy/safety of pimodivir in combination with SOC treatment versus placebo in combination with SOC treatment in adolescent, adult, and elderly hospitalized participants with influenza A infection. The study will be conducted in 3 phases: screening phase, double-blind treatment period of 5 days (with the possibility to extend treatment period by 5 days for participants who will enter an optional double-blind extension treatment arm), and post treatment follow-up period of 23 days. Study evaluations will include efficacy, pharmacokinetic, biomarkers, safety and tolerability. The duration of participation in study for each participant is 28 days, except for participants receiving extended treatment, for whom study duration will be up to 33 days.

Arms:
arm 1: Participants will receive pimodivir 600 milligram (mg) orally twice daily for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of pimodivir on Day 1 \[evening\], dosing will continue until the morning of Day 6) along with SOC treatment. Participants who meet all treatment extension criteria as defined in the protocol may receive an additional 5 day course of same treatment as received at study start. The SOC treatment is determined by investigator based on local practice, may include influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of SOC should be started no later than the day when participants initially receive pimodivir. An influenza antiviral as part of SOC cannot be changed (example, switching one influenza antiviral for another) during either treatment period or extension phase, with the exception that an influenza antiviral may be discontinued in case of suspected adverse event (AE). arm 2: Participants will receive placebo matching to pimodivir orally twice daily for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of placebo on Day 1 \[evening\], dosing will continue until morning of Day 6) along with SOC treatment. Participants who meet all treatment extension criteria as defined in protocol may receive an additional 5 day course of same treatment as received at study start. The SOC treatment determined by investigator based on local practice, 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 day of first study drug intake. An influenza antiviral as part of the SOC cannot be changed (for example, switching one influenza antiviral for another) during either treatment period/extension phase, with the exception that an influenza antiviral may be discontinued in case of a suspected AE.

Interventions: intervention 1: Pimodivir 600 mg intervention 2: Placebo intervention 3: SOC Treatment
Intervention descriptions: intervention 1: Participants will receive pimodivir 600 mg orally twice daily for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of pimodivir on Day 1 \[evening\], dosing will continue until the morning of Day 6). Participants who meet treatment extension criteria may receive an additional 5 day course of the same treatment as received at study start (on Days 6 through 10). intervention 2: Participants will receive placebo matching to pimodivir, orally twice daily for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of placebo on Day 1 \[evening\], dosing will continue until the morning of Day 6). Participants who meet treatment extension criteria may receive an additional 5 day course of the same treatment as received at study start (on Days 6 through 10). intervention 3: Participants may receive SOC treatment as a part of background therapy. 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 started no later than the day when participants initially receive pimodivir. An influenza antiviral as part of the SOC cannot be changed (for example, 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.

Protocol document:
Prot_000.pdf: 
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.


JNJ-63623872-ZCD Pimodivir 
Clinical Protocol 63623872FLZ3001 Amendment 2
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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


JNJ-63623872-ZCD Pimodivir 
Clinical Protocol 63623872FLZ3001 Amendment 2
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Approved, Date: 11 June 2019
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.


JNJ-63623872-ZCD Pimodivir 
Clinical Protocol 63623872FLZ3001 Amendment 2
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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)


JNJ-63623872-ZCD Pimodivir 
Clinical Protocol 63623872FLZ3001 Amendment 2
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Approved, Date: 11 June 2019
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.


JNJ-63623872-ZCD Pimodivir 
Clinical Protocol 63623872FLZ3001 Amendment 2
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Approved, Date: 11 June 2019
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


JNJ-63623872-ZCD Pimodivir 
Clinical Protocol 63623872FLZ3001 Amendment 2
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Approved, Date: 11 June 2019
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.


JNJ-63623872-ZCD Pimodivir 
Clinical Protocol 63623872FLZ3001 Amendment 2
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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, 
vital signs and peripheral capillary oxygen saturation will be measured at the time points 


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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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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


JNJ-63623872-ZCD Pimodivir 
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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

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Approved, Date: 1 July 2020
Janssen Research & Development *
Statistical Analysis Plan
Amendment 1
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 
JNJ-63623872-ZCD  (Pimodivir)
Status:
Approved
Date:
1 July 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV 
Document No.: EDMS-ERI-149599549, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the 
Company customarily holds close and treats as confidential. The information is being provided under the 
assurance that the recipient will maintain the confidentiality of the information under applicable statutes, 
regulations, rules, protective orders or otherwise.
NCT03376321


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 9
1.
INTRODUCTION................................................................................................................................ 11
1.1.
Trial Objectives .............................................................................................................................. 11
1.2.
Trial Design .................................................................................................................................... 12
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 13
1.4.
Sample Size Justification ............................................................................................................... 13
1.5.
Randomization and Blinding .......................................................................................................... 13
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 15
2.1.
Visit Windows, Phase Definitions and Baseline............................................................................. 15
2.1.1.
Phase Definitions........................................................................................................................ 15
2.1.2.
Analysis Visits............................................................................................................................. 16
2.1.3.
Analysis Timepoints.................................................................................................................... 17
2.1.4.
Use of Records per Analysis Visit and Timepoint ...................................................................... 17
2.1.5.
Unscheduled Assessments ........................................................................................................ 18
2.2.
Analysis Sets.................................................................................................................................. 18
2.2.1.
All Randomized Analysis Sets.................................................................................................... 18
2.2.1.1.
All Randomized Analysis Set (RAND)..................................................................................... 18
2.2.1.2.
Randomized and/or Treated Analysis Set (RT)....................................................................... 18
2.2.2.
Efficacy Analysis Sets................................................................................................................. 18
2.2.2.1.
Intent-To-Treat infected (ITT-i) set .......................................................................................... 19
2.2.2.2.
Per Protocol Set (PP) .............................................................................................................. 19
2.2.2.3.
Intent-To-Treat non-infected (ITT-ni) Set ................................................................................ 20
2.2.3.
Safety Analysis Set..................................................................................................................... 21
2.2.3.1.
Safety Set or All Subjects Treated (AST)................................................................................ 21
2.2.4.
Pharmacokinetics (PK) Analysis Set .......................................................................................... 21
2.2.5.
Pharmacodynamics (PD) Analysis Set....................................................................................... 21
2.3.
Definition of Subgroups.................................................................................................................. 21
2.4.
Study Day and Relative Day .......................................................................................................... 24
2.5.
Baseline and Endpoint ................................................................................................................... 24
2.6.
Other Definitions ............................................................................................................................ 25
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 25
3.1.
Interim Analyses............................................................................................................................. 25
3.2.
Independent Data Monitoring Committee ...................................................................................... 26
4.
SUBJECT INFORMATION................................................................................................................ 27
4.1.
Demographics and Baseline Characteristics ................................................................................. 27
4.2.
Disposition Information................................................................................................................... 29
4.3.
Treatment Compliance................................................................................................................... 29
4.4.
Extent of Exposure......................................................................................................................... 30
4.5.
Protocol Deviations ........................................................................................................................ 30
4.6.
Prior and Concomitant Medications ............................................................................................... 30
4.7.
Medical history ............................................................................................................................... 31
5.
EFFICACY ......................................................................................................................................... 33
5.1.
Analysis Specifications................................................................................................................... 33
5.1.1.
Level of Significance................................................................................................................... 33
5.1.2.
Statistical Methodology for Evaluation at the Final Analysis ...................................................... 35


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5.1.3.
Data Handling Rules................................................................................................................... 36
5.1.4.
Stratification Factors................................................................................................................... 37
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 37
5.2.1.
Definition..................................................................................................................................... 37
5.2.2.
Estimand..................................................................................................................................... 40
5.2.3.
Analysis Methods........................................................................................................................ 40
5.3.
Major Secondary Endpoints........................................................................................................... 42
5.3.1.
Definition..................................................................................................................................... 42
5.3.1.1.
Clinical Outcome ..................................................................................................................... 43
5.3.1.2.
Viral kinetics............................................................................................................................. 52
5.3.1.3.
Patient Reported Outcomes .................................................................................................... 55
5.3.2.
Analysis Methods........................................................................................................................ 58
5.3.2.1.
Clinical outcome ...................................................................................................................... 59
5.3.2.2.
Viral Kinetics............................................................................................................................ 60
5.3.2.3.
Patient Reported Outcomes .................................................................................................... 61
6.
TASTE AND SWALLOWABILITY .................................................................................................... 62
6.1.
Definition ........................................................................................................................................ 62
6.2.
Analysis Methods ........................................................................................................................... 62
7.
SAFETY............................................................................................................................................. 63
7.1.
Adverse Events .............................................................................................................................. 63
7.1.1.
Definitions ................................................................................................................................... 63
7.1.2.
Analysis Methods........................................................................................................................ 65
7.2.
Clinical Laboratory Tests................................................................................................................ 68
7.2.1.
Definitions ................................................................................................................................... 68
7.2.2.
Analysis Methods........................................................................................................................ 69
7.3.
Vital signs....................................................................................................................................... 70
7.3.1.
Definitions ................................................................................................................................... 70
7.3.2.
Analysis Methods........................................................................................................................ 70
7.4.
Physical examinations.................................................................................................................... 70
7.5.
Electrocardiogram.......................................................................................................................... 71
7.5.1.
Definitions ................................................................................................................................... 71
7.5.2.
Analysis Methods........................................................................................................................ 71
7.6.
National Early Warning Score........................................................................................................ 72
7.6.1.
Definitions ................................................................................................................................... 72
7.6.2.
Analysis Methods........................................................................................................................ 74
8.
RESISTANCE.................................................................................................................................... 75
8.1.
Viral Phenotype.............................................................................................................................. 75
8.2.
Viral Genotype ............................................................................................................................... 75
9.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 76
9.1.
Pharmacokinetics........................................................................................................................... 76
9.2.
Pharmacokinetic/Pharmacodynamic Relationships....................................................................... 76
10.
HEALTH ECONOMICS ..................................................................................................................... 78
10.1.
Definitions ...................................................................................................................................... 78
10.2.
Analysis Methods ........................................................................................................................... 78
REFERENCES............................................................................................................................................ 79
ATTACHMENTS......................................................................................................................................... 80
ATTACHMENT 1.
: ANTICIPATED EVENTS AND ANTICIPATED EVENT GROUPS ......................... 80
ATTACHMENT 2.
: WHO TOXICITY GRADING SCALE FOR DETERMINING THE SEVERITY 
OF ADVERSE EVENTS (FEB 2003)................................................................................................. 83


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ATTACHMENT 3.
: WHO GRADING SCALE VITAL SIGNS ................................................................. 90
ATTACHMENT 4.
: ECG ABNORMALITIES.......................................................................................... 91
ATTACHMENT 5.
: EQ-5D VALUATION INDEX.................................................................................... 92
ATTACHMENT 6.
: HRS DERIVATION ................................................................................................ 110


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AMENDMENT HISTORY
Amendment 1 (1 July 2020)
The overall reason for the amendment: The overall reason for the amendment is to make general 
updates to the text including minor grammatical, formatting, or spelling changes throughout the 
SAP for clarification purposes and to align with protocol amendment 2. A new section is added: 
to include analysis of pharmacokinetic parameters and pharmacodynamic analyses. Three new 
subgroups were added namely influenza season, study period (before interim, after interim) and 
COVID-19 impacted (Yes/No). To assess the impact of COVID-19, several tables and listings are 
added presenting the COVID-19 impacted subjects separately. Two new secondary endpoints 
based on a clinically relevant change from baseline in EQ-5D VAS are included.  A new endpoint 
related to the HRS is added: the fundamental hospital recovery scale, reflecting the actual 
location/situation, which will be analysed each day from Day 2 to 14. Additionally, the following 
four new secondary endpoints were also added: time to NEWS2 ≤ 2, time to clinical improvement, 
time to clinical failure and incidence of mortality per day. 
The table below gives an overview of the changes in all applicable sections
Summary of changes: An additional analysis set was defined for the analysis of the primary 
endpoint and the six most important secondary endpoints. Additional analysis sets were defined 
for the pharmacodynamic analyses and the analysis of pharmacokinetics parameters. The 
criterion: “Subjects did not switch to another influenza antiviral as a part of the SOC during the 
treatment period” was added and the criterion: “subjects that did not use a concomitant 
medication that may have affected the efficacy of the study drug” was removed from the 
definition of the per protocol analysis set. The in- and exclusion criteria needed to define the per 
protocol analysis set are updated and added.
2.2.2 Efficacy Analysis Sets
2.2.2.2 Per Protocol Set (PP)
2.2.2.3 Intent-To-Treat non-infected (ITT-ni) Set
2.2.4 Pharmacokinetics Analysis Set
2.2.5 Pharmacodynamics Analysis Set
Summary of changes: Baseline resistance categories were defined based on influenza 
polymerase basic protein 2 genotype and phenotype. General re-formatting to assist readability 
of the section. The subgroups influenza season, study period (pre- and post-interim) and 
COVID-19 impacted (yes/no) are added.
2.3 Definition of Subgroups
Summary of changes: Detailing the definition of baseline ECG measurement was added. The 
baseline HRS is clarified. The last study visits for vital signs, NEWS2, ECG and central 
laboratory parameters are also defined.
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Summary of changes: A new section (2.6) was added to describe details of the analysis to 
support marketing authorization approval by FDA and EMA where a subset of patients is used 
with oseltamivir use as part of their SOC treatment and to include text to allow for potential 
analyses for other regions or countries 
2.6 Other Definitions
Summary of changes: The number of subjects impacted by COVID-19 are added in the 
disposition table per analysis set. The table showing the number of subjects that discontinued is 
extended to show the number of subjects that discontinued due to COVID-19. Missed visits or 
changed visits due to COVID will also be presented. A listing showing the exposure to study 
drug for subjects impacted by COVID-19 is added. Major and minor protocol deviations related
to COVID-19 are included. Concomitant therapy that was taken for COVID-19 infection are 
presented in an additional table. 
4 SUBJECT INFORMATION
4.1 Demographics and Baseline Characteristics
4.2 Disposition Information
4.4 Extent of Exposure
4.5 Protocol Deviations
4.6 Prior and Concomitant Medications
Summary of changes: A new section (5.1.3) was added to describe how the actual values of 
the stratification factors are derived.
5.1.3 Stratification Factors
Summary of changes: The text describing the estimand is updated to align with the ICH E9 
addendum guidance and to include MI methods for missing HRS values due to COVID-19 and 
not due to COVID-19
5.2.2 Estimand
Summary of changes: the multiple imputation methods are applied on the missing HRS values 
at day 6 due to COVID-19 and to missing HRS values on day 6 not due to COVID-19 in case 
the prevalence is more then > 5%. A table is added to show the number (%) missing HRS values 
on day 6 by reason of missing.
5.2.3 Analysis Methods
Summary of changes: The fundamental hospital recovery scale, reflecting the actual 
location/situation of the subject evaluated daily from Day 2 to Day 14 is added. Time to NEWS2 
≤ 2, time to clinical improvement, time to clinical failure and incidence of mortality per day are 


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added secondary endpoints. Re-hospitalizations are defined at the description of time to hospital 
discharge.
5.3.1.1 Clinical Outcome
Summary of changes: Adverse events leading to study discontinuation, AEs, serious AEs and 
non-serious AEs related to COVID-19 were added to the list for the adverse events summary 
table. The definition of a treatment emergent AE was detailed. A table of influenza related 
complications as assessed by the investigator was added. Tables that show AEs related to 
COVID-19 infection, SAEs related to COVID-19 infection, AEs related to COVID-19 infection 
leading to death and a listing showing the AEs related to COVID-19 infection are added.
7.1.1 Definitions
7.1.2 Analysis Methods
Summary of changes: The change from baseline in EQ-5D VAS is categorized in two ways 
providing two additional endpoints.
5.3.1.3 Other Patient Reported Outcome
Summary of changes: A bootstrapping method for calculating the median time to event with 
95% confidence interval from the accelerated failure time model was added.
5.3.2 Analysis Methods
Summary of changes: Additional details regarding number of loose stools per day and stool 
consistency will be collected for subjects who report diarrhea adverse events. A confirmed 
diarrhea event is defined and the analysis of these events is described.
7.1.1 Definitions
7.1.2 Analysis Methods
Summary of changes: The use and definition of NEWS2 is explained and added.
NEWS2 will be used in the analyses.
7.6 NEW Score
Summary of changes: A new section was added to describe the analysis of the pharmacokinetic 
parameters and to explore their relationships with efficacy and safety.
9 Pharmacokinetics/Pharmacodynamics
9.1 Pharmacokinetics


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9.2 Pharmacokinetic/Pharmacodynamic Relationships
Summary of changes: the anticipated events table has been corrected for a typo and to include 
an additional MedDRA preferred term for diabetic complications
Attachment 1


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ABBREVIATIONS
ACVPU
Alert, new confusion, voice, pain, unresponsive
AE
adverse event
AFT
accelerated failure time
ATC
Anatomical Therapeutic Chemical
AUC
area under the curve
AUC12h
area under the plasma concentration-time curve from time 0 to 12 hours
bid
bis in die; twice daily
BMI
body mass index
CI
confidence interval
Cmax
maximum plasma concentration
COPD
Chronic Obstructive Pulmonary Disease
CTP
clinical trial protocol
Ctrough
Plasma concentration just prior to the beginning or at the end of a dosing interval
CV
coefficient of variation
DBP
diastolic blood pressure
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
EC50
50% effective concentration
ECG
electrocardiogram
eCRF
EMA
ePRO
EQ-5D
FDA
electronic case report form
European Medicines Agency
Electronic Patient-reported outcome (Device used for recording of patient-reported outcomes)
European Quality of Life 5 Dimensions
Food and Drug Administration
GMR
geometric mean ratio
HRS
Hospital recovery scale
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonization
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
ITT
Intent-To-Treat
ITT-i
Intent-To-Treat infected
ITT-ni
Intent-To-Treat non-infected
IWRS
Interactive web response system
LOD
limit of detection
LOQ
Limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MT
Mid-turbinate
NAI
neuraminidase inhibitor
NEWS
National early warning score
NEWS2
National early warning score 2
OST
oseltamivir
PA
Polymerase acidic protein
PB2 (1)
polymerase basic protein 2 (1)
PD
PGIC
PGIS
pharmacodynamic(s)
Patient Global Impression of Change
Patient Global Impression of Severity
PK
pharmacokinetic(s)
PP
Per Protocol
PT
preferred term
qRT-PCR
quantitative real time polymerase chain reaction
SDTM
Subject Data Tabulation Model
SAE
serious adverse event
SAP
statistical analysis plan


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SBP
systolic blood pressure
SI
international system 
SOC
standard of care
SSG
Statistical support group
TEAE
Treatment Emergent Adverse Events
Tmax
VAS
Time to reach Cmax
Visual analogue scale


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables and 
statistical methods for the analysis of efficacy and safety of the investigational compound 
pimodivir (JNJ-63623872). Separate documents for mock shells and table of contents for TFLs
(DPS) are also produced. The SAP is to be interpreted in conjunction with the protocol. 
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. 
1.1.
Trial 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 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.

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.


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
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 pharmacokinetics (PK) of pimodivir and to explore the PK/pharmacodynamics 
(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.
1.2.
Trial 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
A-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 screening
NEWS2 (4-5 or >5) (NEWS is changed to NEWS2 per CTP amendment 2), 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 


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(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. For further details see protocol Section 3.1.
1.3.
Statistical Hypotheses for Trial Objectives
The primary endpoint is the hospital recovery scale as assessed on Day 6. The alternative 
hypothesis is that 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.
1.4.
Sample Size Justification
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% [11]. 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%
This sample size is robust to mild to moderate changes in this distribution.
1.5.
Randomization and Blinding
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 NEWS2 (4-5 or >5) (NEWS 


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is changed to NEWS2 per CTP amendment 2) at screening, type of baseline SOC (including or not 
including influenza 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 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.


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2.
GENERAL ANALYSIS DEFINITIONS
All analysis dataset preparations and statistical analyses will be performed using SAS® version 9.2
or higher.
2.1.
Visit Windows, Phase Definitions and Baseline
The study is set up as shown in Figure 1. The phases will be constructed as shown in Table 1.
Figure 1: Study time line.
Day
0
1
2
3
4
5
6
7
8
9
10
14
19
28
33
Arm 
1
Scr.
Pimodivir
600 mg 
bid + SOC treatment
Follow-up
Pimodivir 600 mg bid + 
SOC 
treatment
extended1
Arm 
2
Scr.
Placebo bid + SOC 
treatment
Follow-up
Placebo bid + SOC 
treatment extended1
1  A subject with extended treatment will be treated an extra 5 days compared to the subjects without extended 
treatment.
Note: 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, or for subjects with 
extended treatment until the morning of Day 11, so all subjects with extended treatment receive 20 doses in total.
2.1.1.
Phase Definitions
Table 1: Construction of phases
Trial phase
Trial subperiod*1
Start date
End date
Screening
(phase 1)
The date of signing the informed 
consent with 00:00 as a timepart
1 minute before the first study drug
intake 
Treatment
(phase 2)
Datetime of first study drug intake 
*4
Datetime of last study drug intake*4
+ 24 hours
Planned Treatment
(subperiod 1)*2
Datetime of first study drug intake
*4  
If extended treatment then 
Datetime of first study drug intake 
in extended treatment subperiod – 1 
minute
Else
Datetime of last study drug intake*4
+ 24 hours 
Extended Treatment
(subperiod 2)*3
Datetime of first study drug intake 
in extended treatment subperiod*4
Datetime of last study drug intake*4
+ 24 hours
Follow-up
(phase 3)
End of the treatment phase +1 
minute
Trial termination date (or date of last 
contact if later)
*1: A treatment period will be constructed in the derived datasets with the same start and end date as the treatment 
phase.
*2: The planned treatment subperiod will be present for all treated subjects.
*3: The extended treatment subperiod will only be present for all subjects with extended treatment.
*4: In case the time part of the study drug intake is missing the imputed time part will be used as described below.


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Additionally, the treatment phase and follow-up phase will be combined in the analysis.
In case the time part of first study drug intake is missing the randomization time will be used. In 
case the time part of the randomization time is also missing we impute the time part with 8:00 if 
taken in the morning or with 20:00 if study drug was taken in the evening. In case the time of the 
last study drug intake is missing, the time part will be imputed with 8:00 if the last study drug was 
taken in the morning or with 20:00 if the last study drug was taken in the evening. 
In case the time part of first intake of the treatment extension is missing, the time part will be 
imputed with 8:00 if the last study drug of the planned 5 days of treatment was taken in the morning 
or with 20:00 if the last study drug was taken in the evening.
The last phase, whichever it is for a subject, always ends on 23:59 of the day of trial termination 
(or date of last contact if later).
Assessments will be assigned to phases and subperiods based on their start datetime, but seconds 
will not be taken into account. If only one assessment is expected per day and the day part of the 
start date of the assessment is present but the time part is missing, the assessment will be treated 
as if it happened at 00:00 of the day of the assessment (except for Adverse Events see details in 
Section 7.1). No imputations on missing times/time parts will be made in the analysis datasets.
In case more than one assessment per day is expected and time part is missing:
1.
Allocate according to the timepoint: Morning=00:00, Middle of the day=12:00, 
Evening=20:00
2.
If 1 timepoint is missing on day x: Check the non-missing timepoints of the other records 
on this day x. Allocate this record to the timepoint of day x that is not already covered. Then apply 
1.
3.
If 2 timepoints are missing on day x: Check the non-missing timepoint of the other record 
on this day x. Allocate these records to the timepoints of day x that are not already covered, 
assigning the smallest XXSPID value to the earlier timepoint and the larger XXSPID value to the 
later timepoint. Then apply 1.
4.
If 3 timepoints are missing on day x: allocate using the values of XXSPID, i.e. lowest 
number is morning, next is middle of the day, highest number is evening. Then apply 1.
2.1.2.
Analysis Visits
In general, AVISIT will be derived as the day of a scheduled visit, assessment or self-assessment 
as recorded in the respective SDTM, including the safety follow-up visit and day 28 final study 
visit (e.g. ‘Day 4’). AVISITN will be the numeric counterpart (e.g. for ‘Day 4’ AVISITN will be 
4). The AVISIT for scheduled measurements before first intake will be set to ‘Screening’ with 
AVISITN = -1. For specifications on the baseline record and endpoint record see Section 2.5.
For post-baseline assessments of the Daily Activities Resumption (Return to daily activity),
Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC) and 


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the European Quality of Life 5 Dimensions (EQ-5D) questionnaires, AVISIT and AVISITN will 
be derived from the number of days in the study relative to the start of study treatment (reldy, see 
Section 2.4). Post-baseline assessments taken from 00:00 until 02:00 will be assigned to the day 
before (e.g. a recording on Day 4 at 01:00 will be assigned AVISIT= Day 3).
2.1.3.
Analysis Timepoints
For parameters that were assessed more than once daily, the analysis timepoint (ATPT) will be the 
timepoint as reported in the database. In case there are multiple records per planned timepoint take 
the last in time.
For hospitalized subjects we expect 3 assessments per day. If the timepoint is missing but the date 
time is known, then we impute as follows:
If date time is within [00:00, 11:00] then allocate the morning timepoint
If date time is within [11:01, 16:00] then allocate the midday timepoint
if date time is within [16:01, 23:59] then allocate the evening timepoint
For subjects that are discharged we expect only 1 vital sign assessment. Therefore in case the 
timepoint is filled in, we set it to empty. 
For NEWS2, select for each of the parameters one record per timepoint as described above. The 
date and time of the NEWS2 will be derived from the last date time of each of the parameters and 
this will be used to allocate the NEWS2 to a phase. A subject received oxygen at the planned 
timepoint if the date time of the oxygen saturation measurement falls within the period that the 
subject received supplemental oxygen. 
2.1.4.
Use of Records per Analysis Visit and Timepoint
To ensure only one record is used per analysis visit for the Return to daily activity and PGIS
questionnaires only one questionnaire should be selected for analysis. Following rules should be 
followed to select the questionnaire. 
1. The questionnaire latest in time is used.  
2. If more than one questionnaire is still selected, the questionnaire with the highest sequence 
number is used.  
To ensure only one record is used per analysis visit for the PGIC and EQ-5D questionnaires the 
following rules should be followed to select the questionnaire. 
Listed below (Table 2) are the visit windows and the target days for each visit where PGIC and 
EQ-5D are recorded. The reference day is Study Day 1, the date of first intake of study drug.
1. If a subject has 2 or more actual visits in one visit window, the visit closest to the target 
day will be used as the protocol visit for that visit window.
2.
If 2 actual visits are equidistant from the target day within a visit window, the later visit 
in time is used.


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Table 2: Visit Windows for PGIC and EQ-5D
Scheduled Visit 
Number
Time Interval (label on 
output)
Time Interval (Day)*
Target Time Point (Day)
6
Day 6
[2 to 10]
6
14
Day 14
[11 to 20]
14
28
Day 28
[21 to 38]
28
For subjects on extended treatment:
14
Day 14
[11 to 16]
14
19
Day 19
[17 to 22]
19
33
Day 33
[23 to 38]
33
*Relative to Study Day 1
2.1.5.
Unscheduled Assessments
In general, all scheduled assessments after first administration of study drug will be used. 
Unscheduled assessments will not be used in descriptive statistics or any per-time point analysis,
but will be shown in listings as applicable. Pre-dose unscheduled assessments will be taken into 
account for baseline determination and post first dose unscheduled assessments will be taken into 
account for worst-case determination. 
For PRO assessments, both scheduled and unscheduled assessments will be taken into account to 
determine which assessment will be used per analysis visit / timepoint as described in 
Section 2.1.4.
For time to response endpoints, recordings taken at unscheduled visits will be taken into account
unless indicated differently.
2.2.
Analysis Sets
2.2.1.
All Randomized Analysis Sets
2.2.1.1.
All Randomized Analysis Set (RAND)
All randomized subjects with a randomization date time at or before the date time of first intake 
of study drug, or with a randomization date time and no study drug intake. 
2.2.1.2.
Randomized and/or Treated Analysis Set (RT)
All randomized subjects and/or all subjects who received at least 1 dose of study drug. The 
Randomized and/or Treated Analysis Set (RT) will be used in all listings unless specified 
otherwise for a specific display.
2.2.2.
Efficacy Analysis Sets
Efficacy will be analyzed on the intent-to-treat infected (ITT-i) set and by randomized treatment.
The primary efficacy endpoint will also be analyzed on the Per Protocol set. The primary efficacy 
endpoint and the six most important secondary endpoints (all endpoints included in the hierarchical 


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testing procedure at the final analysis) will also be analyzed on the intent-to-treat non-infected 
(ITT-ni) set and by randomized treatment.
2.2.2.1.
Intent-To-Treat infected (ITT-i) set
All subjects from the RAND analysis set who receive at least 1 dose of study drug and who have 
a confirmed infection with influenza A. Confirmation of Influenza A infection will be obtained 
from virology data. If there are no virology data available at the final analysis, then a subject will 
be excluded from the ITT-i set. Analysis on the ITT-i set will be analyzed as randomized.
A subject is considered to have a confirmed infection with influenza A if he/she has: 

at least one positive PCR result from central lab testing at baseline or pre-baseline; 
else 

at least two positive PCR results from central lab testing post-baseline;
else

at least one positive result from local lab testing for influenza A at baseline or pre-baseline, 
provided that no central lab testing is available at baseline or pre-baseline.
Note: viral load (PCR) results from central lab testing recorded as ‘TARGET NOT DETECTED’ 
will be considered as negative, all other non-missing results as positive (i.e. between LOD and 
LOQ, or quantifiable (above LOQ)).
Note: If no viral load measurement is available prior to first study drug intake then the first viral 
load result from the central lab testing obtained up to and including 30 minutes after first dose of 
study drug will be considered as the baseline assessment. If no baseline central lab measurement 
is available, the first viral load result from the local lab test obtained up to and including 30 minutes 
after first dose of study drug will be considered as the baseline local test assessment in case no 
local lab test is available at baseline or pre-baseline.
Note: viral load results from the central lab testing obtained from leftover samples from the local 
virology test will be considered in determining confirmed infection with influenza A.
2.2.2.2.
Per Protocol Set (PP)
All subjects in the ITT-i set without major protocol deviations that may have an impact on the 
efficacy analysis.
Decisions regarding which subjects are included in the per protocol set will be made before 
database lock on following criteria. Subjects will be included in the PP set in case:

Subjects missed at most 3 doses in total or at most 2 consecutive doses. On the day of 
randomization or the next day at least one dose needs to be taken.

The actual treatment must be the same as the planned treatment

No unblinding may have taken place


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
Subjects may not violate inclusion criteria 2,3,4 and 6 and exclusion criteria 1, 6, 9, 12 
and 13.

Influenza antiviral as part of the SOC was started no later than the day of first study drug 
intake,

Subjects did not switch to another influenza antiviral as a part of the SOC 
Inclusion/ 
Exclusion
Criterion 
number
Description
Inclusion
2
Tested positive for influenza A infection after the onset of symptoms, using a rapid 
influenza diagnostic test (RIDT) or, if available, a PCR-based or other rapid molecular 
diagnostic assay.
Inclusion
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.
Inclusion
4
Enrollment and initiation of study drug treatment ≤96hours after onset of influenza 
symptoms.
Inclusion
6
Having a screening/baseline NEWS2 of ≥4.
Exclusion
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 1 day prior to screening.
Exclusion
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, history of a lung transplant).
Exclusion
9
Taken any disallowed therapies as noted in the Protocol, pre-study and concomitant 
therapy before the planned first dose of study drug.
Exclusion
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, subject is 
unable to swallow medication tablets outside the hospital setting), with the exception of 
ePRO completion (see the protocol) ie, if a subject is not able to complete ePRO, the 
subject is still allowed to be enrolled in the study. 
Exclusion
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 when screening a subject for enrollment.
2.2.2.3.
Intent-To-Treat non-infected (ITT-ni) Set
All subjects from the RAND analysis set who receive at least 1 dose of study drug and who do 
not have a confirmed infection with influenza A.


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2.2.3.
Safety Analysis Set
2.2.3.1.
Safety Set or All Subjects Treated (AST)
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.
2.2.4.
Pharmacokinetics (PK) Analysis Set
The PK analysis set is defined as subjects who have received at least 1 dose of pimodivir and have 
at least 1 valid blood sample drawn for PK analysis.
2.2.5.
Pharmacodynamics (PD) Analysis Set
The PD analysis set is defined as all subjects in the PK analysis set for whom at least one PK 
parameter could be derived.
2.3.
Definition of Subgroups
See Table 3 for the definitions of all the subgroups. The third column in the table indicates for 
which endpoints the subgroup is applied.
Descriptive statistics will be produced for the different subgroups. 
In demographics and baseline disease characteristics, the following subgroups will be used:

Region

Influenza A subtype category

Treatment extension

Age group

Time since onset of influenza symptoms (actual:  ≤72 hours, >72 hours)
  Time since onset of influenza symptoms (actual:  ≤48 hours, >48 - 72 hours, >72 hours)

Type of SOC at baseline (actual)

NEWS2 at screening (actual)

Baseline resistance

Any baseline polymorphism

Influenza season

Study Period

COVID-19 impacted
Stratification factors (actual) will be used as subgroups for concomitant medication. 
For the primary and the six most important secondary endpoints (i.e.: All endpoints included in 
the hierarchy testing) the subgroup with subgroup*treatment interaction term will be added in the 
statistical analysis models, except for the study period subgroup, where the analysis will be 
performed separately for each individual category of the subgroup. For further details see 
Section 5.2.3. and Section 5.3.2. For other endpoints, the statistical analysis will be performed 
separately for each individual category of the subgroup.


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Table 3: Subgroups with their definition
Subgroup
Definition
Endpoints
Region
Based on country according to UN classification of 
Geographic regions[9]: 
Europe/Africa
Northern-America
Latin America and the Caribbean
Asia and Oceania
-
Efficacy (primary and 
secondary endpoints, excluding 
viral kinetics endpoints)
Age group (years)
13-17 years
18-65 years
66-85 years
-
Efficacy (primary and 
secondary endpoints, excluding 
viral kinetics endpoints)
-
All Safety
NEWS2 at screening (actual)
4-5
≥6
-
All Efficacy
-
Viral Phenotype
-
Viral Genotype
Type of SOC at baseline
(actual)
SOC including influenza antiviral treatment
SOC not including influenza antiviral 
treatment
-
All Efficacy
-
Viral Phenotype
-
Viral Genotype
-
Safety(AE summary, AEs 
and SAEs by MedDRA 
system organ class and 
preferred term, , influenza-
related complications, 
laboratory toxicity)
Time (hours) from onset of 
influenza symptoms to first 
study drug intake (actual)
≤72 hours
>72 - 96 hours
-
All Efficacy
-
Viral Phenotype
-
Viral Genotype
-
Safety(AE summary, AEs 
and SAEs by MedDRA 
system organ class and 
preferred term, , influenza-
related complications, 
laboratory toxicity)
Time (hours) from onset of 
influenza symptoms to first 
study drug intake (actual) – 3 
categories
≤48 hours
>48 - 72 hours
>72 - 96 hours
-
All Efficacy
-
Viral Phenotype
-
Viral Genotype
Influenza A subtype category
A/H1N1
A/H3N2
Other
-
Primary endpoint
-
The six most important
secondary endpoints
-
All viral kinetics
-
Viral phenotype
-
Viral genotype
Hospitalization status
Hospitalized
Outpatient
-
Only CM TLFs
Treatment extension
Extended treatment
No extended treatment
-
All Efficacy
-
Viral Phenotype
-
Viral Genotype


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Subgroup
Definition
Endpoints
Baseline
polymorphism
(based on
influenza PB2
genotype)
Polymorphism on one or any of these amino-acid
positions of interest:

Q306

F323

S324

F325

S337

H357

F363

K376

T378

F404

Q406

M431
   N510
-
Primary endpoint
-
Viral Phenotype
-
Viral Genotype
-
Viral kinetics
Baseline Resistance (Based on 
influenza PB2 phenotype)
Based on fold change (FC) in EC50 for pimodivir:

FC≤4

FC>4
-
Primary endpoint
-
Viral Phenotype
-
Viral Genotype
-
Viral kinetics
Influenza Season
Northern Hemisphere 2017/2018
Southern Hemisphere 2018
Northern Hemisphere 2018/2019
Southern Hemisphere 2019
Northern Hemisphere 2019/2020
Southern Hemisphere 2020
and so on to capture all enrolled subjects
- Efficacy (primary and the six 
most important secondary 
endpoints only)
- All viral kinetics
- Viral phenotype
-
- Viral genotype
Study period
pre interim (subjects enrolled for the interim 
analysis, i.e.: randomized before or on 
February 28, 2020)
post interim (subjects enrolled after the 
interim analysis, i.e.: randomized after 
February 28, 2020)
-Efficacy (primary and the six 
most important secondary 
endpoints only)
-safety (Safety(AE summary, 
AEs and SAEs by MedDRA 
system organ class and 
preferred term, , influenza-
related complications, 
laboratory toxicity))
COVID-19 impacted
Yes
No
COVID-19 impacted is based on any COVID-19 
related AEs, COVID-19 related PD, any COVID-
19 related treatment or study withdrawal
-Efficacy (primary and the six 
most important secondary 
endpoints only)
- Safety (AE summary, AEs 
and SAEs by MedDRA system 
organ class and preferred term, 
influenza-related 
complications, laboratory 
toxicity)
Subjects enrolled from 1st October 2017 to 31th March 2018 are considered to be in the Northern 
Hemisphere 2017/2018 category and subjects enrolled from 1st April 2018 to 30st September 2018 
are considered to be in the Southern Hemisphere 2018 category. Subjects enrolled from 1st October
2018 to 31th March 2019 are considered to be in the Northern Hemisphere 2018/2019 category and 
subjects enrolled from 1st April 2019 to 30st September 2019 are considered to be in the Southern 
Hemisphere 2019 category, and so on.


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Note: The six most important secondary endpoints are: incidence in post-baseline complications, 
time to hospital discharge, time from ICU admission to ICU discharge, time to return to daily 
activities, time from start of mechanical ventilation to end of mechanical ventilation, rate of re-
hospitalization.
Additional subgroup analysis may be specified in a separate analysis plan and reported separately 
from the clinical study report.
2.4.
Study Day and Relative Day
Reference date refers to the start date of the first study drug administration. All efficacy and safety 
assessments at all visits will be assigned a day relative to this date.
The relative day (reldy) will be defined as:
reldy = visit date – reference date + 1 for visits on or after the reference date, 
reldy = visit date – reference date for visits before the reference date.
Consequently there is no 'day 0' defined.
2.5.
Baseline and Endpoint
The baseline analysis visit is defined as the last assessment before the first intake of the study drug, 
with the possible exception for height, weight, viral load results from the central lab testing and 
the hospital recovery scale (HRS). Height and weight are only recorded once, at screening/baseline 
visit, and the values recorded at this visit will be allocated to the baseline analysis visits irrespective 
of start of study drug For viral load, if no measurement is available prior to first dose of study drug, 
then the first result from the central lab testing obtained up to and including 30 minutes after first 
dose of study drug will be considered as the baseline assessment and will be flagged in the analysis 
dataset. The baseline HRS is defined irrespective of the time of the start of study drug, and is 
covering the screening/baseline/day 1 visit which may be performed over two days as defined per 
protocol. Baseline HRS will be assigned to Day 1.
As specified in the protocol, an ECG recording within 1 calendar day before signing of the 
ICF/assent form can be used as baseline ECG requirement, if no ECG measurement was performed 
between signing ICF and first study drug intake.
For programming purposes the baseline record will be doubled in the ADAM datasets, the doubled 
record will be renamed with AVISIT = ‘Baseline’, AVISITN = 0 and will be assigned to the 
treatment phase.
For vital signs, NEWS2, ECG and central laboratory data the last study visit (Endpoint) is defined 
as the last scheduled study visit/timepoint and will be either the final study visit (day 28) or the 
safety follow-up visit. 
For viral phenotyping, the last visit (Endpoint) is defined as the last study visit/timepoint for which 
an EC50 and/or IC50 result is available (including unscheduled visit results).


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2.6.
Other Definitions
For FDA marketing authorization approval in the US all subjects will be included in the analysis. 
The oseltamivir subset (OST subset) contains only those subjects with oseltamivir (OST) use as 
part of their SOC treatment. The first dose of OST may be given before the subject was randomized 
but should be started no later than the day of first study drug intake.
The complete analysis will be repeated restricted to the OST subset to support marketing 
authorization approval in EMA.
Analyses to support authorization approval in other regions or countries, will include all subjects 
(depending on the enrichment of the interim analysis) unless the Health Authority of the regions 
or country requests otherwise and may be specified in a separate analysis plan and may also be 
reported separately  
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
3.1.
Interim Analyses
An interim analyses will be performed by an independent Statistical Support Group (SSG) and 
will be reviewed by the Independent Data Monitoring Committee (IDMC). 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 


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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 the IDMC SAP. 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.
3.2.
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.


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4.
SUBJECT INFORMATION
All general analyses will be done on the ITT-i Set and the Safety Set unless specified otherwise 
for a specific display.
4.1.
Demographics and Baseline Characteristics
Demographics and baseline disease characteristics will also be done on the PP and ITT-ni sets.
Descriptive statistics or frequency tabulation will be provided for the following parameters.

Demographic parameters:

Sex (Male, Female)

Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiple). The specification of the 
category ‘Multiple’ will only be listed. The ‘Not reported category’ will not be added 
for the denominator.

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Country 

Geographic region (Based on country according to UN classification of Geographic 
regions[9]: Europe/Africa, Northern-America, Latin America and the Caribbean, Asia 
and Oceania)

Age (years and categories: 13-17 years [≥13 - <18], 18-65 years [≥18 - ≤65], 66-85 
years [>65 - ≤85])

Age (years and categories: Adolescents (12-17 years) [≥12 - ≤17], Adults (18-64 
years) [≥18 - ≤64], From 65 to 84 years [≥65 - ≤84], 85 years and over [≥85])

Weight at baseline (kg)

Height at baseline (cm)

BMI at baseline = Weight at baseline (kg) / (Height at baseline (m))2 (rounded to 1 
decimal. Although available in the raw data, BMI will be recalculated from last weight 
and height measurement before start of treatment) 

Current Tobacco use: tobacco, cigarettes, cigars, patches/gum, pipes, E-cigarettes or 
equivalent, smokeless tobacco (Yes, No, Missing). Note that ‘No’ also includes ex-
smokers.

Childbearing potential (only listed)

Baseline disease characteristics:

Influenza A subtype category (A/H1N1, A/H3N2, No subtype)

Baseline influenza A viral load (log10 vp/mL), assessed by qRT-PCR 

Baseline influenza A viral titer (log10 TCID50/mL) assessed by viral culture


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
qRT-PCR negativity at baseline

Viral culture negativity at baseline

Broad respiratory panel (show the reported pathogen)

Return to daily activities at baseline

Patient Global Impression of Severity of Influenza symptoms at baseline

EQ-5D VAS at baseline

EQ-5D Valuation index at baseline

NEW2 Score at screening (4-5, >=6), as randomized

NEW2 Score at screening (4-5, >=6), actual

Hospital recovery scale category at baseline

Fundamental hospital recovery scale category at baseline

Respiration rate at baseline (breaths/min)

Arterial oxygen saturation at baseline on room air (%)

Arterial oxygen saturation at baseline overall (%)

Supplemental oxygen at baseline (yes, no) (following supplemental oxygen types are 
considered: nasal cannula, venturi mask, simple face mask and nonrebreathing face 
mask with reservoir and one way valve)

Mechanical ventilation use at baseline (yes, no)

Temperature (°C) at baseline

Systolic blood pressure at baseline (mmHg)

Heart rate at baseline (beats/min)

Level of consciousness at baseline

Time since onset of influenza symptoms as randomized (≤72, >72 hours),

Time since onset of influenza symptoms, actual time (hours) [the actual time will be 
calculated from start date and time of acute respiratory symptoms until datetime of 
first study drug intake, if the time is missing, the midpoint of the time interval as 
recorded per CRF will be used. ]

Time since onset of influenza symptoms, actual (≤72, >72 hours)

Time since onset of influenza symptoms, actual – 3 categories (≤48, >48 – 72h, >72 
hours)

Type of SOC at baseline, as randomized (including or not including influenza antiviral 
treatment)

Type of SOC at baseline, actual (including or not including influenza antiviral 
treatment), for the SOC including antiviral treatment the influenza antiviral will also 
be shown


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
SOC including oseltamivir (yes, no)

Chronic oxygen use(yes, no)

Primary reason for hospitalization at baseline (prioritize influenza in case >=2 reasons 
are selected, then adverse event and then medical history)

Type of influenza A diagnostic assay (Rapid antigen-based diagnostic test, Rapid 
molecular diagnostic test)

In ICU at baseline (yes, no)

Baseline resistance

Any baseline polymorphism
4.2.
Disposition Information
Summaries will be provided for the following disposition information:

Number of subjects screened, screening failures, randomized, randomized and not treated, 
randomized and/or treated, randomized and treated, randomized and no confirmed Influenza 
A, ITT-i set, ITT-ni set, per protocol set, and safety set.  The planned treatment arm will be 
shown, except for the randomized and/or treated and safety sets where the actual treatment 
will be shown. The number (%) of subjects impacted by the COVID-19 pandemic will be 
presented for the ITT-i, ITT-ni, per protocol and safety analysis sets.

Number of subjects who completed/discontinued treatment and/or the trial, with the reasons 
of discontinuation. The number of subjects that discontinued due to an AE that is related to 
COVID-19 and that discontinued due to another reason related to COVID -19 will be added. 

Kaplan-Meier curves of the time to completion or discontinuation (in days) of the 
treatment/trial per treatment group, overall and separately for subjects with/ without treatment 
extension. Note at the final analysis all subjects will have the event of completion or 
discontinuation and no subjects will be censored.

Number of subjects with a visit at each scheduled analysis timepoint by phase and the missing 
visits and visits different from planned due to COVID-19 per phase.

Number of subjects enrolled per month, quarter, season and year.
4.3.
Treatment Compliance
Treatment compliance for pimodivir/placebo is calculated as the actual number of doses taken, as 
a percentage of the planned number of doses. The actual number of doses taken will be derived 
from the drug accountability information (DA domain) as the amount of drug dispensed minus the 
returned amount (in case both amounts are known, otherwise treatment compliance will be 
missing)
To differentiate between the compliance during the planned treatment subperiod and the planned
treatment extension subperiod, the date of dispensing the tablets will be compared with the 
treatment extension start date (DS Domain). If the drug is dispensed before the treatment extension 


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start date it will be used for the compliance of the treatment subperiod. If the drug is dispensed on 
or after the treatment extension start date the amount will be used for the compliance of the 
treatment extension subperiod.
For placebo or pimodivir the actual number of doses needs to be divided by 2 as the study uses 
300 mg tablets. For subjects without treatment extension the planned number of study drug is 
20 tablets of placebo or pimodivir hence the planned number of doses per study drug equals 
10 doses. For subjects with treatment extension the planned dose is doubled. Note that the planned 
number of doses is irrespective of whether the subject discontinued during the treatment phase.
Dosing compliance will be summarized descriptively in the treatment phase and per subperiod and 
by discontinuing the trial during the treatment period (Yes, No). 
4.4.
Extent of Exposure
The extent of exposure (hours) is defined as datetime of last study drug intake – datetime of first 
study drug intake + 12 hours. Note: treatment interruptions will not be taken into account.
Extent of exposure will be summarized descriptively in the treatment phase, overall and by
treatment subperiod.
A listing will be made to present the exposure to study drug for subjects impacted by COVID-19 
(based on reason ‘Other’ containing ‘COVID’).
4.5.
Protocol Deviations
The number and percentage of subjects with major protocol deviations will be tabulated overall 
and per coded major protocol deviation.
A listing will be made of all major protocol deviations for the subjects in the safety set.
Additionally, a listing of major and separately a listing for minor protocol deviations related to 
COVID-19 will be made.
Additionally, for subjects in the ITT-i set, the number and percentage of subjects with a reason for 
exclusion  from the per protocol set will be tabulated overall and for each reason for exclusion.(see 
Section 2.2.2.2).
A listing will also be made of all reasons for exclusion from the per protocol set for subjects in the 
ITT-i set.
4.6.
Prior and Concomitant Medications
Medications reported from 7 days before first dose of study drug and up to last contact date will 
be summarized by preferred term using the World Health Organization-Drug Dictionary for the 
ITT-i Set and the Safety Set as frequency tables in 2 parts: 


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1. Prior medication: medication that started before the first dose of study drug, regardless of 
when dosing of the medication ended 
2. Concomitant medication: medication received at or after the first dose of study drug, 
medication that was received before initial dosing and continued after initial dosing of 
study drug, or medication with missing stop date.
(Medication that started before the first dose of study drug and continued after the first dose of 
study drug will be summarized as prior medication and separately as concomitant medication.)
A frequency tabulation of concomitant medication will be shown by ATC class level up to level 3.  
Frequency tabulations will be made for concomitant antibiotics, type of SOC, corticosteroids, and 
medication administered to treat COVID-19 infection by ATC class and by hospitalization status. 
Additionally, tabulations will be made of concomitant corticosteroids and antibiotics administered 
because of adverse events reported as influenza complications. 
The ATC level 2 code J01 will be used to identify concomitant antibiotics.
The ATC level 2 code H02 and the ATC level 4 codes M01BA, R03BA, and R03AK will be used 
for identifying corticosteroids. Separate frequency tabulations will be made for antipyretic 
medication and oxygen supplementation. The ATC level 4 codes N02BA and N02BE and the 
generic medication names paracetamol, ibuprofen, and acetylsalicylic acid will be used to identify 
antipyretic medications. The table showing oxygen supplementation will be tabulated per analysis 
visit, phase and treatment subperiod. If a prior/concomitant therapy record misses components of 
its start and/or stop dates (time and/or day and/or month and/or year), the following actions will 
be taken:
1. In case of partial start or stop datetimes, the concomitant therapy records will be allocated 
to prior and/or concomitant using the available partial information, without imputations. 
2. In case of a completely missing start date, the prior and/or concomitant therapy will be 
considered as having started before the trial.
3. In case of a completely missing end date, the prior and/or concomitant therapy will be 
considered as ongoing at the end of the trial.
4.7.
Medical history
The influenza vaccination status will be tabulated by:
-
Vaccinated in previous season, not in current season
-
Vaccinated in current season, not in previous season
-
Vaccinated in previous and current season.
-
Not vaccinated in previous and current season
The use of antiviral influenza medication prior to study drug initiation will be tabulated separately. 


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Influenza history will be listed, including information on first acute respiratory symptoms, 
influenza vaccination status, chronic oxygen use and previous antiviral influenza therapy. Pre-
treatment influenza complications will also be listed.
Other medical history will be tabulated by subcategory and/or will be listed. 


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5.
EFFICACY
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment arm 
and stratification factors (NEWS2 at screening, baseline SOC and time since onset of symptoms).
For the analyses restricted to subjects who received OST as part of their SOC, type of baseline 
SOC will not be included as a stratification factor or model parameter. 
5.1.
Analysis Specifications
5.1.1.
Level of Significance
The population used for the evaluation at the final analysis will depend on the outcome scenario 
of the interim analysis: i.e.; scenario 1: continue with the full study population or scenario 2: 
continue only with the subjects with an onset of symptoms less than 72 hours before first study 
drug intake. Tables/graphs/listings will account for the selected scenario.
As a confirmatory strategy, to account for multiplicity in the statistical evaluation of the most 
important efficacy endpoints, in either scenario, 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. 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 to hospital discharge
4. Time from ICU admission to ICU discharge
5. Time to return to daily activities
6. Time from start of mechanical ventilation 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.
The confirmatory test procedure follows the Serial Gate Keeping strategy as outlined in Section 7 
of the FDA’s draft guidance on Multiple Endpoints to control the overall type I error at the 5% 2-
sided level. The primary and six most important secondary endpoints (listed above) will be tested 
in the hierarchical order per the 5 steps outlined below. All alphas and p-values specified are 2-
sided.
Step 1: Test the primary hypothesis (“Hospital recovery scale at Day 6”)

If the p-value is ≤5%, continue to Step 2.

If the p-value is >5%, stop testing, and no claim will be made.


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Step 2: Test first set of 2 secondary endpoints (“Incidence in post-baseline complications” and 
“Time from start of study drug to hospital discharge”). The Bonferroni-Holm procedure will be 
applied to control the type I error within Step 2.

If the smallest of the 2 p-values is ≤2.5% and the largest of the 2 p-values is ≤5%, continue 
to Step 3.

If the p-value for “Incidence in post-baseline complications” is ≤2.5% but the p-value
for “Time from start of study drug to hospital discharge” is >5%, stop further testing of the 
secondary endpoints, and make a claim on “Hospital recovery scale at Day 6” and
“Incidence in post-baseline complications”.

If the p-value for “Time from start of study drug to hospital discharge” is ≤2.5% but the p-
value for “Incidence in post-baseline complications” is >5%, stop further testing of the 
secondary endpoints, and make a claim on “Hospital recovery scale at Day 6” and “Time 
from start of study drug to hospital discharge”.

If the smallest of the 2 p-values is >2.5%, stop further testing of the secondary endpoints, 
and make a claim on “Hospital recovery scale at Day 6” only.
Step 3: Test second set of 2 secondary endpoints (“Time from ICU admission to ICU
discharge” and “Time to return to daily activities”). The Bonferroni-Holm procedure will be
applied within Step 3.

If the smallest of the 2 p-values is ≤2.5% and the largest of the 2 p-values is ≤5%, continue 
to Step 4.

If the p-value for “Time from ICU admission to ICU discharge” is ≤2.5% but the pvalue
for “Time to return to daily activities” is >5%, stop further testing of the secondary 
endpoints, and make a claim on “Hospital recovery scale at Day 6”, “Incidence in post-
baseline complications”, “Time from start of study drug to hospital discharge” and “Time 
from ICU admission to ICU discharge”.

If the p-value for “Time to return to daily activities” is ≤2.5% but the p-value for “Time
from ICU admission to ICU discharge” is >5%, stop further testing of the secondary
endpoints, and make a claim on “Hospital recovery scale at Day 6”, “Incidence in 
postbaseline complications”, “Time from start of study drug to hospital discharge” and
“Time to return to daily activities”.

If the smallest of the 2 p-values is >2.5%, stop further testing of the secondary endpoints, 
and make a claim on “Hospital recovery scale at Day 6”, “Incidence in postbaseline
complications” and “Time from start of study drug to hospital discharge”.
Step 4: Test the fifth secondary endpoint (“Time from start to end of mechanical
ventilation”)

If the p-value is ≤5%, continue to Step 6.

If the p-value is >5%, stop further testing of the secondary endpoints, and make a claim on 
“Hospital recovery scale at Day 6”, “Incidence in post-baseline complications”, “Time 
from start of study drug to hospital discharge”, “Time from ICU admission to ICU 
discharge”, and “Time to return to daily activities”.
Step 5: Test the sixth secondary endpoint (“Rate of re-hospitalization”)

If the p-value is ≤5%, make a claim on “Hospital recovery scale at Day 6”, “Incidence in 
post-baseline complications”, “Time from start of study drug to hospital discharge”, “Time 


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from ICU admission to ICU discharge”, “Time to return to daily activities”, “Time from 
start to end of mechanical ventilation”, and “Rate of re-hospitalization”.

If the p-value is >5%, make a claim on “Hospital recovery scale at Day 6”, “Incidence in 
post-baseline complications”, “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”.
For the primary endpoint, the results from the proportional odds model will be used in the 
hypothesis testing. If the proportional odds assumption would not hold on the treatment effect, the 
p-value from the van Elteren test will be used. 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. For all these evaluations p-
value combination tests will be used, as described below.
The final analysis on the ITT-i set (to support FDA marketing approval) and the final analysis on
the OST subset (to support marketing authorization approval in EMA) will be performed
independently, using a 5% two-sided significance level for each.
5.1.2.
Statistical Methodology for Evaluation at the Final Analysis
All p-values below are one-sided p-values, to evaluate rejection of the null hypothesis that
pimodivir is not better than placebo.
Scenario 1: The final analysis will be performed in the subgroup with time between onset of 
symptoms and start of treatment between 0 and 72 hours only. P-values for the final analysis will 
be based on 2 inverse-normal combination tests of p-values as outlined below.


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Let:
p
=
p-value (one-sided) from full study population of the pre-interim’ category of the 
study period subgroup 
p1
=
p-value (one-sided) from subgroup with time between onset of symptoms and start 
treatment between 0 and 72 hours of the pre-interim’ category of the study period 
subgroup
p2
=
2*min(p,p1)
q1
=
p-value (one-sided), from subgroup with time between onset of symptoms and start 
treatment between 0 and 72 hours on the patients enrolled of the ‘post-interim’ 
category of the study period subgroup 
N1
=
actual sample size at interim i.e.:all randomized subjects analysis set (RAND)
included in the IA
N
=
600, the initially planned study sample size
w1
=
sqrt(N1/N)
w2
=
sqrt(1-(N1/N))
φ-1(x)
=
the inverse of the standard normal cumulative distribution function in x
Note: p1 and q1 are based on a subset of subjects with onset of symptoms and start treatment between 0 and 72 hours, 
and therefore this stratification factor is not included in the respective models.
The p-values resulting from the following 2 combination tests both should be below the pre-
specified alpha (2.5% one-sided) to claim superiority in subgroup with time between onset of 
symptoms and start of treatment between 0 and 72 hours:
1-φ(C(p1,q1)) where C(p1,q1) = w1 * φ-1(1-p1) + w2 * φ-1(1-q1)
1-φ(C(p2,q1)) where C(p2,q1) = w1 * φ-1(1-p2) + w2 * φ-1(1-q1)
Scenario 2: The final analysis will be performed in the full study population. P-values for the 
final analysis will be based on 2 inverse-normal combination tests of p-values.
Let additionally:
q
=
p-value from full study population on the patients enrolled of the ‘post-interim’ 
category of the study period subgroup
The p-values resulting from the following 2 combination tests both should be below the pre-
specified alpha to claim superiority in the full study population:
1-φ(C(p,q)) where C(p,q)   = w1 * φ-1(1-p) + w2 * φ-1(1-q)
1-φ(C(p2,q)) where C(p2,q) = w1 * φ-1(1-p2) + w2 * φ-1(1-q)
5.1.3.
Data Handling Rules
For analysis purposes the log10 qRT-PCR viral load will be imputed with 2.12 when the result is 
‘TARGET DETECTED’ (.i.e. below the limit of quantification: <2.18) and with 2.05 if result is 


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‘TARGET NOT DETECTED’ (i.e. below limit of detection: <2.05). The log10 TCID50 viral titer 
will be imputed with 0.74 when the result is ‘<0.75’ (below limit of quantification).
5.1.4.
Stratification Factors
The actual values of the stratification factors will be used for all analyses.
The concomitant medications indicated as standard-of-care treatment on the concomitant 
medication form will be used for determining the actual strata for type of baseline SOC. If no
influenza antiviral is recorded it will be assumed that the subject received SOC not including 
influenza antiviral. The following ATC level 4 code and generic medication names indicate an 
influenza antiviral: 

J05AH (including neuraminidase inhibitors)

Laninamivir

Umifenovir

Amantadine

Rimantadine

Ribavirin

Baloxavir Marboxil
The datetime when first acute respiratory symptoms appeared and the datetime of first dose of 
study drug will be used for determining the actual strata for time since symptom onset relative to 
treatment initiation. 
The actual NEWS2 will be calculated as explained in Section 7.6. Note that a subject is considered 
to receive supplemental oxygen if the subject received oxygen according to the CM dataset at least 
at one point between 15 min before randomization date time to the randomization date time.
When an incorrect stratification occurred for the NEWS(2) such that the actual NEWS2 is lower 
than 4 or for the time to onset of symptoms to first study drug intake (i.e.: >96 hours) then use the 
randomized stratification category instead. Similarly, in case of missing data to calculate the actual 
NEWS2 stratification the randomized stratification factor will be used, except if the NEWS2 is 
greater or equal to 6 based on the available non-missing parameters, then the actual stratification 
will be ‘6 or more’.
There will be no missing stratification factors values for randomized subjects receiving study drug.
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Definition
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.
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. A subject will be evaluated in the same ordering of the categories 
as below. Once a subject fulfils the criteria for a category, the category is assigned to the subject 
and the evaluation stops.
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 (e.g., 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
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 


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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% (e.g., 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
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 (e.g., in case of lack of bed 
availability in a skilled nursing facility, lack of social support at home).


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Notes: If a subject was discharged from the hospital “Against Medical Advice” on the day prior to 
the day of assessment, the subject will be considered as hospitalized (evaluating the other aspects 
of the HRS to define the correct category based on available data, e.g.: requiring supplemental 
oxygen, on the day of assessment). The hospital recovery scale category will be considered missing 
on subsequent days. 
The HRS will be missing after a subject withdrew (except for withdrawal due to death) from the 
study.
See Attachment 6 for details of the derivation of the HRS categories.
5.2.2.
Estimand
The population of interest is  hospitalized subjects between 13 to 85 years old with a confirmed 
influenza A infection. 
The primary variable is the hospital recovery scale as assessed on Day 6 and will be compared 
between pimodivir and placebo on top of SOC. The hospital recovery scale is an ordinal mutually
exclusive scale of six categories (death, requiring mechanical ventilation, requiring ICU, non-ICU 
hospitalized requiring supplemental oxygen, non-ICU hospitalized not requiring supplemental 
oxygen and non-hospitalized).
The intercurrent event of the use of influenza antivirals as part of SOC is handled in a treatment 
policy strategy as the primary endpoint is derived in the same way irrespective of the components 
of SOC. Treatment discontinuation is an intercurrent event that is also handled in a treatment policy 
strategy. Death as intercurrent event is handled in a composite strategy as it is one of the categories 
of the HRS. Other factors as for example bed availability that can influence the status of the subject
are intercurrent events that are also handled with the composite strategy as the HRS accounts for 
the status of where the subject ‘should be’ instead of where the subject physically is.
The common odds ratio estimated by a proportional odds model is used as the population-level 
summary. If the assumption (by testing the parallel slopes for the treatment effect only) of the 
proportional odds would not hold for the treatment effect, the Van Elteren test will be used in a 
sensitivity analysis and the resulting p-value would be used in the formal testing. A second 
sensitivity analysis is conducted to handle missing data by an MAR/MNAR multiple imputations 
method. This is done for all missing HRS values on day 6 and separately for HRS values on day 6 
that are missing due to COVID-19 and for HRS values that are missing not due to COVID-19.
5.2.3.
Analysis Methods
A proportional odds model will be used as primary model to analyze the hospital recovery scale
on Day 6, modeling the common odds ratio of improvement on the ordinal scale of active treatment 
versus placebo. The model will include treatment, hospital recovery scale category at baseline and 
the stratification factors (NEWS2 category at screening, type of baseline SOC, and time since onset 
of influenza symptoms). In a first step equal slopes (i.e. proportional odds) for the treatment effect 
only and unequal slopes for the other covariates, will be modeled. If this model does not fit a full 


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proportional odds model will be applied, i.e. implying proportional odds for all covariates in the 
model. The common odds ratio from the final model will be considered as the estimate of the 
treatment effect. The actual values of the stratification factors will be used for all models, not as 
randomized. The proportional odds model will be defined in such a way that a common odds ratio 
smaller than 1 indicates larger improvement in the pimodivir treatment group.
Graphical displays and tabulations will be provided showing the proportion of subjects per hospital 
recovery scale category and day. Also, shift tabulations will be provided of the baseline hospital 
recovery scale category versus the post-baseline hospital recovery scale category, per day.
The proportional odds assumption will be assessed by testing for parallel slopes for the treatment 
effect only.
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 treatment, hospital recovery scale
category at baseline and stratification factors. 
The hospital recovery scale will also be analyzed using the Van Elteren test with strata defined by 
the stratification factors[3, 6].
A table will be created showing the number (%) missing HRS values at day 6 overall and by 
reason: study discontinuation: due to COVID-19 and not due to COVID-19, discharged against 
medical advice prior to day 5 and subjects that have no confirmed influenza A.  
In case of more than 10% missing data on Day 6: multiple imputation will be employed as 
sensitivity analyses for the proportional odds model of the HRS (excluding the subgroup analyses), 
under the
missing-at-random (MAR) assumption and missing-not-at-random (NMAR) 
assumption. 

If more than 5% of the patients have a missing HRS value due to COVID-19 (i.e.: 
discontinued due to COVID-19), the multiple imputation method will also be done 
separately on these subjects.

If more than 5% of the patients have a missing HRS values unrelated to COVID-19, then 
also multiple imputation will be done separately in this group. 
The Markov Chain Monte Carlo (MCMC) method will be used to create a number of multiple 
imputation datasets with monotone missingness in the clinical outcomes (baseline until Day 14). 
The number of imputation datasets will be the same as the percentage of missing data[10]. For MAR 
assumptions, a monotone ordinal logistic regression imputation model will be used to complete 
the remaining missing clinical outcomes. 


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For the NMAR assumption, the imputed datasets obtained from the MAR assumption described 
above will be used, but with a structural shift in hospital recovery scale category on Day 6 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:
o
1 category down, eg, from ‘1. Not hospitalized’ to ‘2. Non-ICU hospitalization, 
not requiring supplemental oxygen’
o
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:
o
1 category down, eg, from ‘1. Not hospitalized’ to ‘2. Non-ICU hospitalization, not
requiring supplemental oxygen’
o
2 categories down, eg, from ‘1. Not hospitalized’ to ‘3. Non-ICU hospitalization,
requiring supplemental oxygen’
In all cases, ‘6. Death’ will be the worst hospital recovery scale category after imputation and
structural shift and ‘1 Not hospitalized’ will be the best hospital recovery category after imputation 
and structural shift.
The models fitted using the multiple imputation datasets will be the same as the final model on the 
actual data. The results from the models on the multiple imputation datasets will be combined 
taking into account the between and within variation of the results.
The analyses on the primary endpoint will be repeated by subgroups for efficacy as defined in 
Section 2.3. The final model above will be repeated adding these subgroups (defined in 
Section 2.3) as an additional covariate and interaction with treatment. Per subgroup the common 
odds ratio and the odds ratios calculated for the dichotomizations will be derived from these 
models. In addition, for each category in a subgroup, the Van Elteren test with strata defined by 
the stratification factors will be repeated.
5.3.
Major Secondary Endpoints
5.3.1.
Definition
Formulae to be used for derived variables, including data conversions, are provided in the tables
below. 
Note that for time-to event variables the actual date or times that the endpoint is met will be used.
For the time-to-event variables, in case of death prior to the event, the subject will be censored 
using a time-to equal to the maximum time across all subjects.


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5.3.1.1.
Clinical Outcome
Measurement
Formula
Time to hospital
discharge (hours) 
[Time-to event]
The time from first study drug intake to first hospital discharge 
(=event) in hours. Note this excludes time in hospital because of re-
hospitalization (a new hospitalization is considered as a re-
hospitalization if there is at least 1 day in between the start date of the 
new hospitalization and the end date of the previous hospitalization)
and hospitalizations that ended before first intake.
Subjects who complete or withdraw from the study while still 
hospitalized will be censored at the date of completion or withdrawal. 
If the time is not available they will be censored at 23:59. 
If time of end of hospitalization is not known but we have a date of 
discharge then time will be imputed at 23:59.
(Date and time of event or censoring–- date and time of first dose of 
study drug)/3600, rounded to one decimal.
Time to readiness for 
hospital discharge 
(days) [Time-to event]
The time from first study drug intake until the time to readiness for 
hospital discharge (= event) in days, with readiness for hospital 
discharge defined by the investigator. In case at the date of discharge 
the subject is not ready to be discharged as per investigator assessment, 
the discharge readiness day will be set to the next day.
Censoring of the time will be done analogous to “Time to hospital 
discharge”, only using the date information, as time is not available for 
the event.
Total length of hospital
stay (hours) [Duration]
The total number of hours a subject stayed in the hospital during the 
period from first study drug intake until study termination, calculated 
as sum of [(end date and time of hospitalization–- start date and time 
of first intake)/3600], rounded to one decimal for all separate hospital 
stays per subject. If the time is not available it will be put at 23:59
If hospitalization started before first study drug intake, then datetime 
of first study drug will be used. 
If hospitalization is still ongoing at study end, the end date and time 
will be imputed by the end date and time of the last phase as defined 
in table 1.


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ICU admission started 
post-baseline
Incidence of post-baseline ICU admission
- Admitted to ICU post-baseline
- Not admitted to ICU post-baseline
Note: In case a patient is in the ICU at baseline and (after discharge 
from the ICU) the patient is re-admitted post-baseline, this subject will 
be counted as ‘'Admitted to ICU post-baseline’'.
First admission to 
intensive care unit 
(ICU) 
When was the subject first admitted to the ICU during the study? 
Categories:
-
In ICU at baseline
-
Admitted in ICU Post-baseline
-
Never admitted to ICU
Time from ICU 
admission to ICU 
discharge (hours) 
[Time-to event]
The time from max(first admission to ICU, first study drug intake)
until the time of first discharge from the ICU.
Censoring and calculation of the time will be done analogous to “Time 
to hospital discharge”.
Only subjects admitted to the ICU (at any point during the trial) are 
included in the analysis and analysis is restricted to the first ICU 
admission. 
Time from ICU 
admission requiredness
to ICU discharge
readiness (days)  
[Time-to event]
The date from max(requiring ICU level of care , first study drug intake)
until the date of not requiring ICU anymore(= event), requiring ICU 
level of care to be defined by the investigator.
Censoring and calculation of the time (days) will be done analogous to 
“Time to hospital discharge”
Subjects that do not require ICU level of care will be excluded from 
this analysis and this analysis is restricted to the first required ICU 
level of care.


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Total time in intensive 
care unit (ICU) stay 
(hours) [Duration]
The total number of hours a subject stayed in ICU during the period 
from first intake until study termination, calculated as sum of [(end 
date and time of discharge–- start date and time of admission)/3600], 
rounded to one decimal for all separate events per subject
In case ICU admission took place before first intake or in case the start 
datetime of ICU is missing, then the date and time of first intake will 
be used.
In case the ICU stay ended after the end of the trial or in case the end 
datetime of ICU stay is missing, then the end datetime of last contact 
date will be used.
If time of the start of ICU admission is missing then use 00:00. If time 
of the end of ICU admission is missing then use 23:59. The derivation 
of total time in ICU is analogous to “total length of hospital stay”.
Type of supplemental 
oxygen administration
Tabulation will be done as collected per CRF page “Oxygen 
Supplementation”. In addition, the following categorization will be 
done:
- Invasive Mechanical Ventilation
- Non-Invasive Mechanical Ventilation
- Non-Invasive, Non-mechanical Ventilation
- None
Mechanical ventilation 
during study
Incidence of mechanical ventilation (invasive or non-invasive)
Categories:
-
Mechanical ventilation at baseline
-
First administration of mechanical ventilation post-baseline
-
No administration of mechanical ventilation
Mechanical ventilation 
started post-baseline
Incidence of post-baseline mechanical ventilation (invasive or non-
invasive) 
- Started post-baseline
- Not started post-baseline
Note: In case mechanical ventilation is present at baseline and a second 
episode of mechanical ventilation is initiated post-baseline, this subject 
will be counted as started post-baseline.


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Time from start of 
mechanical ventilation 
to end of mechanical 
ventilation (hours) 
[Time-to event]
The time from max(start date and time of first mechanical ventilation,
study drug intake) until the end date and time of mechanical 
ventilation. 
Note: Invasive and non-invasive mechanical ventilation are considered
and are defined on the Oxygen Supplementation form: Type of 
supplemental oxygen administration. Only the first mechanical 
ventilation period is considered.
Censoring and calculation of the end time will be done analogous to 
“Time to hospital discharge” if time part of the start of mechanical 
ventilation is missing then it will be imputed with 00:00.
Subjects that are not on mechanical ventilation (at any point during the 
trial) are excluded from this analysis and this analysis is restricted to 
the first time mechanical ventilation is used.
Total time on
mechanical ventilation 
(hours) [Duration]
The total number of hours of mechanical ventilation during the period 
from first intake until study termination, calculated as sum of [(end 
date and time of mechanical ventilation–- start date and time of 
mechanical ventilation)/3600], rounded to one decimal for all separate 
events per subject
In case mechanical ventilation was started before first intake or in case 
the start datetime of mechanical ventilation is missing, then the date 
and time of first intake will be used.
In case mechanical ventilation ended after the end of the trial or in case 
the end datetime of mechanical ventilation is missing, then the end 
datetime of last contact date will be used.
If time of the start of mechanical ventilation is missing, then use 00:00. 
If time of the end of mechanical ventilation is missing, then use 23:59. 
The derivation of the total time is analogous to “Total length of 
hospital stay”.
Time to clinical 
response (hours)
[Time-to event]
The time to clinical response is defined as the time (in hours) from first 
study drug intake until the first assessment (actual date and time) of a 
successive series of 4 recordings (over 5 scheduled successive analysis 
timepoints, 1 missing timepoint is allowed) where at least 4 of 5 
symptoms (temperature, blood oxygen saturation, heart rate, SBP, 
respiration rate) are normalized, with at least normalization of 
temperature and blood oxygen saturation. 
Normalization of clinical response is defined in Table 4. 


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Only vital signs assessments performed during hospitalization 
(excluding measurements during re-hospitalization) and up to Day 14 
(during hospitalization) or Day 19 (for subjects with extended 
treatment during hospitalization) will be taken into account to 
determine time to clinical response. Assessments taken after hospital 
discharge or after Day 14 or Day 19 (for subjects with extended 
treatment), whichever comes first, will not be taken into account. In 
case there was more than one hospitalization period, only assessments 
of the first hospitalization period will be used. 
In case clinical response is not met, data will be censored. Censoring will 
be done as follows 
1) Last non-missing record in the applicable period indicate 
normalization (but insufficient recordings to meet the time to 
clinical response criteria)
Censoring will be done at the first record of normalization
2) Last non-missing record in applicable period does not indicate 
normalization
Censoring will be done after the last observation of vital signs 
recordings, which is 13:00 on the same day if the last observation was 
a morning assessment (from 3:01 until 11:00), 21:00 if the last 
observation was an afternoon assessment (from 11:01 until 19:00), 
5:00 the next day if the last assessment was an evening assessment 
(from 19:01 until 03:00).
When not all parameters are available on a certain timepoint then 
following rules apply:
-
If temperature or oxygen saturation are available but not 
normalized then there is no resolution for this timepoint
-
If more than 2 parameters are not normalized then there is no 
resolution for this timepoint
-
If 4 parameters including temperature and oxygen saturation are 
normalized (allowing 1 missing parameter) then there is 
resolution for this timepoint.
Else the resolution on this timepoint is missing
Subjects without postbaseline data are excluded.


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Within 1 timepoint the assessments of the different parameters are 
taken together for evaluating the clinical response and the time of the 
last record within that time point is used. Unscheduled assessments 
are not taken into account. When multiple assessments for 1 
parameter occur within one timepoint then only the last is used for 
that parameter.  
Table 4: Resolution Criteria for Vital Signs
Assessment 
Resolution Criterion
Temperature
Oral temperature ≤ 37.0 °C (without the use of antipyretics 
within 8 hours)*1
Oxygen saturation
a)  ≥ 94% on room air without supplemental oxygen*2
b)  In case pre-influenza infection oxygen saturation 
<94%*3: Return to pre-influenza oxygen saturation*4
Respiration rate
≤ 24/min or
return to pre-influenza infection oxygen requirement in 
patients with chronic oxygen use*4,5
Heart rate
≤ 100/min
Systolic 
blood 
pressure
≥ 90 mmHg (without inotropic support given within 2 
hours of assessment) *6
*1Based on the Vital Signs form, question“"Were there any antipyretic medications 
given within 8 hours before temperature measurement”"
*2Based on the oxygen saturation level measured on room air  and “YES” on the 
question ‘Is the patient able to sustain a blood oxygen saturation >= 94% when 
breathing room air for 15 min at any time on the day of assessment?’ on the vital 
signs form. 
*3 If pre-influenza oxygen saturation level  is below 94% and measured on room air 
*4Return to pre-influenza infection oxygen requirement is based on the oxygen 
supplementation form: “Has supplemental oxygen administration returned to that 
level provided prior to the current respiratory infection?” 
*5Chronic oxygen use is based on the question “Does the subject require chronic 
oxygen”
*6 Inotropic support given within 2 hours of assessment as recorded in the vital signs 
form.
Time to respiratory 
response (hours)
[Time-to event]
Time respiratory response is defined as the time (in hours) from first 
study drug intake until the first assessment (actual date and time) of a 
successive series of 4 recordings (over 5 scheduled successive analysis 
timepoints, 1 missing timepoint is allowed) where the resolution 
criteria of both blood oxygen saturation and respiration rate as 
specified in Table 4 are met.
Censoring and calculation of the time will be done analogous to “Time 
to clinical response”. 
In case 1 of the parameters is missing and the available parameter is  
not normalized then there is no resolution on this timepoint.
In the other cases where 1 or 2 parameters are missing, the resolution 
will be also missing.


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Incidence of treatment-
emergent adjudicated 
influenza complications
The incidence of treatment-emergent adjudicated influenza complications 
from first study drug intake until the end of the study will be categorized 
in a hierarchical fashion. The incidence will be presented for the overall 
category, for the subcategories and for each adjudicated complication
within a subcategory.
The overall category will consist of any adjudicated complication.
The following subcategories are defined:

Pulmonary complications:
o
respiratory failure,
o
primary viral pneumonia,
o
secondary bacterial pneumonia,
o
exacerbations of chronic underlying pulmonary diseases,
o
bronchitis
o
other complications

Extrapulmonary complications:
o
Cardiovascular and cerebrovascular disease (eg, myocardial 
infarction, congestive heart failure, arrhythmia, stroke),
o
Muscular disorders (eg, myositis, rhabdomyolysis),
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)
o
Other complications

Pulmonary complications including sinusitis and otitis

Major / minor complications

Infectious / non-infectious complications
The complications sinusitis and otitis are determined based on their 
MedDRA preferred terms as listed in Attachment 1, table 6, for the 
protocol terms ‘Sinus infection’ and ‘ear infection’ respectively. Only 
if those terms are judged to be complications by the adjudication 
committee they will be included for the endpoint ‘Pulmonary 
complications including sinusitis and otitis.
Incidence of not being 
hospitalized on Day 6.
On Day 6 (relative day) subject is in the hospital at least a part of the 
day (‘Yes’) or the subject is not in the hospital during the whole day
(‘No’).
Incidence of hospital 
readmission
Does the subject require hospital readmission after first discharge
(The start date of the hospital readmission must be at least 1 day in 
between the end of the previous hospitalization)? Categories will be 
Yes (1) or No (0).


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Incidence of all-cause 
mortality
Did the subject die after first dose of study drug?
Categories will be Yes (1) or No (0).
Hospital recovery scale 
outcome assessed on 
Day 2 to 14 excluding 
Day 6
The hospital recovery scale outcome defined per day for Day 2 to 14 
excluding Day 6 is defined analogous to the primary endpoint.
Fundamental Hospital 
recovery scale outcome 
assessed on Day 2 to 14 
The fundamental hospital recovery scale reflects the status of the 
subject objectively independent of the opinion of the investigator
(irrespective of being ready for discharge or requiring ICU level of 
care). The Fundamental hospital recovery scale outcome assessed on 
Day 2 to Day 14 is defined as follows:
6. Death

Subject died at any time on the day of assessment or earlier 
(all-cause mortality).
5. On invasive mechanical ventilation

Invasive mechanical ventilation is used at any time on the day 
of assessment.
4. In ICU 
3. Non-ICU hospitalization, on supplemental oxygen

Non-ICU hospitalized on the day of assessment (including 
readmittance) and the subject is on supplemental oxygen. On
supplemental oxygen is defined by:

Receiving supplemental oxygen through a face mask or nasal 
cannula.  
2. Non-ICU hospitalization, without supplemental oxygen

Non-ICU hospitalized on the day of assessment (including 
readmittance) 
1. Not hospitalized

Discharged from the hospital before the day of assessment .
Incidence of antibiotic 
treatment
Did the subject use antibiotic treatment after first dose of study drug?
Categories will be Yes (1) or No (0). The derivation of the categories 
will be based on the ATC level 2 categorization of concomitant 
medications. Concomitant medications coded as “J01” will be 
indicated as antibiotic treatment.


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Duration of antibiotic 
treatment (hours) 
[Duration]
The total number of hours a subject used antibiotic treatment (= event) 
during the period from first intake until study termination, calculated 
as sum of [(end date and time of event – start date and time of 
event)/3600], rounded to one decimal for all separate events per 
subject.
In case the start datetime is entirely or partially unknown and the 
medication was used before start of first intake the date and time of 
first intake will be used.
In case the end datetime is entirely or partially unknown and the 
medication was used after the trial ended, the last contact date will be 
used to calculate the duration.
If time of the start antibiotic treatment is missing, then use 00:00. If 
time of the end of antibiotic treatment is missing, then use 23:59The 
derivation of the duration is analogous to “Total length of hospital 
stay”.
Time to NEWS2 <= 2
(hours)
[Time- to event]
The time (hours) from first study drug to first time NEWS2<=2 
maintained for 24 hours i.e. the time of the first of at least 2 consecutive 
NEWS2 assessments with 24 hours in between.
If time is missing for the NEWS2, but timepoint is available then time 
will be imputed: if morning then time will be 08:00, if midday then 
time will be 12:00, if evening then time will be 20:00.
Subjects that did not maintain a NEWS2<= 2 for 24 hours until 
completion of the trial or withdrawal, will be censored at the time of 
completion of withdrawal of the study. If time is not available then it 
will be imputed with 23:59.
If the subject died before having a NEWS2 <=2 for 24 hours, the 
subject will be censored at the maximum time of all subjects.
Time to clinical 
improvement (hours)
[time- to event]
The time (hours) from first study drug to clinical improvement. 
Clinical improvement is defined as the minimum of the time to hospital 
discharge or time to NEWS2 <=2 maintained for 24 hours. 
Censoring will be done similarly as ‘time to hospital discharge’ and 
‘time to NEWS2<=2’.


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Time to clinical failure
(days)
[Time-to event]
The time (in days) from first study drug intake to first clinical 
failure(=event). 
Clinical failure is defined as having one of the following events

HRS >3
The first event will be considered. In case mechanical ventilation is 
started multiple times, only the first start of mechanical ventilation 
after first study drug intake is used.
Subjects without a clinical failure at the time of completion or at the 
time of withdrawal from the study will be censored at the date of 
completion or withdrawal. 
(Date of event or censoring–- date of first dose of study drug) + 1
Incidence of Mortality 
per day
Number and percentage of subjects that died and cumulative number
and percentage of subjects that died per day after first study drug.
5.3.1.2.
Viral kinetics
The viral culture (TCID50) measurements are analyzed using two methods (depending on influenza 
subtype); i.e. NP ELISA and Hemagglutination Inhibition Assay. For analysis purposes the results 
from the NP ELISA method will be used when available, otherwise the results from the 
Hemagglutination Inhibition Assay will be used. This will be determined per analysis visit. As a 
consequence, the series of results of a subject can be a combination of both methods (for example 
at baseline the NP ELISA result is used and at Day 3 the Hemagglutination Inhibition Assay result 
is used).
Endpoints listed below will be based on results from nasal mid-turbinate (MT) swabs taken from 
central testing, excluding data from leftover samples from local virology tests.
Measurement
Formula
Log10 viral load actual 
values
Log10 of the actual values as measured with qRT PCR
Viral load negativity 
(Log10 vp/mL)
Viral load will be categorized as Negative or Positive:

Negative (“TARGET NOT DETECTED”)

Positive (’TARGET DETECTED’ or an actual value).


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Viral 
load 
categorization
(Log10 
vp/mL)
Viral load will be categorized as Target not detected, Target detected, 
and Quantifiable:

Target not detected 

Target detected 

Quantifiable
Log10 viral load change 
from baseline
Log10 viral load post-baseline value – log10 viral load baseline value
Log10 viral titer actual 
values
Log10 of the actual values as measured with viral culture
Viral titer negativity 
(Log10 TCID50/mL)
Viral titer will be categorized as Negative or Positive:

Negative (lower than LOQ)

Positive (quantifiable results)
Log10 viral titer change 
from baseline
Log10 viral titer post-baseline value – log10 viral titer baseline value
Viral load AUC0-10d
trapezoidal method
■
Viral load AUC calculated from baseline to Day 10: 
AUC is calculated by the trapezoidal summation rule, based on 
planned days of sampling, including the timepoints with 
(imputed) values available:
Sum over i of (ti+1-ti)*(Viral loadti+1+Viral loadti)/2
The following rules will be applied in the order described below 
to deal with missing values before calculating the Viral load 
AUC:

If the baseline value is missing, then the mean baseline 
value over all subjects in the ITT-i set will be used.

If a single or sequential intermediate value (not the baseline 
value) is missing, then the missing value will be replaced 
by linear interpolation of the two adjacent values. Note: this 
is done automatically when applying the trapezoidal 
summation rule. If Day 10 value is missing, but there is an 
assessment after Day 10, then this value will be used to 
interpolate the value of Day 10. 

If the Day 10 value is missing, and there are no values 
available after Day 10, then it will be imputed with the last 
observed post-baseline value (LOCF).
Note: In case no post baseline value is available the AUC will be 
missing.


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Viral titer AUC0-10d
trapezoidal method
Viral titer AUC calculated from baseline to Day 10: 
AUC is calculated by the trapezoidal summation rule, based on 
planned days of, including the timepoints with (imputed) values 
available:
Sum over i of (ti+1-ti)*(Viral titerti+1+Viral titerti)/2
The following rules will be applied in the order described below
to deal with missing values before calculating the Viral titer
AUC:

If the baseline value is missing, then the mean baseline 
value over all subjects in the ITT-i set will be used.

If a single or sequential intermediate value (not the baseline 
value) is missing, then the missing value will be replaced 
by linear interpolation of the two adjacent values. Note: this 
is done automatically when applying the trapezoidal 
summation rule. If Day 10 value is missing, but there is an 
assessment after Day 10, then this value will be used to 
interpolate the value of Day 10.

If the Day 10 value is missing, and there are no values 
available after Day 10, then it will be imputed with the last 
observed post-baseline value (LOCF).
Note: In case no post baseline value is available the AUC will be 
missing.
Time to viral negativity 
by qRT-PCR (days)
[Time-to event]
The time to viral negativity is defined as the time (in days) from first 
study drug intake until a subject is considered influenza A viral 
negative. This is the first timepoint of two consecutive timepoints 
with a negative nasal MT swab, i.e. the first and next assessment 
equal to ’negative’ (ignoring missing values). In case the first 
‘negative’ is the last available assessment the subject is considered to 
have reached viral negativity at this last assessment. 
If this doesn’t occur, a subject will be censored at the time of the last 
observed non-negative swab + 1 day. Note that for deriving the time 
to viral negativity by qRT-PCR every subject is considered positive
at baseline. For subjects without postbaseline records, they are 
censored at Day 1.
Time to viral negativity 
by viral culture (days)
[Time-to event]
The algorithm for Time to viral negativity by viral titer is similar as 
‘Time to viral negativity by viral load’ but viral titer assessments are 
used instead.


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5.3.1.3.
Patient Reported Outcomes
Measurement
Formula
Daily activities 
resumption
The daily activities resumption 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 category “returned to daily activities” and responses 
'Somewhat', 'Quite a Bit' and 'Very much' will be considered in 
category “not returned to daily activities”. 
Time to return to daily 
activities (days)
[Time-to event]
The time to return to daily activities is defined as the time in days 
from initiation of study treatment (baseline assessment excluded) to 
the first of a successive series of 2 recordings in which the response 
is considered as returned to daily activities. The 2 successive 
recordings may have been done over 3 scheduled successive 
analysis timepoints, in case of 1 missing in between timepoint. 
In case the return to daily activities is not achieved, data will be 
censored. 
Censoring will be done as follows:
1) Last non-missing record in indicate return to daily activities 
(but insufficient recordings)
Censoring will be done at the first record of return to daily 
activities
2) Last non-missing record does not indicate return to daily 
activities
Censoring will be done one day (24 hours) after the last 
observation.
The time to return to daily activities is calculated as: Date and time 
of event (actual) or censoring - date and time of first dose of study 
drug)/(3600*24), rounded to one decimal.
Subjects without postbaseline records are excluded from the analysis. 
Patient Global 
Impression of Severity 
of Influenza symptoms
The PGIS captures daily influenza symptom severity from the 
subjects’ perspective per timepoint. Responses will be categorized as 
:“No Flu symptoms today”, and “Mild”, "Moderate", "Severe" or 
“Very Severe”. 


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Patient global 
Impression of Change 
in Influenza symptoms
The PGIC[4] is 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 and this is done per timepoint.[5]
Categories are: “Much better”, “Somewhat better”, “A little better” 
“About the same”, “A little worse”, “Somewhat worse” and “Much 
worse”. 
EQ-5D dimension 
parameters: 
Mobility, 
Self-care, 
Usual activities, 
Pain/discomfort, 
Anxiety/depression
The EQ-5D (Attachment 5)[2] descriptive system consists of 5 
dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) with 5 possible levels (no problems (level code 
= 1), slight problems (level code = 2), moderate problems (level code 
= 3), severe problems (level code = 4), extreme problems (level code 
= 5)) (see Table 5). Each dimension will be captured in one parameter
Table 5: EQ-5D Dimensions
Dimension
Level
Interpretation
1
Mobility
1
No problems
I have no problems in walking about
2
Slight problems
I have slight problems in walking about
3
Moderate 
problems
I have moderate problems in walking about
4
Severe 
problems
I have severe problems in walking about 
5
Extreme 
problems
I am unable to walk about
2
Self-care
1
No problems
I have no problems washing or dressing myself 
2
Slight problems
I have slight problems washing or dressing 
myself 
3
Moderate 
problems
I have moderate problems washing or dressing 
myself 
4
Severe 
problems
I have severe problems washing or dressing 
myself 
5
Extreme 
problems
I am unable to wash or dress myself 
3
Usual activities
1
No problems
I have no problems doing my usual activities
2
Slight problems
I have slight problems doing my usual activities
3
Moderate 
problems
I have moderate problems doing my usual 
activities
4
Severe 
problems
I have severe problems doing my usual activities
5
Extreme 
problems
I am unable to do my usual activities
4
Pain/discomfort
1
No problems
I have no pain or discomfort
2
Slight problems
I have slight pain or discomfort
3
Moderate 
problems
I have moderate pain or discomfort
4
Severe 
problems
I have severe pain or discomfort
5
Extreme 
problems
I have extreme pain or discomfort
5
Anxiety/depression
1
No problems
I am not anxious or depressed
2
Slight problems
I am slightly anxious or depressed


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3
Moderate 
problems
I am moderately anxious or depressed
4
Severe 
problems
I am severely anxious or depressed
5
Extreme 
problems
I am extremely anxious or depressed
EQ-5D visual analogue 
scale (VAS)
EQ-5D VAS is a continuous score ranging from 0 (worst health you 
can imagine) to 100 (best health you can imagine).
EQ-5D VAS change 
from baseline
EQ-5D VAS post-baseline value – EQ-5D VAS baseline value
EQ-5D VAS clinically 
relevant change from 
baseline
The change from baseline in EQ-5D VAS will be categorized in two 
ways:
1. ≤-7, -6 to 6, ≥7
2. ≤-10, -9 to 9, ≥10
EQ-5D Valuation index
EQ-5D Valuation index summarizes the information of the 5 
dimensions of the descriptive system.
a.
Assign the level code 1, 2, 3, 4 and 5 to each level of the 
5 dimensions (see table)
b. Create a health state for each patient-time point 
combination. A health state is a combination of 5 level 
codes; one level code for each dimension. The dimensions 
are 
ordered 
as 
described 
in 
the 
table 
above.
E.g. health state 12543 indicates ‘no problems in walking 
about, slight problems washing or dressing myself, unable 
to do my usual activities, severe pain or discomfort, 
moderately anxious or depressed’.
c.
Assign an index value to each health state as defined in 
Attachment 5 where EQ-5D health state is converted to a 
single summary index by applying a formula that 
essentially attaches weights to each of the levels in each 
dimension. The algorithm is based on the valuation of EQ-
5D health states using the UK TTO (=time trade-off 
method) based value set.
EQ-5D Valuation index 
change from baseline
EQ-5D valuation index post-baseline value – EQ-5D valuation index 
baseline value


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5.3.2.
Analysis Methods
Descriptive statistics
The descriptive statistics that will be shown may include the number of subjects, mean, standard 
deviation, standard error, 95% CI, median, range, interquartile range and geometric mean with 
corresponding 95% CI.
Kaplan-Meier analysis, Gehan-Wilcoxon test and Log-rank test
All Time-to event variables will be analyzed using a stratified Gehan-Wilcoxon test, a stratified 
log-rank test and Kaplan-Meier estimates. For endpoints where the start time is not the start of the 
treatment A summary table including number of subjects included in the analysis, number of 
subjects censored, 25th and 75th percentiles and median time-to event, with 95% confidence 
intervals based on log-log transformation method, and the p-values calculated based on the
stratified Gehan-Wilcoxon test and stratified log-rank test will be presented. 
The data will be presented graphically using the Kaplan-Meier estimate of the survival function 
by treatment.
For all subgroup analyses, Kaplan-Meier plots will be produced per subgroup and Gehan-
Wilcoxon test will be produced for each category of a subgroup.
Accelerated failure time (AFT) model
When indicated, time-to event variables will be compared between pimodivir and placebo using 
an accelerated failure time (AFT) model. The distribution to be used will be determined based on 
the goodness of fit of the model using Akaike’s information criterion and will be selected from the 
following parametric families: lognormal, log-logistic, or Weibull. The AFT model will include
the fixed, categorical effects for treatment (with placebo as the reference), the time from admission 
to start of treatment (for the time to hospital discharge and time to hospital discharge readiness) 
and stratification factors (type of baseline SOC, time of onset of symptoms and screening
NEWS2). The scale parameter will be the same across groups
A summary of the final AFT model will include parameter estimates and associated standard 
errors, estimated accelerated failure time ratios versus placebo and associated 95% confidence 
intervals, and p-values. The survival curves per treatment group of the accelerated failure time 
model will also be shown with the Kaplan-Meier plots included in the same output.
For subgroup analyses the survival curves will be shown for each subgroup category separately.
Bootstrapping with replacement, considering also the actual proportion of subjects in each stratum, 
will be used to obtain a 100% sample size 10001 times. The median (95% CI) time-to event will 
be derived from the 10001 bootstrapped samples.
Cox Proportional Hazard model
A stratified Cox proportional hazards model will be used adjusted for the stratification factors and 
for the time from admission to start of treatment (for the time to hospital discharge and time to 
hospital discharge readiness),. The hazard ratio for the comparison of pimodivir versus placebo
will be reported together with the 95% confidence interval. A Log-log plot of survival will be 
added to check the proportional hazard assumption of the Cox proportional hazards model.


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For the subgroup analyses the Log-Log plot of survival will be shown for each subgroup category 
separately.
Logistic regression model 
A logistic regression model (Firth’s penalized likelihood approach), with treatment group and 
stratification factors as fixed effects, will be used to analyze binary outcomes and to obtain the 
odds ratios (95% CI) for the comparison of pimodivir versus placebo. 
5.3.2.1.
Clinical outcome
Time-to event parameters for clinical outcome
The time-to event parameters for clinical outcome will be analyzed as described above using a 
stratified Gehan-Wilcoxon test, a stratified log-rank test, a Kaplan‑Meier analysis, an accelerated 
failure time model and a Cox proportional hazards model The Gehan-Wilcoxon test is the primary 
analysis for time-to-event parameters. The Kaplan-Meier analysis will provide the primary 
estimation of time-to-event.
Duration parameters
Descriptive statistics of the duration parameters will be shown for all subjects that had the specific 
event. e.g. only subjects admitted to ICU will be included in the total time in ICU analysis
Total length of hospitalization, total time in ICU, total duration of antibiotics, and total time on 
mechanical ventilation will be analyzed by using the Hodges-Lehman approach. Corresponding 
95% CIs will be presented as well.
Incidence parameters
For each parameter the number and percentage of subjects in each category and subcategory will 
be tabulated and listed. All Subjects in the applicable analysis set will be counted for the 
denominator of the proportion.
The occurrence (yes/no) as described for the incidence parameters will be analyzed using logistic 
regression as described above (Section 5.3.2).
The occurrence (yes/no) of influenza complications will be analyzed using logistic regression as 
described above for the following categories:

the overall influenza complications 

the pulmonary complications, 

the extrapulmonary complications 

the infectious complications

the non-infectious complications 

the major complications

the minor complications 

the pulmonary complications including sinusitis and otitis


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Hospital recovery scale outcome and fundamental hospital recovery scale outcome on Day 
2 to 14
This parameter will be analyzed analogous to the primary endpoint: hospital recovery scale 
outcome on Day 6, but then for Day 2 to 14 with Day 6 excluded for the HRS and including Day 6
for the fundamental HRS. The proportional odds model will be applied, and the proportional odds 
assumption will be tested for the treatment effect. The same 5 dichotomization of the HRS will be 
analyzed using a logistic regression model. Also, similarly as the primary endpoint the Van Elteren 
test will be provided in case the proportional odds assumption is not valid. The MI analysis will 
not be applied.
A tabulation will be made of the (fundamental) hospital recovery scale outcomes at each day
(including Day 6), taking only non-missing values into account (i.e.: the percentages of the six 
categories per day should sum up to 100%). A second tabulation will be made of the hospital 
recovery scale outcomes at each day including a category for missing values. The first day with 
30% of subjects not hospitalized will be identified. All Subjects in the applicable analysis set will 
be counted for the denominator of the calculation.
5.3.2.2.
Viral Kinetics
Viral load and viral titer over time
The actual values and change from baseline of the viral load and viral titer over time will be shown 
descriptively and by mean (SE) plots per analysis timepoint.
Individual AUCs from baseline to Day 10 for both viral load and viral titer will be calculated using 
the trapezoid method and summarized using descriptive statistics.
Viral load negativity, viral load categorization and viral titer negativity will be summarized using 
frequency tabulations (n and %) at each analysis visit. All subjects with lab data on the specific 
visits/timepoints will be used as denominator. 
■
Difference in mean viral load AUC calculated from baseline to Day 10:
Post-baseline mean viral load values up to and including Day 10 over time will be analyzed using 
a restricted maximum likelihood based repeated measures approach. Analyses will include the 
fixed, categorical effects of treatment, strata, visit, and treatment-by-visit interaction, as well as 
the continuous, fixed covariates of baseline viral load and baseline viral load -by-visit interaction. 
The following list of covariance structures will be applied in the model fit, in the specified order, 
and the first correlation structure to yield convergence will be applied in the analysis:
■
Unstructured [UN]     
■
Ante-dependence [ANTE(1)]      
■
Heterogenous Toeplitz [TOEPH]    
■
Heterogeneous CS [CSH]    
■
Heterogeneous AR(1) [ARH(1)]    
■
Toeplitz [TOEP]


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The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
The model above will be used to estimate the difference in the viral AUCs for active versus 
placebo. 
Post-baseline mean viral titer values up to and including Day 10 will be analyzed similarly.
A least squares means ±95% CI plot will also be provided for the estimated viral load and estimated 
viral titer over time.
Time to viral negativity by viral load and by viral titer
Analysis will be done analogous to the time-to event parameters for clinical outcome. The baseline 
viral load or viral titer will be added as covariate to the AFT and Cox Proportional Hazard model.
5.3.2.3.
Patient Reported Outcomes
Time to return to daily activities
Time to return to daily activities will be analyzed analogous to the time-to event parameters for 
clinical outcomes.
Patient Global Impression parameters and daily activities resumption
The subject’s perception of severity and changes of influenza symptoms (PGIS, PGIC) and daily 
activities resumption will be tabulated per parameter and per category by analysis timepoint using 
frequency tabulations.
EQ-5D dimension parameters
Tabulations of the number (and percentage) of subjects per parameter, response and time point 
will be shown per treatment group. 
EQ-5D VAS, EQ-5D Valuation index
The actual values and changes from baseline will be shown descriptively and by mean (SE) plots 
per analysis visit.
The proportion of subjects with a clinically relevant change from baseline of 7 or more (decrease 
or increase) and of 10 or more (decrease or increase) will be tabulated.
Missing data
1) If – for a questionnaire – one (or more) dimensions of the descriptive system are missing then

The EQ-5D VAS will be included in the analysis

The valuation index will not be included in the analysis

The non-missing dimensions of EQ-5D descriptive system will be 
       included in the analysis of the separate dimensions
2) If – for a questionnaire – the EQ-5D VAS is missing then
the EQ-5D descriptive system and valuation index will be included in the analysis if complete 
(otherwise see 1)


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6.
TASTE AND SWALLOWABILITY
6.1.
Definition
Taste and swallowability will only be assessed for adolescents in this study. 
The acceptability of the taste will be derived from the responses to the overall question on taste, 
dichotomizing the responses 'None' and 'Weak' as acceptable and responses 'Moderate' or 'Strong' 
as unacceptable.
For swallowability, a dichotomization of the responses will be made of ‘slightly difficult’ or worse 
vs ‘neither difficult nor easy’ or better.
6.2.
Analysis Methods
Taste and swallowability questionnaire results (collected for adolescents only 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 of the actual responses. Additionally the number of subjects (%) will be presented by 
response category (including dichotomization) for swallowability and taste separately. Analyses 
will be done on the safety set.


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7.
SAFETY
All safety analyses will be done on the Safety Set. 
7.1.
Adverse Events
7.1.1.
Definitions
Coding of AE
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities. Events are looked at on the level of their preferred 
term.
Treatment-emergent AE
Pre-treatment AEs are defined as AEs that were reported or worsened after signing the ICF up to 
the start of study drug dosing. Treatment-emergent AEs (TEAE) are defined as AEs that were 
reported or worsened on or after the start of study drug dosing and up to and including the end of 
the follow-up phase. 
An AE, at the preferred term level, is considered treatment-emergent if:
-
an AE starts after or at first dose of study drug and
o
The AE was not present prior to first dose of study drug
-
an AE was present prior to first dose of study drug:

the same AE (based on preferred term) starts at the end date or the day 
after the end date of the AE present prior to first dose and new AE has 
worsened, ie an increase in toxicity grade or changed to an SAE

the same AE (based on preferred term) started 2 or more days after the end 
date of the AE present prior to first dose
-
The start date of the AE is missing
-
The start time of the AE is missing, and the AE was not present the day before first dose 
of study drug, and the start date of the AE is the same as the start date of first dose of 
study drug
-
The day is missing of the AE start date but month and year are the same as month and 
year of first study drug intake.
-
The month is missing of the AE start date but the year is the same as the year of the first 
study drug intake.
Phase allocation of AE
Adverse events present in the SDTM database are allocated to phases based on their start date and 
time. If the start date and time of an event falls between (or on) the start and stop date and time of 
a phase, the AE is attributed to that phase (treatment-emergent principle).
Rule: phase start datetime ≤ AE start datetime ≤ phase stop datetime.
Incomplete AE dates and or times (i.e. time and/or day and/or month and/or year missing):

In case of partial AE start dates and or times, the events are allocated to the phases using the 
available partial information on start and end datetime; no imputation will be done. If, for 
instance, for the AE start date only month and year are available, these data are compared to 


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the month and year information of the phases. This rule may lead to multiplication of the event 
as a consequence of its assignment to multiple phases or subperiods. 

In case of a completely missing AE start date, the event is allocated to the first active treatment 
phase and subperiod, except if the end date of the AE falls before the start of this active 
treatment phase and subperiod.

In case of a completely missing AE end date, the following rules apply: 
-
in case the date is identified as unknown the date will remain missing; 
-
in case the date is not flagged as unknown the date is assumed to be the cut-off date of 
the analysis for subjects still ongoing in the study, and the end date of the last phase for 
subjects who discontinued or completed the study. 
Examples:
Screening phase: start date: 02JAN2017 - stop date: 28JAN2017
Treatment phase: start date: 29JAN2017 - stop date: 12AUG2017
1) Adverse event: start date: JAN2017- stop date: 15JUL2017
As the AE start date only has information about month and year, only this information will 
be used from the phases and therefore the AE will be assigned to the screening phase as well 
as to the treatment phase.
2) Adverse event: start date: JAN2017- stop date 27JAN2017 As the AE stops before or at the 
start of the treatment phase, it is only assigned to the Screening phase.
Remarks: In addition to the date information, time information is taken into account to allocate 
AEs to phases.
Adverse events
The variables attributed to adverse events are

AE term (verbatim and MedDRA preferred term and system organ class)

Onset datetime, End datetime and duration of AE

Serious AE (Yes/No), if yes classification will be listed

Toxicity grade (Mild, Moderate, Severe, Potentially life-threatening)

Action taken with study treatment (Dose not changed, Dose interrupted, Drug withdrawn, 
Not applicable, Unknown)

Relation to study treatment (Not related, Doubtful, Possible, Probable, Very likely)

Outcome of AE

AE leading to death (Yes/No)

Concomitant treatment taken for AE (Yes/No)

Influenza-related complication (Yes/No)

Required hospitalization/prolonged hospitalization (Yes/No)
Anticipated Events
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.


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For the purposes of this study the following events will be considered anticipated events (see 
Attachment 1: for the classification of AEs into Anticipated Events and Anticipated Event 
Groups):

Pneumonia

Bronchitis

Sinus infections

Ear infections

Worsening of asthma, asthma attack

COPD exacerbation

Complications of sickle cell disease, sickle cell crisis

Complications of diabetes mellitus, diabetic ketoacidosis

Acute respiratory distress syndrome (ARDS)
Influenza-related complications
The categories of influenza-related complications are defined in 5.3.1.1
Confirmed diarrhea events
Additional details required to confirm a diarrhea event, including number of loose stools episodes 
per day and stool consistency, will be collected for subjects who report a diarrhea type event.
A confirmed diarrhea event is defined as three or more loose stools episodes per day with a 
consistency of ‘loose’ or ‘watery’.
7.1.2.
Analysis Methods
Treatment-emergent adverse events
There will be no formal statistical testing unless indicated otherwise.
A summary will be provided for the following TEAEs per phase (Treatment phase, Follow-up 
phase), subperiod and for the combination of Treatment and Follow-up phase:
-
any adverse events, 
-
serious adverse events, 
-
deaths due to AE, 
-
adverse events by worst toxicity grade, 
-
AEs of worst grade 3 or 4
-
AEs of worst grade 3 
-
AEs of worst grade 4
-
AEs at least possibly related to study drug, 
-
AEs for which study drug was temporarily stopped, 
-
AEs for which study drug was permanently stopped, 
-
AEs leading to study discontinuation
-
serious adverse events that were at least possibly related to study drug,
-
Adjudicated influenza related complications
-
COVID-19 AEs
-
COVID-19 Serious AEs
-
COVID-19 Non-serious AEs


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The adverse events will be shown by MedDRA system organ class and preferred term, in order of 
descending overall frequency in the pimodivir group. For each AE, the percentage of subjects who 
experience at least 1 occurrence of the given event will be summarized by treatment group and per 
phase (Treatment phase, Follow-up phase), subperiod and for the combination of Treatment and 
Follow-up phase. The tabulations will be provided for the following categories:

any adverse events

serious adverse events

AEs at least possibly related to study drug

AEs for which study drug was temporarily stopped

AEs for which study drug was permanently stopped

AEs leading to study discontinuation

serious adverse events that were at least possibly related to study drug

AEs related to COVID-19 infection

Serious AEs related COVID-19 infection

AEs related to COVID-19 infection leading to death
and in addition for treatment emergent adverse events with incidence of at least 5% in any 
treatment group. 
In order to fulfil requirements for the plain language summary document and presentations for 
EudraCT the following adverse event categories will be shown by MedDRA system organ class 
and preferred term per phase (Treatment phase, Follow-up phase) and subperiods (treatment 
subperiod and treatment extension subperiod) and for the combination of Treatment and Follow-
up phases. No tabulations by subgroups will be provided for these categories:

deaths due to AEs that were at least possibly related to study drug

AEs for which study drug was permanently stopped that were at least possibly related to 
study drug

non-serious AEs that were at least possibly related to study drug

any non-serious AEs
AEs leading to death, SAEs, AEs leading to dose interruption or permanent stop of study drug, 
AEs related to COVID-19 infection will be listed separately. All AEs will be listed in an individual 
subject data listing, including pre-treatment AEs. All listings will be provided for the safety set.
The duration (in days) of an AE is calculated based on the AE start date and AE end date as: 
AE duration = AE end date – AE start date +1


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Note that the AE duration will be calculated in case the start date and end date is fully known, in 
case of partial or missing start and end dates the AE duration will be put on missing.
Anticipated Events
Frequency tabulations of anticipated events and anticipated event grouped terms will be shown for 
treatment phase and subperiods, follow-up phase and for the combination of treatment + follow-
up phases. The tabulation will show per treatment the number (%) of subjects with serious, non-
serious and total anticipated events and anticipated event grouped terms and a one-sided p-value 
of Fisher exact test for anticipated events and anticipated event grouped terms.
A listing of the anticipated events will be added. 
More details on the anticipated events analysis can be found in the Anticipated Events Safety 
Monitoring plan.
Influenza-related complications
Adverse Events adjudicated as influenza-related complications will be will be tabulated for 
treatment phase and subperiods, follow-up phase and for the combination of treatment + follow-
up phases. 
Adverse events that were assessed by the investigator as influenza-related complications will also 
be tabulated by category, subcategory (see Section 5.3.1.1) and adverse event, for treatment phase
and subperiods, follow-up phase and for the combination of treatment and follow-up phases. A 
listing showing the AEs reported as influenza-related complications and complication information 
will be made linking the information to the AE listing. Additional analyses on adjudicated 
influenza-related complications are described in Section 5.3.2.1.
Confirmed diarrhea events
The number and percentage of subjects who experience at least 1 occurrence of confirmed diarrhea 
events will be summarized by treatment group and per phase (Treatment phase, Follow-up phase) 
and subperiods (treatment subperiod and treatment extension subperiod) and for the combination 
of Treatment and Follow-up phases.
For all subjects that complete the additional diarrhea form, a cross-tabulation of number of loose 
stools episodes per day (categorized as 1, 2, 3 or more) versus stool consistency will be produced
by treatment group and per phase (Treatment phase, Follow-up phase) and for the combination of 
Treatment and Follow-up phases. If a subject has more than 1 diarrhea event per phase, then the 
worst response from all events in that phase will be tabulated.
Descriptive statistics will be produced by treatment group for the number of days from first dose 
of study drug to onset of first diarrhea event and for total duration of diarrhea events. A frequency 
tabulation will be produced by treatment group for the number of days from last dose of study drug 
to resolution of last diarrhea event.


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Frequency tabulations will be produced by treatment group and per phase (Treatment phase, 
Follow-up phase and subperiods) and for the combination of Treatment and Follow-up phases for
the severity grade of the diarrhea event and for whether any concomitant medication was used to 
treat the diarrhea event.
No tabulations by subgroups will be provided.
All information recorded on the specific diarrhea form will be listed.
7.2.
Clinical Laboratory Tests
7.2.1.
Definitions
Laboratory parameters of hematology, serum chemistry and urinalysis will be investigated: all 
analyses will be done on SI-converted values as available in the database.
Imputations of numerical values expressed as characters
In case a laboratory test result is censored (no numeric value is available, but only a verbatim 
term), the following rules are applied:

‘<x’ or ‘>x’: a numeric value will be imputed by the cut-off value decreased or increased with 
one unit respectively

‘≤x’ or ‘≥x’: imputation by x.
Toxicity grades and abnormalities for laboratory parameters:
The laboratory abnormalities will be determined according to the criteria specified in the WHO 
grading table[12] (see Attachment 2). Available toxicity grades in the laboratory raw data will not 
be used. In case no toxicity grades are defined for a test, the abnormalities (above/below normal 
range) will be used. 
In determining toxicity grades/abnormalities for each subject the following rules are applied:

Worst grades/abnormalities are determined over the whole observational period, per phase 
(treatment, follow-up and combination treatment + follow-up) and per subperiod (treatment, 
treatment extension) separately, including all post-baseline scheduled and unscheduled 
measurements of that phase.

The abnormalities “abnormally low” and “abnormally high” are considered equally important, 
i.e. if a subject has as well an abnormally low as an abnormally high value post-baseline, both 
abnormalities are shown in the tables. (This implies that the sum of the percentages can be 
more than 100%)

If, for a specific test, the grading list provides distinct limits for abnormally low (=hypo) 
values as well as for abnormally high (=hyper) values, this test should be repeated for hyper 
and hypo limits separately in cross-tabulations.


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Treatment-emergent definition for toxicity grades and abnormalities
An abnormality (toxicity grade or abnormality based on normal ranges) will be considered 
treatment-emergent if it is worse than the baseline abnormality. If the baseline abnormality is 
missing, the abnormality is always considered as treatment-emergent. A shift from “abnormally 
low” at baseline to “abnormally high” post-baseline (or vice versa) is also treatment-emergent. 
7.2.2.
Analysis Methods
Actual values and changes from baseline will be summarized by treatment group at each scheduled 
timepoint.
A tabulation of the toxicities/abnormalities per timepoint will be presented. This table will also 
show the number and percentage of subjects per toxicity/abnormality, the number and percentage 
of subjects per treatment-emergent abnormality, and the cumulative number of subjects per 
treatment-emergent abnormality per post-baseline timepoint. Include in this table the safety 
follow-up visit, the Day 28 final study visit and the last study visit. 
Additionally, a tabulation of the worst toxicity/abnormality will be presented. This table will show 
the number and percentage of subjects per worst toxicity/abnormality. A cross-tabulation of the 
worst toxicity/abnormality versus baseline will be presented per phase (treatment, follow-up and 
combination treatment + follow-up) and per subperiod (treatment, treatment extension). This table 
will also show the number and percentage of subjects per worst toxicity/abnormality, the number 
and percentage of subjects per treatment-emergent worst toxicity/abnormality, and the cumulative 
number of subjects per treatment-emergent toxicity/abnormality.
For tabulations of hyperglycemia, the results will also be presented for the subgroup of subjects 
that had been fasting for at least 10 hours.
Mean ± SE graphs over time for the actual values and changes from baseline will be generated for 
all tests performed.  
A listing of abnormal individual subject hematology and clinical chemistry values from scheduled 
and unscheduled timepoints will be provided. This listing will include all other timepoints for the 
corresponding subject/parameter.
Grade 3 or higher toxicity laboratory values will be listed separately
Frequency tables (n %) will be produced for the categorical urinalysis parameters by treatment 
group at each scheduled timepoint. Include in this table the safety follow-up visit, the Day 28 final 
study visit and the last study visit. 
All urinalysis results will be listed.


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7.3.
Vital signs
7.3.1.
Definitions
Vital signs (including temperature, pulse rate, respiratory rate, and blood pressure), peripheral
capillary oxygen saturation, and level of consciousness (AVPU) will be included in the analysis. 
Vital Signs abnormalities will be determined according to the WHO grading scale boundaries 
defined in Attachment 3, Table 4: Resolution Criteria for Vital Signs.
Worst abnormalities are determined over the whole observational period and per phase (treatment, 
follow-up and combination treatment + follow-up) and per subperiod (treatment, treatment 
extension), including all post-baseline scheduled and unscheduled measurements.  
An abnormality (based on normal ranges) will be considered treatment-emergent if it is worse than 
the baseline abnormality. If the baseline abnormality is missing, the abnormality is always 
considered as treatment-emergent. A shift from “abnormally low” at baseline to “abnormally high” 
post-baseline (or vice versa) is also treatment-emergent.
Assessments (except oxygen saturation) taken while the subject was not in a supine position will 
not be included in descriptive statistics but will be considered in determining worst case values.
7.3.2.
Analysis Methods
Actual values and changes from baseline will be summarized by treatment group at each scheduled 
timepoint. 
A tabulation of the abnormalities per timepoint will be presented. This table will also show the 
number and percentage of subjects per abnormality, the number and percentage of subjects per 
treatment-emergent abnormality, and the cumulative number of subjects per treatment-emergent 
abnormality per post-baseline timepoint. Include in this table the safety follow-up visit, the Day 
28 final study visit and the last study visit.
Additionally, a tabulation of the worst abnormality will be presented. This table will show the 
number and percentage of subjects per worst abnormality.
A cross-tabulation of the worst abnormality versus baseline will be presented per phase (treatment, 
follow-up and combination treatment + follow-up) and per subperiod (treatment, treatment 
extension). This table will also show the number and percentage of subjects per worst abnormality, 
the number and percentage of subjects per treatment-emergent worst abnormality, and the 
cumulative number of subjects per treatment-emergent abnormality.
Mean ± SE graphs over time for the actual values and changes from baseline will be generated for 
all tests performed.  
Vital signs data for subjects having at least one treatment-emergent abnormality will be listed.
7.4.
Physical examinations
Abnormal physical examination results will be listed.


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7.5.
Electrocardiogram
PR interval, QT interval, QRS interval, Heart Rate and QTc intervals using Bazett’s correction 
formula and Fridericia's correction formula will be investigated[1]. QTc values will be used as 
reported, they will not be recalculated. If the ECG is performed in triplicates the mean of the non-
missing ECG recordings will be used as the value for each specific parameter and timepoint.
7.5.1.
Definitions
ECG abnormalities will be determined according to the boundaries defined in Attachment 4.
An abnormality (based on normal ranges) will be considered treatment-emergent if it is worse than 
the baseline abnormality. If the baseline abnormality is missing, the abnormality is always 
considered as treatment-emergent. A shift from “abnormally low” at baseline to “abnormally high” 
post-baseline (or vice versa) is also treatment-emergent. The treatment-emergent definition is 
applicable in both, the treatment and follow-up phase.
Assessments taken while the subject was not in a supine position will not be included in descriptive 
statistics but will be considered in determining worst case values.
7.5.2.
Analysis Methods
Actual values and changes from baseline will be summarized by treatment group at each scheduled 
timepoint. 
A tabulation of the abnormalities per timepoint will be presented. This table will also show the 
number and percentage of subjects per abnormality, the number and percentage of subjects per 
treatment-emergent abnormality, and the cumulative number of subjects per treatment-emergent 
abnormality per post-baseline timepoint. Include in this table the safety follow-up visit, the Day 28 
final study visit and the last study visit.
A cross-tabulation of the worst abnormalities versus baseline will be presented per phase 
(treatment and follow-up, treatment and follow-up phase and subperiods). This table will also show 
the number and percentage of subjects per worst abnormality, the number and percentage of 
subjects per treatment-emergent abnormality, and the cumulative number of subjects per 
treatment-emergent abnormality.
Mean ± SE graphs over time for the actual values and changes from baseline will be generated for 
all tests performed.
A frequency tabulation of the QT/QTc change categories at Day 28 versus baseline will be 
presented.
ECG data for subjects having at least one treatment-emergent abnormality will be listed.


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7.6.
National Early Warning Score
7.6.1.
Definitions
NEWS
The NEW Score[7] is an aggregated score with a range from 0 to 20 calculated as the sum of the 
scores per parameter (see Table 6, all parameters are based on the VS dataset and CM). However, 
in case information for a parameter is missing the NEW score cannot be calculated. 
Table 6: National Early Warning Score (NEWS)*
Physiological
Parameters
3
2
1
0
1
2
3
Respiration 
Rate
≤8
9 - 11
12 - 20
21 - 24
≥25
Oxygen
Saturations
≤91
92 - 93
94 - 95
≥96
Any 
Supplemental
Oxygen
Yes
No
Temperature
≤35.0
35.1 - 36.0
36.1 - 38.0
38.1 - 39.0
≥39.1
Systolic BP
≤90
91 - 100
101 - 110
111 - 219
≥220
Heart Rate
≤40
41 - 50
51 - 90
91 - 110
111 - 130
≥131
Level Of
Consciousness
A
V,P, or U
*The NEWS initiative flowed from the Royal College of Physicians’ NEWS Development and Implementation Group 
(NEWSDIG) report, and was jointly developed and funded in collaboration with the Royal College of Physicians, 
Royal College of Nursing, National Outreach Forum and NHS Training for Innovation
Note: The following parameters for the NEWS for subjects that are on invasive mechanically
ventilation while NEWS is assessed will be adjusted:
Oxygen saturation = 90%
Any Supplemental oxygen = YES
Level of Consciousness =Unresponsive
The observed data values for these parameters will be ignored and replaced by above values.
Subsequently all parameters will be evaluated according to Table 6.
NEWS2
The original NEWS was designed for patients whose normal range for oxygen saturation is 
between 96 – 100%. For SpO2 values below this, the NEW score increases. The NEWS is updated 
by a new version, NEWS2[8], to more accurately score the acute-illness severity of subjects with 
routinely low oxygen saturation. Subjects that have a prescribed oxygen saturation requirement of 


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88 - 92%, i.e. patients with hypercapnic respiratory failure, often referred to as ‘type 2’ respiratory 
failure (Although COPD is the most common cause of hypercapnic respiratory failure, there are 
other causes such as morbid obesity, chest‐wall deformities or neuromuscular disorders) will be 
evaluated with the new SpO2 scoring scale 2.
In addition, a new consciousness level is added to capture a change in confusion: new Confusion 
(C). Note: The following parameters for the NEWS2 for subjects that are on invasive mechanical 
ventilation and that met the criteria for the SpO2 scale 2 will be adjusted:
Oxygen saturation = 82%
Any Supplemental oxygen = YES
Level of Consciousness =Unresponsive
The observed data values for these parameters will be ignored and replaced by above values. 
Subsequently all parameters will be evaluated according to Table 7
Table 7: The NEWS2 scoring system
Note: the physiological parameter: ‘Air or Oxygen’ is evaluated by checking the use of the supplemental oxygen. 
For the SpO2 scale 2, to evaluate if the assessment is taken on room air or on oxygen, the answer to the question 
‘Was this measurement taken on room air’ is used. Oxygen saturation measurements lower or equal to 92% are 
scored 0 to 3 in the SpO2 scale 2 independent if the measurement was taken on room air or not. Oxygen 
saturation measurements of 92% or more on room air will have a score 0 for the SpO2 scale 2. Oxygen 
saturation measurements of 93 or more taken on oxygen are scored 1 to 3 in the SpO2 scale 2 (last 3 columns)


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The subjects for who the oxygen saturations levels need to be evaluated with the SpO2 scale 2, met 
following criteria at (or before) the time of randomization:
-
Oxygen saturation of the last assessment before randomizing is lower or equal to 92%
-
Chronic oxygen was used
The SpO2 scale 2 will then be used for the NEWS2 calculation throughout the rest of the trial for 
the subject. The SpO2 scale 1 will be used for the other subjects.
Note that for the NEWS2 by timepoint a subject receives supplemental oxygen if he received 
oxygen at the time of the measurement of oxygen saturation. For the NEWS(2) stratification this 
is checked within the randomization window as explained in Section 5.1.4
NEWS2 Category
The NEWS 2 will be categorized into its clinical risk according to the following categories:

No clinical risk: (score 0)

Low clinical risk: (score 1 – 4)

Medium clinical risk: (score 5 – 6, or 1 individual parameter with a score 3)

High clinical risk: (score 7 and more)
In case a parameter is missing to calculate the NEWS 2 but based on the available information the 
NEWS 2 is 7 or more, the NEWS2 category will be 'High clinical risk'.
7.6.2.
Analysis Methods
Descriptive statistics of the NEWS2 and the change from baseline will be shown by analysis 
timepoint. Additionally, a mean +/- SE graph of the scores over time will be provided.
A frequency table of the ACVPU score by timepoint and treatment group will be provided. Include 
in this table the safety follow-up visit, the Day 28 final study visit and the last study visit.
A tabulation of the clinical risk categories will be made per analysis timepoint. Include in this table 
the safety follow-up visit, the Day 28 final study visit and the last study visit.
A listing of the NEWS2 by analysis timepoint for each subject will be provided.


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8.
RESISTANCE
8.1.
Viral Phenotype
The pimodivir EC50 and oseltamivir IC50 with their fold change values will be analyzed at baseline 
and at all post-baseline visits with available data (FC = fold change in EC50 (IC50) value). 
FC is calculated as the EC50 (or IC50) of the subject’s influenza strain divided by the EC50 (or 
IC50) of a reference strain. If the patient EC50 (or IC50) is censored, the fold change value gets
the same censor, e.g. patient EC50 = >20 nM, reference EC50 = 4nM, Fold Change value >5.
The following output will be provided:

Emerging phenotypic resistance: descriptive statistics for FC in EC50 and IC50 value for 
pimodivir and oseltamivir respectively at baseline and at all post-baseline visits with available 
data. The number (%) of subjects by treatment arm with censored phenotype data (by lower 
and upper bound) at baseline and at all post-baseline visits with available data will also be 
shown.

Descriptive statistics for fold change ratio of all post-baseline visits with available data versus 
baseline including geometric mean and 95% CI.

A listing showing viral load data together with phenotype data (EC50, IC50 and fold change 
values) per subject and influenza subtype for all available timepoints including 
screening/baseline.
8.2.
Viral Genotype
Assessment of viral sequences will be done to determine amino-acid substitutions that may be 
associated with resistance to pimodivir and to other influenza antivirals if present as part of the 
SOC. To that end, genotypic data for PB2, PB1, PA, NA, HA and optionally other genome 
segments of the influenza virus will be gathered.
All positions in the gathered regions will be analyzed for all samples, overall and by influenza 
subtype.
The gathered regions most relevant for pimodivir are PB2, PB1 and PA, those for neuraminidase 
inhibitors (NAI) (including oseltamivir) are NA and HA
The following 12 amino-acid positions in PB2 are of interest: 306, 323, 324, 325, 337, 357, 363, 
376, 378, 404, 406, 431, and 510.
The following mutations in NA, associated with resistance to oseltamivir, are of interest:

For subtype H1N1: D199N, I223R, H275Y, and N295S 

For subtype H3N2: E119V, H274Y, R292K, and N294S
The list of positions of interest might be updated during the analysis.
A mutation is treatment-emerging at a specific (post-baseline) time-point if the amino-acid of the 
considered position is absent at screening/baseline and present at that timepoint. 


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The baseline is the collection of all polymorphisms present at any timepoint up to the first intake 
of study. A table with an overview of the time points underlying the “baseline” will be generated.
Data will be summarized using frequency tabulations (n and %). Displays and individual mutations 
should be presented for each genome segment separately (i.e. PB1, PB2,
PA, NA and HA 
separately). The following output will be provided:

Baseline polymorphisms: number (%) of subjects with available genotype data, with any 
baseline polymorphism, and the number of subjects per polymorphism, for all polymorphisms, 
per treatment arm.  

Baseline polymorphisms: number (%) of subjects with any baseline polymorphism and with 
specific baseline polymorphisms at the positions of interest.

Frequency tabulations for the presence of all emerging mutations overall post-baseline.

Frequency tabulations for the presence of all emerging mutations overall post-baseline at 
positions of interest.

Listing for genotype data per subject for all available timepoints including screening/baseline 
including viral load data (include influenza subtype and influenza subtype category). A patient 
profile will be created including this data supplemented with the phenotypic data.
9.
PHARMACOKINETICS/PHARMACODYNAMICS
Blood samples for PK assessments of pimodivir will be collected at the Day 1, 3, 5, 6 and/or Day 7 
visit depending on when the subject is discharged from the hospital.
Descriptive statistics of pimodivir plasma concentration over time will be tabulated for the PK 
analysis set.
9.1.
Pharmacokinetics
Based on the individual plasma concentration-time data from all subjects, exposure parameters of 
pimodivir will be derived using population PK modelling. The following exposure parameters will 
be derived for the samples collected after the first intake (Day 1), after the 5th intake (Day 3) and
after the last intake (the last intake can be on Day 5, 6 or 7 and will be reported as Day 5 in the 
tables): AUC12h, Ctrough, and, if feasible, Cmax, and Tmax. 
Descriptive statistics, including arithmetic mean, standard deviation, coefficient of variation, 
geometric mean, median, minimum, maximum, and interquartile range will be calculated at 
available timepoints for all available parameters for the PK analysis set.
9.2.
Pharmacokinetic/Pharmacodynamic Relationships
Pharmacokinetic/Pharmacodynamic relationships will be analyzed for the PD analysis set. The 
exposure parameters AUC12h and Ctrough will be categorized into quartiles for Day 1, Day 3 and 
Day 5 (i.e.: after the last intake, this can be on Day 5, Day 6 or Day 7) (if available). Relationships 
of these parameters with the primary and selected secondary efficacy endpoints will be explored 
as follows.


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The distribution of subjects over the hospital recovery scale on Day 6 will be tabulated per quartile 
for each exposure parameter for each PK timepoint.
The number and percentage of subjects with treatment-emergent adjudicated influenza 
complications will be tabulated for each quartile for each exposure parameter for each PK
timepoint.
The Kaplan Meier estimates for the time to hospital discharge will be produced per quartile for 
each exposure parameter for each PK timepoint.
The Kaplan Meier estimates for the time from ICU admission to ICU discharge will be produced 
per each quartile for each exposure parameter for each PK timepoint.
The Kaplan Meier estimates for the time to return to daily activities will be produced per quartile 
for each exposure parameter for each PK timepoint.
The Kaplan Meier estimates for the time from start of mechanical ventilation to end of mechanical 
ventilation will be produced per each quartile for each exposure parameter for each PK timepoint.
The number and percentage of subjects readmitted to the hospital after the first discharge will be 
tabulated for each quartile for each exposure parameter for each PK timepoint.
Relationships of AUC12h with safety will be explored as follows. The number and percentage of 
subjects with the following treatment-emergent adverse events by AUC12h quartile for each PK 
timepoint will be tabulated:

Any AE

AEs of worst grade 3 or 4

Deaths due to AE

Serious AEs

AEs for which study drug was permanently stopped

AEs at least possibly related to study drug

Confirmed diarrhea events
A frequency table of the worst treatment-emergent toxicity grades versus AUC12h quartile will be 
presented for the laboratory parameters AST, ALT, and total bilirubin.
Separate frequency table will be produced for the worst treatment-emergent toxicity grades at each 
PK timepoint.


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10.
HEALTH ECONOMICS
Following medical resource utilization data will be explored
10.1. Definitions
Measurement
Formula
Number of medical care 
encounters
Medical care encounters other than those mandated per trial 
protocol, including surgeries and other selected procedures 
(inpatient and outpatient), as recorded on the eCRF.
The number of medical care encounters is derived as the 
frequency of the medical encounters other than those mandated 
in the protocol (eCRF).
Type of
practitioner
for 
hospital 
outpatient 
department encounters
Type of practitioner as recorded in the eCRF in case of 
Outpatient Department is selected.
Frequency 
of 
visits
of 
outpatient 
medical 
care 
encounters
Frequency of visits will be provided per outpatient medical 
encounter type (Hospital Outpatient Department Laboratory 
Department, Medical Practitioner Office, Home Care)
Number 
of 
outpatient 
medical care encounters
Similar to the description for number of medical care 
encounters, but only for outpatient medical care encounters, as 
recorded on the eCRF (Hospital Outpatient Department, 
Laboratory Department,
Medical Practitioner Office, Home Care).
10.2.
Analysis Methods
Frequency tabulations of medical care encounters, per category (as defined above) and by medical 
encounter type, will be provided.
Frequency tabulations of the frequency of visits will be provided, per following medical encounter 
types:
- Hospital Outpatient Department, 
- Laboratory Department, 
- Medical Practitioner Office,
- Home Care 
Frequency tabulations of the type of practitioner will be provided, for the Hospital Outpatient 
Department.


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Hodges J.L., Lehmann E.L., Estimates of location based on rank tests. The Annals of 
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Hurst H., Bolton J. Assessing the clinical significance of change scores recorded on subjective 
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Jaeschke R., Singer J., Guyatt G.H.. Measurement of health status. Ascertaining the minimal 
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Lehmann E. L. Nonparametric confidence intervals for a shift parameter. The Annals of 
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assessment 
of 
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severity 
in 
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NHS; 
2012. 
www.rcplondon.ac.uk/resources/national-earlywarning-score-news
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Royal College of Physicians of London. National early warning score (NEWS) 2: 
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https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-score-news-2
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adverse events."; 2003


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ATTACHMENTS
ATTACHMENT 1.
: ANTICIPATED EVENTS AND ANTICIPATED EVENT GROUPS 
Table 8 shows an overview of the anticipated event groups with group number. 
Table 9 indicates which adverse event preferred terms (MedDRA PT) are Anticipated Events (AnE) and Closely Related Medical Events (ME)
based on MedDRA Version 18.1. These adverse events will be classified as an Anticipated Event according to the protocol term and are grouped 
into Anticipated Event Groups. 
Table 8: Anticipated Event groups
Group Number
Grouped Term 
Group 1 
Infections and infestations
Group 2
Diabetic complications
Table 9: Anticipated Events (AnE) and Closely Related Medical Events (ME). 
Protocol Term
AnE 
ME
MedDRA PT *
MedDRA 
Code*
Grouped Term
Group 
Number
Pneumonia
☒
☐
Pneumonia
10035664
Infections and infestations
1
Pneumonia
☐
☒
Enterobacter pneumonia
10054218
Infections and infestations
1
Pneumonia
☐
☒
Pneumonia haemophilus
10035702
Infections and infestations
1
Pneumonia
☐
☒
Pneumonia staphylococcal
10035734
Infections and infestations
1
Pneumonia
☐
☒
Pneumonia streptococcal
10035735
Infections and infestations
1
Bronchitis
☒
☐
Bronchitis
10006451
Infections and infestations
1
Bronchitis
☐
☒
Bronchitis bacterial
10061736
Infections and infestations
1
Bronchitis
☐
☒
Bronchitis haemophilus
10006460
Infections and infestations
1
Sinus infection
☒
☐
Sinusitis1
10040753
Infections and infestations
1
Sinus infection
☐
☒
Acute sinusitis1
10001076
Infections and infestations
1


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Protocol Term
AnE 
ME
MedDRA PT *
MedDRA 
Code*
Grouped Term
Group 
Number
Sinus infection
☐
☒
Chronic sinusitis1
10009137
Infections and infestations
1
Sinus infection
☐
☒
Viral sinusitis
10051513
Infections and infestations
1
Ear infection
☒
☐
Ear infection 
10014011
Infections and infestations
1
Ear infection
☐
☒
Middle ear effusion
10062545
Infections and infestations
1
Ear infection
☐
☒
Otitis externa
10033072
Infections and infestations
1
Ear infection
☐
☒
Otitis media
10033078
Infections and infestations
1
Ear infection
☐
☒
Otitis media acute
10033079
Infections and infestations
1
Worsening of asthma, asthma attack2
☐
☒
Asthma
10003553
NA
Worsening of asthma, asthma attack2
☐
☒
Asthmatic crisis
10064823
NA
Worsening of asthma, asthma attack2
☐
☒
Status asthmaticus
10041961
NA
COPD exacerbation 3
☒
☐
Chronic obstructive pulmonary disease
10009033
NA
COPD exacerbation 3
☐
☒
Emphysema
10014561
NA
Complications of sickle cell disease, 
sickle cell crisis4
☐
☒
Sickle cell anaemia
10040641
NA
Complications of sickle cell disease, 
sickle cell crisis4
☐
☒
Sickle cell anaemia with crisis
10040642
NA
Complications of sickle cell disease, 
sickle cell crisis4
☐
☒
Acute chest syndrome
10051895
NA
Complications of sickle cell disease, 
sickle cell crisis4
☐
☒
Ischaemic stroke
10061256
NA
Complications of sickle cell disease, 
sickle cell crisis4
☐
☒
Embolic stroke
10014498
NA
Complications of sickle cell disease, 
sickle cell crisis4
☐
☒
Deep vein thrombosis
10051055
NA
Complications of sickle cell disease, 
sickle cell crisis4
☐
☒
Pulmonary embolism
10037377
NA
Complications of diabetes mellitus,
diabetic ketoacidosis4
☒
☐
Diabetic complication
10061104
Diabetic complications
2


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Protocol Term
AnE 
ME
MedDRA PT *
MedDRA 
Code*
Grouped Term
Group 
Number
Complications of diabetes mellitus, 
diabetic ketoacidosis4
☒
☐
Diabetic ketoacidosis
10012671
Diabetic complications
2
Complications of diabetes mellitus, 
diabetic ketoacidosis4
☐
☒
Diabetes mellitus5
10012601
Diabetic complications
2
Complications of diabetes mellitus, 
diabetic ketoacidosis4
☐
☒
Diabetic ketoacidotic hyperglycaemic coma
10012672
Diabetic complications
2
Complications of diabetes mellitus, 
diabetic ketoacidosis4
☐
☒
Hypoglycaemia
10020993
Diabetic complications
2
Complications of diabetes mellitus 
diabetic ketoacidosis4
☐
☒
Diabetic metabolic decompensation
100126655
Diabetic complications
2
Acute Respiartory Distress Syndrome 
(ARDS)
☒
☐
Acute respiratory distress syndrome
10001052
NA
Acute Respiartory Distress Syndrome 
(ARDS)
☐
☒
Acute respiratory failure6
10001053
NA
1 Infectious etiology only
2 Please note that asthma aggravated codes to a PT of asthma. These PTs will be considered as anticipated events only if the subjects have documented those conditions (such 
as: asthma, COPD, Sickle cell disease, or diabetes) before enrolling the study.
3 Please note that chronic obstructive airways disease exacerbated codes to a PT of chronic obstructive pulmonary disease.  These PTs will be considered as anticipated events 
only if the subjects have documented those conditions (such as: asthma, COPD, Sickle cell disease, or diabetes) before enrolling the study.
4 These PTs will be considered as anticipated events only if the subjects have documented those conditions (such as: asthma, COPD, Sickle cell disease, or diabetes) before 
enrolling the study.
5 Please note that diabetes mellitus aggravated and diabetes mellitus exacerbated codes to a PT of diabetes mellitus.
6 This event will be considered anticipated only if it occurs in the context of ARDS


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ATTACHMENT 2.
: 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
Gamma-
glutamyltransfer
ase
≥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


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Item
Grade 1
Grade 2
Grade 3
Grade 4
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
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


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Item
Grade 1
Grade 2
Grade 3
Grade 4
Hypomagnesem
ia
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
Hypophosphate
mia
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
Hyperbilirubine
mia
≥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
* Grading based on Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, version 2.0, November 2014.
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/persist
ent; 
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


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Item
Grade 1
Grade 2
Grade 3
Grade 4
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; 
pericardiocente
sis or surgery 
required
Hemorrhage, 
Blood Loss
microscopic/occu
lt
mild, 
no 
transfusion
gross blood loss; 
1-2 units 
transfused
massive blood 
loss; >3 units 
transfused
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


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Item
Grade 1
Grade 2
Grade 3
Grade 4
Vomiting
transient emesis
occasional/moder
ate 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 
dysdiadochokine
sis
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/agitati
on; 
ADL 
unaffected
moderate 
confusion/agitati
on 
some 
limitation 
of 
ADL; 
minimal 
Rx
severe 
confusion/agitati
on 
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
Other Parameters


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Item
Grade 1
Grade 2
Grade 3
Grade 4
Fever: 
oral, 
>12 hours
37.7-38.5 °C or 
100.0-101.5 °F
38.6-39.5 °C or 
101.6-102.9 °F
39.6-40.5 °C or 
103-105 °F
>40.5 °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 3.
: WHO GRADING SCALE VITAL SIGNS
The following abnormalities are defined for vital signs:
Vital Signs parameter
Abnormality Code 
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
-
-
* The classification of AEs related to hypotension and hypertension will be done according to the WHO grading 
scale
Abnormality Code
Vital Signs parameter
Temperature
(°C/°F)
Respiratory rate
(breaths per 
minute)
Oxygen Saturation
(%)
Normal
≥95% - 100%
Grade 1 or mild
37.7 - 38.5 °C or
100.0 - 101.5 °F
17-20
≥90% - <95%
Grade 2 or moderate
38.6 - 39.5 °C or
101.6 - 102.9 °F
21-25
≥85% - <90%
Grade 3 or severe
39.6 - 40.5 °C or
103.0 - 105.0 °F
>25
<85%
Grade 4 or potentially 
life-threatening
>40.5°C or
>105.0°F


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ATTACHMENT 4.
: ECG ABNORMALITIES 
The following abnormalities are defined for ECG:
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


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ATTACHMENT 5.
: EQ-5D VALUATION INDEX
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
11111
1
11242
0,498
11423
0,606
11554
0,018
11112
0,879
11243
0,484
11424
0,437
11555
-0,066
11113
0,848
11244
0,323
11425
0,26
12111
0,846
11114
0,635
11245
0,157
11431
0,653
12112
0,779
11115
0,414
11251
0,235
11432
0,596
12113
0,761
11121
0,837
11252
0,179
11433
0,582
12114
0,548
11122
0,768
11253
0,164
11434
0,412
12115
0,327
11123
0,75
11254
0,083
11435
0,236
12121
0,737
11124
0,537
11255
-0,001
11441
0,475
12122
0,678
11125
0,316
11311
0,883
11442
0,419
12123
0,663
11131
0,796
11312
0,827
11443
0,404
12124
0,45
11132
0,74
11313
0,812
11444
0,27
12125
0,229
11133
0,725
11314
0,599
11445
0,131
12131
0,709
11134
0,512
11315
0,378
11451
0,209
12132
0,653
11135
0,291
11321
0,785
11452
0,153
12133
0,638
11141
0,584
11322
0,728
11453
0,138
12134
0,425
11142
0,527
11323
0,714
11454
0,057
12135
0,204
11143
0,513
11324
0,501
11455
-0,027
12141
0,497
11144
0,352
11325
0,28
11511
0,556
12142
0,441
11145
0,186
11331
0,76
11512
0,5
12143
0,426
11151
0,264
11332
0,704
11513
0,485
12144
0,266
11152
0,208
11333
0,689
11514
0,404
12145
0,099
11153
0,193
11334
0,476
11515
0,32
12151
0,177
11154
0,112
11335
0,255
11521
0,458
12152
0,121
11155
0,028
11341
0,548
11522
0,401
12153
0,106
11211
0,906
11342
0,491
11523
0,387
12154
0,025
11212
0,837
11343
0,477
11524
0,306
12155
-0,059
11213
0,819
11344
0,316
11525
0,222
12211
0,806
11214
0,606
11345
0,15
11531
0,433
12212
0,748
11215
0,385
11351
0,228
11532
0,377
12213
0,733
11221
0,795
11352
0,172
11533
0,362
12214
0,52
11222
0,736
11353
0,157
11534
0,281
12215
0,299
11223
0,721
11354
0,076
11535
0,197
12221
0,706
11224
0,508
11355
-0,008
11541
0,328
12222
0,649
11225
0,287
11411
0,776
11542
0,272
12223
0,634
11231
0,767
11412
0,719
11543
0,257
12224
0,421
11232
0,711
11413
0,705
11544
0,176
12225
0,2
11233
0,696
11414
0,535
11545
0,092
12231
0,681
11234
0,483
11415
0,359
11551
0,17
12232
0,624
11235
0,262
11421
0,677
11552
0,114
12233
0,61
11241
0,555
11422
0,621
11553
0,099
12234
0,397


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
93
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
12235
0,176
12424
0,35
13113
0,744
13252
0,075
12241
0,468
12425
0,174
13114
0,531
13253
0,06
12242
0,412
12431
0,566
13115
0,31
13254
-0,021
12243
0,397
12432
0,51
13121
0,717
13255
-0,105
12244
0,237
12433
0,495
13122
0,66
13311
0,779
12245
0,071
12434
0,325
13123
0,646
13312
0,723
12251
0,149
12435
0,149
13124
0,433
13313
0,708
12252
0,092
12441
0,389
13125
0,212
13314
0,495
12253
0,078
12442
0,332
13131
0,692
13315
0,274
12254
-0,003
12443
0,318
13132
0,636
13321
0,681
12255
-0,088
12444
0,184
13133
0,621
13322
0,624
12311
0,796
12445
0,044
13134
0,408
13323
0,61
12312
0,74
12451
0,122
13135
0,187
13324
0,397
12313
0,725
12452
0,066
13141
0,48
13325
0,176
12314
0,512
12453
0,051
13142
0,423
13331
0,656
12315
0,291
12454
-0,03
13143
0,409
13332
0,6
12321
0,698
12455
-0,114
13144
0,248
13333
0,585
12322
0,642
12511
0,469
13145
0,082
13334
0,372
12323
0,627
12512
0,413
13151
0,16
13335
0,151
12324
0,414
12513
0,398
13152
0,104
13341
0,444
12325
0,193
12514
0,317
13153
0,089
13342
0,387
12331
0,673
12515
0,233
13154
0,008
13343
0,373
12332
0,617
12521
0,371
13155
-0,076
13344
0,212
12333
0,602
12522
0,315
13211
0,786
13345
0,046
12334
0,389
12523
0,3
13212
0,73
13351
0,124
12335
0,168
12524
0,219
13213
0,715
13352
0,068
12341
0,461
12525
0,135
13214
0,502
13353
0,053
12342
0,405
12531
0,346
13215
0,281
13354
-0,028
12343
0,39
12532
0,29
13221
0,688
13355
-0,112
12344
0,23
12533
0,275
13222
0,631
13411
0,672
12345
0,063
12534
0,194
13223
0,617
13412
0,615
12351
0,141
12535
0,11
13224
0,404
13413
0,601
12352
0,085
12541
0,241
13225
0,183
13414
0,431
12353
0,07
12542
0,185
13231
0,663
13415
0,255
12354
-0,011
12543
0,17
13232
0,607
13421
0,573
12355
-0,095
12544
0,089
13233
0,592
13422
0,517
12411
0,689
12545
0,005
13234
0,379
13423
0,502
12412
0,633
12551
0,083
13235
0,158
13424
0,333
12413
0,618
12552
0,027
13241
0,451
13425
0,156
12414
0,448
12553
0,012
13242
0,394
13431
0,549
12415
0,272
12554
-0,069
13243
0,38
13432
0,492
12421
0,591
12555
-0,153
13244
0,219
13433
0,478
12422
0,534
13111
0,815
13245
0,053
13434
0,308
12423
0,52
13112
0,759
13251
0,131
13435
0,132


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
94
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
13441
0,371
14125
0,185
14314
0,435
14453
0,007
13442
0,315
14131
0,6
14315
0,247
14454
-0,074
13443
0,3
14132
0,544
14321
0,588
14455
-0,158
13444
0,166
14133
0,529
14322
0,532
14511
0,425
13445
0,027
14134
0,348
14323
0,517
14512
0,369
13451
0,105
14135
0,16
14324
0,337
14513
0,354
13452
0,049
14141
0,414
14325
0,149
14514
0,273
13453
0,034
14142
0,357
14331
0,564
14515
0,189
13454
-0,047
14143
0,343
14332
0,508
14521
0,327
13455
-0,131
14144
0,202
14333
0,493
14522
0,27
13511
0,452
14145
0,055
14334
0,312
14523
0,256
13512
0,396
14151
0,133
14335
0,124
14524
0,175
13513
0,381
14152
0,077
14341
0,378
14525
0,091
13514
0,3
14153
0,062
14342
0,321
14531
0,302
13515
0,216
14154
-0,019
14343
0,307
14532
0,246
13521
0,354
14155
-0,103
14344
0,166
14533
0,231
13522
0,297
14211
0,694
14345
0,019
14534
0,15
13523
0,283
14212
0,638
14351
0,097
14535
0,066
13524
0,202
14213
0,623
14352
0,041
14541
0,197
13525
0,118
14214
0,442
14353
0,026
14542
0,141
13531
0,329
14215
0,254
14354
-0,055
14543
0,126
13532
0,273
14221
0,596
14355
-0,139
14544
0,045
13533
0,258
14222
0,539
14411
0,601
14545
-0,039
13534
0,177
14223
0,525
14412
0,545
14551
0,039
13535
0,093
14224
0,344
14413
0,53
14552
-0,017
13541
0,224
14225
0,156
14414
0,382
14553
-0,032
13542
0,168
14231
0,571
14415
0,228
14554
-0,113
13543
0,153
14232
0,515
14421
0,502
14555
-0,197
13544
0,072
14233
0,5
14422
0,446
15111
0,436
13545
-0,012
14234
0,319
14423
0,431
15112
0,38
13551
0,066
14235
0,131
14424
0,283
15113
0,365
13552
0,01
14241
0,385
14425
0,13
15114
0,284
13553
-0,005
14242
0,328
14431
0,478
15115
0,2
13554
-0,086
14243
0,314
14432
0,422
15121
0,338
13555
-0,17
14244
0,173
14433
0,407
15122
0,281
14111
0,723
14245
0,026
14434
0,259
15123
0,267
14112
0,667
14251
0,104
14435
0,105
15124
0,186
14113
0,652
14252
0,048
14441
0,318
15125
0,102
14114
0,471
14253
0,033
14442
0,262
15131
0,313
14115
0,283
14254
-0,048
14443
0,247
15132
0,257
14121
0,624
14255
-0,132
14444
0,126
15133
0,242
14122
0,568
14311
0,687
14445
0
15134
0,161
14123
0,553
14312
0,631
14451
0,078
15135
0,077
14124
0,373
14313
0,616
14452
0,022
15141
0,208


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
95
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
15142
0,152
15331
0,277
21115
0,357
21254
0,026
15143
0,137
15332
0,221
21121
0,767
21255
-0,058
15144
0,056
15333
0,206
21122
0,708
21311
0,826
15145
-0,028
15334
0,125
21123
0,693
21312
0,77
15151
0,05
15335
0,041
21124
0,48
21313
0,755
15152
-0,006
15341
0,172
21125
0,259
21314
0,542
15153
-0,021
15342
0,116
21131
0,739
21315
0,321
15154
-0,102
15343
0,101
21132
0,683
21321
0,728
15155
-0,186
15344
0,02
21133
0,668
21322
0,671
15211
0,407
15345
-0,064
21134
0,455
21323
0,657
15212
0,351
15351
0,014
21135
0,234
21324
0,444
15213
0,336
15352
-0,042
21141
0,527
21325
0,223
15214
0,255
15353
-0,057
21142
0,47
21331
0,703
15215
0,171
15354
-0,138
21143
0,456
21332
0,647
15221
0,309
15355
-0,222
21144
0,296
21333
0,632
15222
0,252
15411
0,381
21145
0,129
21334
0,419
15223
0,238
15412
0,325
21151
0,207
21335
0,198
15224
0,157
15413
0,31
21152
0,151
21341
0,491
15225
0,073
15414
0,229
21153
0,136
21342
0,434
15231
0,284
15415
0,145
21154
0,055
21343
0,42
15232
0,228
15421
0,282
21155
-0,029
21344
0,26
15233
0,213
15422
0,226
21211
0,836
21345
0,093
15234
0,132
15423
0,211
21212
0,778
21351
0,171
15235
0,048
15424
0,13
21213
0,762
21352
0,115
15241
0,179
15425
0,046
21214
0,549
21353
0,1
15242
0,123
15431
0,258
21215
0,328
21354
0,019
15243
0,108
15432
0,202
21221
0,735
21355
-0,065
15244
0,027
15433
0,187
21222
0,679
21411
0,719
15245
-0,057
15434
0,106
21223
0,664
21412
0,663
15251
0,021
15435
0,022
21224
0,451
21413
0,648
15252
-0,035
15441
0,153
21225
0,23
21414
0,478
15253
-0,05
15442
0,097
21231
0,71
21415
0,302
15254
-0,131
15443
0,082
21232
0,654
21421
0,62
15255
-0,215
15544
-0,038
21233
0,639
21422
0,564
15311
0,4
15545
-0,122
21234
0,426
21423
0,549
15312
0,344
15551
-0,044
21235
0,205
21424
0,38
15313
0,329
15552
-0,1
21241
0,498
21425
0,204
15314
0,248
15553
-0,115
21242
0,442
21431
0,596
15315
0,164
15554
-0,196
21243
0,427
21432
0,54
15321
0,302
15555
-0,28
21244
0,267
21433
0,525
15322
0,245
21111
0,877
21245
0,1
21434
0,355
15323
0,231
21112
0,809
21251
0,178
21435
0,179
15324
0,15
21113
0,791
21252
0,122
21441
0,419
15325
0,066
21114
0,578
21253
0,107
21442
0,362


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
96
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
21443
0,348
22132
0,596
22321
0,641
22455
-0,17
21444
0,213
22133
0,582
22322
0,585
22511
0,413
21445
0,074
22134
0,369
22323
0,57
22512
0,356
21451
0,152
22135
0,148
22324
0,357
22513
0,342
21452
0,096
22141
0,44
22325
0,136
22514
0,261
21453
0,081
22142
0,384
22331
0,617
22515
0,177
21454
0
22143
0,369
22332
0,56
22521
0,314
21455
-0,084
22144
0,209
22333
0,546
22522
0,258
21511
0,499
22145
0,043
22334
0,333
22523
0,243
21512
0,443
22151
0,121
22335
0,112
22524
0,162
21513
0,428
22152
0,064
22341
0,404
22525
0,078
21514
0,347
22153
0,05
22342
0,348
22531
0,29
21515
0,263
22154
-0,031
22343
0,333
22532
0,233
21521
0,401
22155
-0,115
22344
0,173
22533
0,219
21522
0,344
22211
0,747
22345
0,007
22534
0,138
21523
0,33
22212
0,691
22351
0,085
22535
0,054
21524
0,249
22213
0,676
22352
0,028
22541
0,185
21525
0,165
22214
0,463
22353
0,014
22542
0,128
21531
0,376
22215
0,242
22354
-0,067
22543
0,114
21532
0,32
22221
0,648
22355
-0,151
22544
0,033
21533
0,305
22222
0,592
22411
0,632
22545
-0,051
21534
0,224
22223
0,577
22412
0,576
22551
0,027
21535
0,14
22224
0,364
22413
0,561
22552
-0,03
21541
0,271
22225
0,143
22414
0,392
22553
-0,044
21542
0,215
22231
0,624
22415
0,216
22554
-0,125
21543
0,2
22232
0,567
22421
0,534
22555
-0,209
21544
0,119
22233
0,553
22422
0,477
23111
0,758
21545
0,035
22234
0,34
22423
0,463
23112
0,702
21551
0,113
22235
0,119
22424
0,293
23113
0,687
21552
0,057
22241
0,411
22425
0,117
23114
0,474
21553
0,042
22242
0,355
22431
0,509
23115
0,253
21554
-0,039
22243
0,34
22432
0,453
23121
0,66
21555
-0,123
22244
0,18
22433
0,438
23122
0,603
22111
0,778
22245
0,014
22434
0,269
23123
0,589
22112
0,72
22251
0,092
22435
0,093
23124
0,376
22113
0,705
22252
0,035
22441
0,332
23125
0,155
22114
0,492
22253
0,021
22442
0,276
23131
0,635
22115
0,271
22254
-0,06
22443
0,261
23132
0,579
22121
0,678
22255
-0,144
22444
0,127
23133
0,564
22122
0,621
22311
0,74
22445
-0,013
23134
0,351
22123
0,606
22312
0,683
22451
0,066
23135
0,13
22124
0,393
22313
0,669
22452
0,009
23141
0,423
22125
0,172
22314
0,456
22453
-0,005
23142
0,366
22131
0,653
22315
0,235
22454
-0,086
23143
0,352


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
97
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
23144
0,192
23333
0,528
23522
0,24
24155
-0,16
23145
0,025
23334
0,315
23523
0,226
24211
0,637
23151
0,103
23335
0,094
23524
0,145
24212
0,581
23152
0,047
23341
0,387
23525
0,061
24213
0,566
23153
0,032
23342
0,33
23531
0,272
24214
0,385
23154
-0,049
23343
0,316
23532
0,216
24215
0,198
23155
-0,133
23344
0,156
23533
0,201
24221
0,539
23211
0,729
23345
-0,011
23534
0,12
24222
0,482
23212
0,673
23351
0,067
23535
0,036
24223
0,468
23213
0,658
23352
0,011
23541
0,167
24224
0,287
23214
0,445
23353
-0,004
23542
0,111
24225
0,099
23215
0,224
23354
-0,085
23543
0,096
24231
0,514
23221
0,631
23355
-0,169
23544
0,015
24232
0,458
23222
0,575
23411
0,615
23545
-0,069
24233
0,443
23223
0,56
23412
0,559
23551
0,009
24234
0,262
23224
0,347
23413
0,544
23552
-0,047
24235
0,075
23225
0,126
23414
0,374
23553
-0,062
24241
0,328
23231
0,606
23415
0,198
23554
-0,143
24242
0,272
23232
0,55
23421
0,516
23555
-0,227
24243
0,257
23233
0,535
23422
0,46
24111
0,666
24244
0,116
23234
0,322
23423
0,445
24112
0,61
24245
-0,03
23235
0,101
23424
0,276
24113
0,595
24251
0,048
23241
0,394
23425
0,1
24114
0,414
24252
-0,009
23242
0,338
23431
0,492
24115
0,227
24253
-0,023
23243
0,323
23432
0,436
24121
0,568
24254
-0,104
23244
0,163
23433
0,421
24122
0,511
24255
-0,188
23245
-0,004
23434
0,251
24123
0,497
24311
0,63
23251
0,074
23435
0,075
24124
0,316
24312
0,574
23252
0,018
23441
0,315
24125
0,128
24313
0,559
23253
0,003
23442
0,258
24131
0,543
24314
0,378
23254
-0,078
23443
0,244
24132
0,487
24315
0,191
23255
-0,162
23444
0,109
24133
0,472
24321
0,532
23311
0,722
23445
-0,03
24134
0,291
24322
0,475
23312
0,666
23451
0,048
24135
0,104
24323
0,461
23313
0,651
23452
-0,008
24141
0,357
24324
0,28
23314
0,438
23453
-0,023
24142
0,3
24325
0,092
23315
0,217
23454
-0,104
24143
0,286
24331
0,507
23321
0,624
23455
-0,188
24144
0,145
24332
0,451
23322
0,567
23511
0,395
24145
-0,002
24333
0,436
23323
0,553
23512
0,339
24151
0,077
24334
0,255
23324
0,34
23513
0,324
24152
0,02
24335
0,068
23325
0,119
23514
0,243
24153
0,006
24341
0,321
23331
0,599
23515
0,159
24154
-0,076
24342
0,264
23332
0,543
23521
0,297
24155
-0,16
24343
0,25


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
98
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
24344
0,109
24533
0,175
25222
0,196
25411
0,324
24345
-0,038
24534
0,094
25223
0,181
25412
0,268
24351
0,041
24535
0,01
25224
0,1
25413
0,253
24352
-0,016
24541
0,14
25225
0,016
25414
0,172
24353
-0,031
24542
0,084
25231
0,227
25415
0,088
24354
-0,112
24543
0,069
25232
0,171
25421
0,226
24355
-0,196
24544
-0,012
25233
0,156
25422
0,169
24411
0,544
24545
-0,096
25234
0,075
25423
0,155
24412
0,488
24551
-0,018
25235
-0,009
25424
0,074
24413
0,473
24552
-0,074
25241
0,122
25425
-0,01
24414
0,325
24553
-0,089
25242
0,066
25431
0,201
24415
0,172
24554
-0,17
25243
0,051
25432
0,145
24421
0,446
24555
-0,254
25244
-0,03
25433
0,13
24422
0,389
25111
0,379
25245
-0,114
25434
0,049
24423
0,375
25112
0,323
25251
-0,036
25435
-0,035
24424
0,227
25113
0,308
25252
-0,092
25441
0,096
24425
0,073
25114
0,227
25253
-0,107
25442
0,04
24431
0,421
25115
0,143
25254
-0,188
25443
0,025
24432
0,365
25121
0,281
25255
-0,272
25444
-0,056
24433
0,35
25122
0,224
25311
0,343
25445
-0,14
24434
0,202
25123
0,21
25312
0,287
25451
-0,062
24435
0,049
25124
0,129
25313
0,272
25452
-0,118
24441
0,262
25125
0,045
25314
0,191
25453
-0,133
24442
0,205
25131
0,256
25315
0,107
25454
-0,214
24443
0,191
25132
0,2
25321
0,245
25455
-0,298
24444
0,069
25133
0,185
25322
0,188
25511
0,285
24445
-0,057
25134
0,104
25323
0,174
25512
0,229
24451
0,022
25135
0,02
25324
0,093
25513
0,214
24452
-0,035
25141
0,151
25325
0,009
25514
0,133
24453
-0,05
25142
0,095
25331
0,22
25515
0,049
24454
-0,131
25143
0,08
25332
0,164
25521
0,187
24455
-0,215
25144
-0,001
25333
0,149
25522
0,13
24511
0,369
25145
-0,085
25334
0,068
25523
0,116
24512
0,312
25151
-0,007
25335
-0,016
25524
0,035
24513
0,298
25152
-0,063
25341
0,115
25525
-0,049
24514
0,217
25153
-0,078
25342
0,059
25531
0,162
24515
0,133
25154
-0,159
25343
0,044
25532
0,106
24521
0,27
25155
-0,243
25344
-0,037
25533
0,091
24522
0,214
25211
0,35
25345
-0,121
25534
0,01
24523
0,199
25212
0,294
25351
-0,043
25535
-0,074
24524
0,118
25213
0,279
25352
-0,099
25541
0,057
24525
0,034
25214
0,198
25353
-0,114
25542
0,001
24531
0,246
25215
0,114
25354
-0,195
25543
-0,014
24532
0,189
25221
0,252
25355
-0,279
25544
-0,095


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
99
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
25545
-0,179
31234
0,414
31423
0,537
32112
0,707
25551
-0,101
31235
0,193
31424
0,368
32113
0,692
25552
-0,157
31241
0,486
31425
0,191
32114
0,479
25553
-0,172
31242
0,429
31431
0,584
32115
0,258
25554
-0,253
31243
0,415
31432
0,527
32121
0,665
25555
-0,337
31244
0,254
31433
0,513
32122
0,609
31111
0,85
31245
0,088
31434
0,343
32123
0,594
31112
0,794
31251
0,166
31435
0,167
32124
0,381
31113
0,779
31252
0,11
31441
0,406
32125
0,16
31114
0,566
31253
0,095
31442
0,35
32131
0,64
31115
0,345
31254
0,014
31443
0,335
32132
0,584
31121
0,752
31255
-0,07
31444
0,201
32133
0,569
31122
0,695
31311
0,814
31445
0,062
32134
0,356
31123
0,681
31312
0,758
31451
0,14
32135
0,135
31124
0,468
31313
0,743
31452
0,084
32141
0,428
31125
0,247
31314
0,53
31453
0,069
32142
0,372
31131
0,727
31315
0,309
31454
-0,012
32143
0,357
31132
0,671
31321
0,716
31455
-0,096
32144
0,197
31133
0,656
31322
0,659
31511
0,487
32145
0,03
31134
0,443
31323
0,645
31512
0,431
32151
0,108
31135
0,222
31324
0,432
31513
0,416
32152
0,052
31141
0,515
31325
0,211
31514
0,335
32153
0,037
31142
0,458
31331
0,691
31515
0,251
32154
-0,044
31143
0,444
31332
0,635
31521
0,389
32155
-0,128
31144
0,283
31333
0,62
31522
0,332
32211
0,735
31145
0,117
31334
0,407
31523
0,318
32212
0,678
31151
0,195
31335
0,186
31524
0,237
32213
0,664
31152
0,139
31341
0,479
31525
0,153
32214
0,451
31153
0,124
31342
0,422
31531
0,364
32215
0,23
31154
0,043
31343
0,408
31532
0,308
32221
0,636
31155
-0,041
31344
0,247
31533
0,293
32222
0,58
31211
0,821
31345
0,081
31534
0,212
32223
0,565
31212
0,765
31351
0,159
31535
0,128
32224
0,352
31213
0,75
31352
0,103
31541
0,259
32225
0,131
31214
0,537
31353
0,088
31542
0,203
32231
0,612
31215
0,316
31354
0,007
31543
0,188
32232
0,555
31221
0,723
31355
-0,077
31544
0,107
32233
0,541
31222
0,666
31411
0,707
31545
0,023
32234
0,328
31223
0,652
31412
0,65
31551
0,101
32235
0,107
31224
0,439
31413
0,636
31552
0,045
32241
0,399
31225
0,218
31414
0,466
31553
0,03
32242
0,343
31231
0,698
31415
0,29
31554
-0,051
32243
0,328
31232
0,642
31421
0,608
31555
-0,135
32244
0,168
31233
0,627
31422
0,552
32111
0,763
32245
0,002


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
100
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
32251
0,08
32435
0,08
33124
0,364
33313
0,639
32252
0,023
32441
0,32
33125
0,143
33314
0,426
32253
0,009
32442
0,263
33131
0,623
33315
0,205
32254
-0,072
32443
0,249
33132
0,567
33321
0,612
32255
-0,157
32444
0,115
33133
0,552
33322
0,555
32311
0,727
32445
-0,025
33134
0,339
33323
0,541
32312
0,671
32451
0,053
33135
0,118
33324
0,328
32313
0,656
32452
-0,003
33141
0,411
33325
0,107
32314
0,443
32453
-0,018
33142
0,354
33331
0,587
32315
0,222
32454
-0,099
33143
0,34
33332
0,531
32321
0,629
32455
-0,183
33144
0,179
33333
0,516
32322
0,573
32511
0,4
33145
0,013
33334
0,303
32323
0,558
32512
0,344
33151
0,091
33335
0,082
32324
0,345
32513
0,329
33152
0,035
33341
0,375
32325
0,124
32514
0,248
33153
0,02
33342
0,318
32331
0,604
32515
0,164
33154
-0,061
33343
0,304
32332
0,548
32521
0,302
33155
-0,145
33344
0,143
32333
0,533
32522
0,246
33211
0,717
33345
-0,023
32334
0,32
32523
0,231
33212
0,661
33351
0,055
32335
0,099
32524
0,15
33213
0,646
33352
-0,001
32341
0,392
32525
0,066
33214
0,433
33353
-0,016
32342
0,336
32531
0,277
33215
0,212
33354
-0,097
32343
0,321
32532
0,221
33221
0,619
33355
-0,181
32344
0,161
32533
0,206
33222
0,562
33411
0,603
32345
-0,006
32534
0,125
33223
0,548
33412
0,546
32351
0,072
32535
0,041
33224
0,335
33413
0,532
32352
0,016
32541
0,172
33225
0,114
33414
0,362
32353
0,001
32542
0,116
33231
0,594
33415
0,186
32354
-0,08
32543
0,101
33232
0,538
33421
0,504
32355
-0,164
32544
0,02
33233
0,523
33422
0,448
32411
0,62
32545
-0,064
33234
0,31
33423
0,433
32412
0,564
32551
0,014
33235
0,089
33424
0,264
32413
0,549
32552
-0,042
33241
0,382
33425
0,087
32414
0,379
32553
-0,057
33242
0,325
33431
0,48
32415
0,203
32554
-0,138
33243
0,311
33432
0,423
32421
0,522
32555
-0,222
33244
0,15
33433
0,409
32422
0,465
33111
0,746
33245
-0,016
33434
0,239
32423
0,451
33112
0,69
33251
0,062
33435
0,063
32424
0,281
33113
0,675
33252
0,006
33441
0,302
32425
0,105
33114
0,462
33253
-0,009
33442
0,246
32431
0,497
33115
0,241
33254
-0,09
33443
0,231
32432
0,441
33121
0,648
33255
-0,174
33444
0,097
32433
0,426
33122
0,591
33311
0,71
33445
-0,042
32434
0,256
33123
0,577
33312
0,654
33451
0,036


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
101
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
33452
-0,02
34141
0,345
34325
0,08
34514
0,204
33453
-0,035
34142
0,288
34331
0,495
34515
0,12
33454
-0,116
34143
0,274
34332
0,439
34521
0,258
33455
-0,2
34144
0,133
34333
0,424
34522
0,201
33511
0,383
34145
-0,014
34334
0,243
34523
0,187
33512
0,327
34151
0,064
34335
0,055
34524
0,106
33513
0,312
34152
0,008
34341
0,309
34525
0,022
33514
0,231
34153
-0,007
34342
0,252
34531
0,233
33515
0,147
34154
-0,088
34343
0,238
34532
0,177
33521
0,285
34155
-0,172
34344
0,097
34533
0,162
33522
0,228
34211
0,625
34345
-0,05
34534
0,081
33523
0,214
34212
0,569
34351
0,028
34535
-0,003
33524
0,133
34213
0,554
34352
-0,028
34541
0,128
33525
0,049
34214
0,373
34353
-0,043
34542
0,072
33531
0,26
34215
0,185
34354
-0,124
34543
0,057
33532
0,204
34221
0,527
34355
-0,208
34544
-0,024
33533
0,189
34222
0,47
34411
0,532
34545
-0,108
33534
0,108
34223
0,456
34412
0,476
34551
-0,03
33535
0,024
34224
0,275
34413
0,461
34552
-0,086
33541
0,155
34225
0,087
34414
0,313
34553
-0,101
33542
0,099
34231
0,502
34415
0,159
34554
-0,182
33543
0,084
34232
0,446
34421
0,433
34555
-0,266
33544
0,003
34233
0,431
34422
0,377
35111
0,367
33545
-0,081
34234
0,25
34423
0,362
35112
0,311
33551
-0,003
34235
0,062
34424
0,214
35113
0,296
33552
-0,059
34241
0,316
34425
0,061
35114
0,215
33553
-0,074
34242
0,259
34431
0,409
35115
0,131
33554
-0,155
34243
0,245
34432
0,353
35121
0,269
33555
-0,239
34244
0,104
34433
0,338
35122
0,212
34111
0,654
34245
-0,043
34434
0,19
35123
0,198
34112
0,598
34251
0,035
34435
0,036
35124
0,117
34113
0,583
34252
-0,021
34441
0,249
35125
0,033
34114
0,402
34253
-0,036
34442
0,193
35131
0,244
34115
0,214
34254
-0,117
34443
0,178
35132
0,188
34121
0,555
34255
-0,201
34444
0,057
35133
0,173
34122
0,499
34311
0,618
34445
-0,069
35134
0,092
34123
0,484
34312
0,562
34451
0,009
35135
0,008
34124
0,304
34313
0,547
34452
-0,047
35141
0,139
34125
0,116
34314
0,366
34453
-0,062
35142
0,083
34131
0,531
34315
0,178
34454
-0,143
35143
0,068
34132
0,475
34321
0,519
34455
-0,227
35144
-0,013
34133
0,46
34322
0,463
34511
0,356
35145
-0,097
34134
0,279
34323
0,448
34512
0,3
35151
-0,019
34135
0,091
34324
0,268
34513
0,285
35152
-0,075


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
102
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
35153
-0,09
35342
0,047
35531
0,15
41215
0,299
35154
-0,171
35343
0,032
35532
0,094
41221
0,686
35155
-0,255
35344
-0,049
35533
0,079
41222
0,629
35211
0,338
35345
-0,133
35534
-0,002
41223
0,615
35212
0,282
35351
-0,055
35535
-0,086
41224
0,411
35213
0,267
35352
-0,111
35541
0,045
41225
0,2
35214
0,186
35353
-0,126
35542
-0,011
41231
0,661
35215
0,102
35354
-0,207
35543
-0,026
41232
0,605
35221
0,24
35355
-0,291
35544
-0,107
41233
0,59
35222
0,183
35411
0,312
35545
-0,191
41234
0,387
35223
0,169
35412
0,256
35551
-0,113
41235
0,176
35224
0,088
35413
0,241
35552
-0,169
41241
0,456
35225
0,004
35414
0,16
35553
-0,184
41242
0,4
35231
0,215
35415
0,076
35554
-0,265
41243
0,385
35232
0,159
35421
0,213
35555
-0,349
41244
0,231
35233
0,144
35422
0,157
41111
0,813
41245
0,07
35234
0,063
35423
0,142
41112
0,757
41251
0,149
35235
-0,021
35424
0,061
41113
0,742
41252
0,092
35241
0,11
35425
-0,023
41114
0,539
41253
0,078
35242
0,054
35431
0,189
41115
0,327
41254
-0,004
35243
0,039
35432
0,133
41121
0,714
41255
-0,088
35244
-0,042
35433
0,118
41122
0,658
41311
0,777
35245
-0,126
35434
0,037
41123
0,643
41312
0,721
35251
-0,048
35435
-0,047
41124
0,44
41313
0,706
35252
-0,104
35441
0,084
41125
0,229
41314
0,503
35253
-0,119
35442
0,028
41131
0,69
41315
0,291
35254
-0,2
35443
0,013
41132
0,634
41321
0,678
35255
-0,284
35444
-0,068
41133
0,619
41322
0,622
35311
0,331
35445
-0,152
41134
0,416
41323
0,607
35312
0,275
35451
-0,074
41135
0,204
41324
0,404
35313
0,26
35452
-0,13
41141
0,485
41325
0,193
35314
0,179
35453
-0,145
41142
0,429
41331
0,654
35315
0,095
35454
-0,226
41143
0,414
41332
0,598
35321
0,233
35455
-0,31
41144
0,26
41333
0,583
35322
0,176
35511
0,273
41145
0,099
41334
0,38
35323
0,162
35512
0,217
41151
0,177
41335
0,168
35324
0,081
35513
0,202
41152
0,121
41341
0,449
35325
-0,004
35514
0,121
41153
0,106
41342
0,393
35331
0,208
35515
0,037
41154
0,025
41343
0,378
35332
0,152
35521
0,175
41155
-0,059
41344
0,224
35333
0,137
35522
0,118
41211
0,784
41345
0,063
35334
0,056
35523
0,104
41212
0,728
41351
0,141
35335
-0,028
35524
0,023
41213
0,713
41352
0,085
35341
0,103
35525
-0,062
41214
0,51
41353
0,07


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
103
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
41354
-0,011
41543
0,17
42232
0,518
42421
0,491
41355
-0,095
41544
0,089
42233
0,504
42422
0,434
41411
0,676
41545
0,005
42234
0,3
42423
0,42
41412
0,62
41551
0,083
42235
0,089
42424
0,257
41413
0,605
41552
0,027
42241
0,37
42425
0,087
41414
0,442
41553
0,012
42242
0,313
42431
0,466
41415
0,272
41554
-0,069
42243
0,299
42432
0,41
41421
0,577
41555
-0,153
42244
0,144
42433
0,395
41422
0,521
42111
0,726
42245
-0,016
42434
0,232
41423
0,506
42112
0,67
42251
0,062
42435
0,063
41424
0,343
42113
0,655
42252
0,006
42441
0,294
41425
0,174
42114
0,452
42253
-0,009
42442
0,238
41431
0,553
42115
0,241
42254
-0,09
42443
0,223
41432
0,497
42121
0,628
42255
-0,174
42444
0,093
41433
0,482
42122
0,572
42311
0,69
42445
-0,042
41434
0,319
42123
0,557
42312
0,634
42451
0,036
41435
0,149
42124
0,353
42313
0,619
42452
-0,021
41441
0,381
42125
0,142
42314
0,416
42453
-0,035
41442
0,325
42131
0,603
42315
0,205
42454
-0,116
41443
0,31
42132
0,547
42321
0,592
42455
-0,2
41444
0,18
42133
0,532
42322
0,536
42511
0,383
41445
0,044
42134
0,329
42323
0,521
42512
0,326
41451
0,122
42135
0,118
42324
0,317
42513
0,312
41452
0,066
42141
0,399
42325
0,106
42514
0,231
41453
0,051
42142
0,342
42331
0,567
42515
0,147
41454
-0,03
42143
0,328
42332
0,511
42521
0,284
41455
-0,114
42144
0,173
42333
0,496
42522
0,228
41511
0,469
42145
0,013
42334
0,293
42523
0,213
41512
0,413
42151
0,091
42335
0,082
42524
0,132
41513
0,398
42152
0,034
42341
0,363
42525
0,048
41514
0,317
42153
0,02
42342
0,306
42531
0,26
41515
0,233
42154
-0,061
42343
0,292
42532
0,203
41521
0,371
42155
-0,145
42344
0,137
42533
0,189
41522
0,315
42211
0,698
42345
-0,023
42534
0,108
41523
0,3
42212
0,641
42351
0,055
42535
0,024
41524
0,219
42213
0,627
42352
-0,002
42541
0,155
41525
0,135
42214
0,423
42353
-0,016
42542
0,098
41531
0,346
42215
0,212
42354
-0,097
42543
0,084
41532
0,29
42221
0,599
42355
-0,181
42544
0,003
41533
0,275
42222
0,543
42411
0,589
42545
-0,081
41534
0,194
42223
0,528
42412
0,533
42551
-0,003
41535
0,11
42224
0,325
42413
0,518
42552
-0,06
41541
0,241
42225
0,113
42414
0,355
42553
-0,074
41542
0,185
42231
0,575
42415
0,186
42554
-0,155


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
104
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
42555
-0,239
43244
0,127
43433
0,378
44122
0,467
43111
0,709
43245
-0,034
43434
0,215
44123
0,452
43112
0,653
43251
0,045
43435
0,045
44124
0,278
43113
0,638
43252
-0,012
43441
0,277
44125
0,098
43114
0,435
43253
-0,027
43442
0,221
44131
0,499
43115
0,223
43254
-0,108
43443
0,206
44132
0,442
43121
0,61
43255
-0,192
43444
0,076
44133
0,428
43122
0,554
43311
0,673
43445
-0,06
44134
0,254
43123
0,539
43312
0,617
43451
0,018
44135
0,074
43124
0,336
43313
0,602
43452
-0,038
44141
0,318
43125
0,125
43314
0,399
43453
-0,053
44142
0,262
43131
0,586
43315
0,187
43454
-0,134
44143
0,247
43132
0,53
43321
0,574
43455
-0,218
44144
0,11
43133
0,515
43322
0,518
43511
0,365
44145
-0,032
43134
0,312
43323
0,503
43512
0,309
44151
0,047
43135
0,1
43324
0,3
43513
0,294
44152
-0,01
43141
0,381
43325
0,089
43514
0,213
44153
-0,024
43142
0,325
43331
0,55
43515
0,129
44154
-0,105
43143
0,31
43332
0,494
43521
0,267
44155
-0,189
43144
0,156
43333
0,479
43522
0,211
44211
0,593
43145
-0,005
43334
0,276
43523
0,196
44212
0,536
43151
0,073
43335
0,064
43524
0,115
44213
0,522
43152
0,017
43341
0,345
43525
0,031
44214
0,348
43153
0,002
43342
0,289
43531
0,242
44215
0,168
43154
-0,079
43343
0,274
43532
0,186
44221
0,494
43155
-0,163
43344
0,12
43533
0,171
44222
0,438
43211
0,68
43345
-0,041
43534
0,09
44223
0,423
43212
0,624
43351
0,037
43535
0,006
44224
0,249
43213
0,609
43352
-0,019
43541
0,137
44225
0,069
43214
0,406
43353
-0,034
43542
0,081
44231
0,47
43215
0,195
43354
-0,115
43543
0,066
44232
0,413
43221
0,582
43355
-0,199
43544
-0,015
44233
0,399
43222
0,525
43411
0,572
43545
-0,099
44234
0,225
43223
0,511
43412
0,516
43551
-0,021
44235
0,045
43224
0,307
43413
0,501
43552
-0,077
44241
0,289
43225
0,096
43414
0,338
43553
-0,092
44242
0,233
43231
0,557
43415
0,168
43554
-0,173
44243
0,218
43232
0,501
43421
0,473
43555
-0,257
44244
0,082
43233
0,486
43422
0,417
44111
0,622
44245
-0,06
43234
0,283
43423
0,402
44112
0,565
44251
0,018
43235
0,072
43424
0,239
44113
0,551
44252
-0,039
43241
0,352
43425
0,07
44114
0,377
44253
-0,053
43242
0,296
43431
0,449
44115
0,197
44254
-0,134
43243
0,281
43432
0,393
44121
0,523
44255
-0,218


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
105
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
44311
0,586
44445
-0,087
45134
0,074
45323
0,144
44312
0,529
44451
-0,009
45135
-0,01
45324
0,063
44313
0,515
44452
-0,065
45141
0,121
45325
-0,021
44314
0,341
44453
-0,08
45142
0,065
45331
0,19
44315
0,161
44454
-0,16
45143
0,05
45332
0,134
44321
0,487
44455
-0,245
45144
-0,031
45333
0,119
44322
0,431
44511
0,339
45145
-0,115
45334
0,038
44323
0,416
44512
0,282
45151
-0,037
45335
-0,046
44324
0,242
44513
0,268
45152
-0,093
45341
0,085
44325
0,062
44514
0,187
45153
-0,108
45342
0,029
44331
0,463
44515
0,103
45154
-0,189
45343
0,014
44332
0,406
44521
0,24
45155
-0,273
45344
-0,067
44333
0,392
44522
0,184
45211
0,321
45345
-0,151
44334
0,218
44523
0,169
45212
0,264
45351
-0,073
44335
0,038
44524
0,088
45213
0,25
45352
-0,129
44341
0,282
44525
0,004
45214
0,169
45353
-0,144
44342
0,226
44531
0,216
45215
0,085
45354
-0,225
44343
0,211
44532
0,159
45221
0,222
45355
-0,309
44344
0,074
44533
0,145
45222
0,166
45411
0,294
44345
-0,068
44534
0,064
45223
0,151
45412
0,238
44351
0,011
44535
-0,02
45224
0,07
45413
0,223
44352
-0,046
44541
0,111
45225
-0,014
45414
0,142
44353
-0,06
44542
0,054
45231
0,198
45415
0,058
44354
-0,141
44543
0,04
45232
0,141
45421
0,196
44355
-0,225
44544
-0,041
45233
0,127
45422
0,139
44411
0,504
44545
-0,126
45234
0,046
45423
0,125
44412
0,448
44551
-0,047
45235
-0,039
45424
0,044
44413
0,433
44552
-0,104
45241
0,092
45425
-0,04
44414
0,29
44553
-0,118
45242
0,036
45431
0,171
44415
0,142
44554
-0,199
45243
0,021
45432
0,115
44421
0,406
44555
-0,283
45244
-0,06
45433
0,1
44422
0,35
45111
0,349
45245
-0,144
45434
0,019
44423
0,335
45112
0,293
45251
-0,066
45435
-0,065
44424
0,192
45113
0,278
45252
-0,122
45441
0,066
44425
0,043
45114
0,197
45253
-0,137
45442
0,01
44431
0,381
45115
0,113
45254
-0,218
45443
-0,005
44432
0,325
45121
0,251
45255
-0,302
45444
-0,086
44433
0,31
45122
0,195
45311
0,313
45445
-0,17
44434
0,167
45123
0,18
45312
0,257
45451
-0,092
44435
0,019
45124
0,099
45313
0,242
45452
-0,148
44441
0,226
45125
0,015
45314
0,161
45453
-0,163
44442
0,169
45131
0,226
45315
0,077
45454
-0,244
44443
0,155
45132
0,17
45321
0,215
45455
-0,328
44444
0,036
45133
0,155
45322
0,159
45511
0,255


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
106
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
45512
0,199
51151
-0,05
51335
-0,059
51524
-0,009
45513
0,184
51152
-0,106
51341
0,072
51525
-0,093
45514
0,103
51153
-0,121
51342
0,016
51531
0,119
45515
0,019
51154
-0,202
51343
0,001
51532
0,063
45521
0,157
51155
-0,286
51344
-0,08
51533
0,048
45522
0,101
51211
0,307
51345
-0,164
51534
-0,033
45523
0,086
51212
0,251
51351
-0,086
51535
-0,117
45524
0,005
51213
0,236
51352
-0,142
51541
0,014
45525
-0,079
51214
0,155
51353
-0,157
51542
-0,042
45531
0,132
51215
0,071
51354
-0,238
51543
-0,057
45532
0,076
51221
0,209
51355
-0,322
51544
-0,138
45533
0,061
51222
0,152
51411
0,281
51545
-0,222
45534
-0,02
51223
0,138
51412
0,225
51551
-0,144
45535
-0,104
51224
0,057
51413
0,21
51552
-0,2
45541
0,027
51225
-0,027
51414
0,129
51553
-0,215
45542
-0,029
51231
0,184
51415
0,045
51554
-0,296
45543
-0,044
51232
0,128
51421
0,182
51555
-0,38
45544
-0,125
51233
0,113
51422
0,126
52111
0,249
45545
-0,209
51234
0,032
51423
0,111
52112
0,193
45551
-0,131
51235
-0,052
51424
0,03
52113
0,178
45552
-0,187
51241
0,079
51425
-0,054
52114
0,097
45553
-0,202
51242
0,023
51431
0,158
52115
0,013
45554
-0,283
51243
0,008
51432
0,102
52121
0,151
45555
-0,367
51244
-0,073
51433
0,087
52122
0,095
51111
0,336
51245
-0,157
51434
0,006
52123
0,08
51112
0,28
51251
-0,079
51435
-0,078
52124
-0,001
51113
0,265
51252
-0,135
51441
0,053
52125
-0,085
51114
0,184
51253
-0,15
51442
-0,003
52131
0,126
51115
0,1
51254
-0,231
51443
-0,018
52132
0,07
51121
0,238
51255
-0,315
51444
-0,099
52133
0,055
51122
0,181
51311
0,3
51445
-0,183
52134
-0,026
51123
0,167
51312
0,244
51451
-0,105
52135
-0,11
51124
0,086
51313
0,229
51452
-0,161
52141
0,021
51125
0,002
51314
0,148
51453
-0,176
52142
-0,035
51131
0,213
51315
0,064
51454
-0,257
52143
-0,05
51132
0,157
51321
0,202
51455
-0,341
52144
-0,131
51133
0,142
51322
0,145
51511
0,242
52145
-0,215
51134
0,061
51323
0,131
51512
0,186
52151
-0,137
51135
-0,023
51324
0,05
51513
0,171
52152
-0,193
51141
0,108
51325
-0,035
51514
0,09
52153
-0,208
51142
0,052
51331
0,177
51515
0,006
52154
-0,289
51143
0,037
51332
0,121
51521
0,144
52155
-0,373
51144
-0,044
51333
0,106
51522
0,087
52211
0,221
51145
-0,128
51334
0,025
51523
0,073
52212
0,164


JNJ-63623872-ZCD  (Pimodivir)
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107
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
52213
0,15
52352
-0,229
52541
-0,073
53225
-0,131
52214
0,069
52353
-0,244
52542
-0,129
53231
0,08
52215
-0,016
52354
-0,325
52543
-0,144
53232
0,024
52221
0,122
52355
-0,409
52544
-0,225
53233
0,009
52222
0,066
52411
0,194
52545
-0,309
53234
-0,072
52223
0,051
52412
0,138
52551
-0,231
53235
-0,156
52224
-0,03
52413
0,123
52552
-0,287
53241
-0,025
52225
-0,114
52414
0,042
52553
-0,302
53242
-0,081
52231
0,098
52415
-0,042
52554
-0,383
53243
-0,096
52232
0,041
52421
0,096
52555
-0,467
53244
-0,177
52233
0,027
52422
0,04
53111
0,232
53245
-0,261
52234
-0,054
52423
0,025
53112
0,176
53251
-0,183
52235
-0,139
52424
-0,056
53113
0,161
53252
-0,239
52241
-0,008
52425
-0,14
53114
0,08
53253
-0,254
52242
-0,064
52431
0,071
53115
-0,004
53254
-0,335
52243
-0,079
52432
0,015
53121
0,134
53255
-0,419
52244
-0,16
52433
0
53122
0,077
53311
0,196
52245
-0,244
52434
-0,081
53123
0,063
53312
0,14
52251
-0,166
52435
-0,165
53124
-0,019
53313
0,125
52252
-0,222
52441
-0,034
53125
-0,103
53314
0,044
52253
-0,237
52442
-0,09
53131
0,109
53315
-0,04
52254
-0,317
52443
-0,105
53132
0,053
53321
0,098
52255
-0,402
52444
-0,186
53133
0,038
53322
0,041
52311
0,213
52445
-0,27
53134
-0,043
53323
0,027
52312
0,157
52451
-0,192
53135
-0,127
53324
-0,055
52313
0,142
52452
-0,248
53141
0,004
53325
-0,139
52314
0,061
52453
-0,263
53142
-0,052
53331
0,073
52315
-0,023
52454
-0,344
53143
-0,067
53332
0,017
52321
0,115
52455
-0,428
53144
-0,148
53333
0,002
52322
0,059
52511
0,155
53145
-0,232
53334
-0,079
52323
0,044
52512
0,099
53151
-0,154
53335
-0,163
52324
-0,037
52513
0,084
53152
-0,21
53341
-0,032
52325
-0,121
52514
0,003
53153
-0,225
53342
-0,088
52331
0,09
52515
-0,081
53154
-0,306
53343
-0,103
52332
0,034
52521
0,057
53155
-0,39
53344
-0,184
52333
0,019
52522
0,001
53211
0,203
53345
-0,268
52334
-0,062
52523
-0,014
53212
0,147
53351
-0,19
52335
-0,146
52524
-0,095
53213
0,132
53352
-0,246
52341
-0,015
52525
-0,179
53214
0,051
53353
-0,261
52342
-0,071
52531
0,032
53215
-0,033
53354
-0,342
52343
-0,086
52532
-0,024
53221
0,105
53355
-0,426
52344
-0,167
52533
-0,039
53222
0,048
53411
0,177
52345
-0,251
52534
-0,12
53223
0,034
53412
0,121
52351
-0,173
52535
-0,204
53224
-0,047
53413
0,106


JNJ-63623872-ZCD  (Pimodivir)
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108
Approved, Date: 1 July 2020
Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
53414
0,025
53553
-0,319
54242
-0,108
54431
0,027
53415
-0,059
53554
-0,4
54243
-0,123
54432
-0,029
53421
0,078
53555
-0,484
54244
-0,204
54433
-0,044
53422
0,022
54111
0,205
54245
-0,288
54434
-0,125
53423
0,007
54112
0,149
54251
-0,21
54435
-0,209
53424
-0,074
54113
0,134
54252
-0,266
54441
-0,078
53425
-0,158
54114
0,053
54253
-0,281
54442
-0,134
53431
0,054
54115
-0,031
54254
-0,362
54443
-0,149
53432
-0,002
54121
0,107
54255
-0,446
54444
-0,23
53433
-0,017
54122
0,05
54311
0,169
54445
-0,314
53434
-0,098
54123
0,036
54312
0,113
54451
-0,236
53435
-0,182
54124
-0,045
54313
0,098
54452
-0,292
53441
-0,051
54125
-0,129
54314
0,017
54453
-0,307
53442
-0,107
54131
0,082
54315
-0,067
54454
-0,388
53443
-0,122
54132
0,026
54321
0,071
54455
-0,472
53444
-0,203
54133
0,011
54322
0,014
54511
0,111
53445
-0,287
54134
-0,07
54323
0
54512
0,055
53451
-0,209
54135
-0,154
54324
-0,081
54513
0,04
53452
-0,265
54141
-0,023
54325
-0,165
54514
-0,041
53453
-0,28
54142
-0,079
54331
0,046
54515
-0,125
53454
-0,361
54143
-0,094
54332
-0,01
54521
0,013
53455
-0,445
54144
-0,175
54333
-0,025
54522
-0,044
53511
0,138
54145
-0,259
54334
-0,106
54523
-0,058
53512
0,082
54151
-0,181
54335
-0,19
54524
-0,139
53513
0,067
54152
-0,237
54341
-0,059
54525
-0,223
53514
-0,014
54153
-0,252
54342
-0,115
54531
-0,012
53515
-0,098
54154
-0,333
54343
-0,13
54532
-0,068
53521
0,04
54155
-0,417
54344
-0,211
54533
-0,083
53522
-0,017
54211
0,176
54345
-0,295
54534
-0,164
53523
-0,032
54212
0,12
54351
-0,217
54535
-0,248
53524
-0,113
54213
0,105
54352
-0,273
54541
-0,117
53525
-0,197
54214
0,024
54353
-0,288
54542
-0,173
53531
0,015
54215
-0,06
54354
-0,369
54543
-0,188
53532
-0,041
54221
0,078
54355
-0,453
54544
-0,269
53533
-0,056
54222
0,022
54411
0,15
54545
-0,353
53534
-0,137
54223
0,007
54412
0,094
54551
-0,275
53535
-0,221
54224
-0,074
54413
0,079
54552
-0,331
53541
-0,09
54225
-0,158
54414
-0,002
54553
-0,346
53542
-0,146
54231
0,053
54415
-0,086
54554
-0,427
53543
-0,161
54232
-0,003
54421
0,052
54555
-0,511
53544
-0,242
54233
-0,018
54422
-0,005
55111
0,122
53545
-0,326
54234
-0,099
54423
-0,019
55112
0,066
53551
-0,248
54235
-0,183
54424
-0,1
55113
0,051
53552
-0,304
54241
-0,052
54425
-0,184
55114
-0,03


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Health state
Index Value
Health state
Index Value
Health state
Index Value
Health state
Index Value
55115
-0,114
55254
-0,445
55443
-0,232
55121
0,024
55255
-0,529
55444
-0,313
55122
-0,033
55311
0,086
55445
-0,397
55123
-0,048
55312
0,03
55451
-0,319
55124
-0,129
55313
0,015
55452
-0,375
55125
-0,213
55314
-0,066
55453
-0,39
55131
-0,001
55315
-0,15
55454
-0,471
55132
-0,057
55321
-0,013
55455
-0,555
55133
-0,072
55322
-0,069
55511
0,028
55134
-0,153
55323
-0,084
55512
-0,028
55135
-0,237
55324
-0,165
55513
-0,043
55141
-0,106
55325
-0,249
55514
-0,124
55142
-0,162
55331
-0,037
55515
-0,208
55143
-0,177
55332
-0,093
55521
-0,071
55144
-0,258
55333
-0,108
55522
-0,127
55145
-0,342
55334
-0,189
55523
-0,142
55151
-0,264
55335
-0,273
55524
-0,223
55152
-0,32
55341
-0,142
55525
-0,307
55153
-0,335
55342
-0,198
55531
-0,095
55154
-0,416
55343
-0,213
55532
-0,151
55155
-0,5
55344
-0,294
55533
-0,166
55211
0,093
55345
-0,378
55534
-0,247
55212
0,037
55351
-0,3
55535
-0,331
55213
0,022
55352
-0,356
55541
-0,2
55214
-0,059
55353
-0,371
55542
-0,256
55215
-0,143
55354
-0,452
55543
-0,271
55221
-0,005
55355
-0,536
55544
-0,352
55222
-0,062
55411
0,067
55545
-0,436
55223
-0,076
55412
0,011
55551
-0,358
55224
-0,157
55413
-0,004
55552
-0,414
55225
-0,241
55414
-0,085
55553
-0,429
55231
-0,03
55415
-0,169
55554
-0,51
55232
-0,086
55421
-0,032
55555
-0,594
55233
-0,101
55422
-0,088
55234
-0,182
55423
-0,103
55235
-0,266
55424
-0,184
55241
-0,135
55425
-0,268
55242
-0,191
55431
-0,056
55243
-0,206
55432
-0,112
55244
-0,287
55433
-0,127
55245
-0,371
55434
-0,208
55251
-0,293
55435
-0,292
55252
-0,349
55441
-0,161
55253
-0,364
55442
-0,217


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ATTACHMENT 6.
: HRS DERIVATION
The HRS categories should be evaluated from 6 to 1. First check if the subject falls in category 6 
(has the subject died?) if not then we evaluate category 5, if not 5 then evaluate category 4 and so 
on.
The HRS is evaluated at baseline and per day, relative to the first study drug intake. 
The baseline HRS is covering the full baseline/screening/day 1 visit which can occur on 2 days. 
Timing of first study drug intake is not taken into account.
Note: 

VSOXYSAT is assessed 3 times per day (or per baseline visit). In case one of the 
assessments says ‘N’ then the final result for that day (or baseline visit) is ‘N’, else if one 
of the assessments is ‘NA’ then the final result is ‘NA’ else if one of the assessments is 
missing then final result is missing. 
So a combination of ‘Y’, “”, “N”
result =’N’
‘Y’, “”, “NA” result =’NA’
‘Y;’Y’,’’
result =’’
‘Y;’Y’,’Y’
result =’Y’
On the baseline visit, on days at or after HO end date or on the day of discontinuation it 
might be that less than 3 assessments are done. Therefore, take only the records into 
account from the dataset on those days as planned. The same rules above apply to derive 
the final result per day when more than 1 assessment is collected.

In case the subject withdrew from the study, the HRS will be set to missing from the next 
day onwards.

In case of chronic oxygen use and multiple CMARTN values on a day we consider the
worst value: In case one of the values is ‘N’ then final result for that day (or baseline 
visit) is ‘N’, else if one of the assessments is missing then final result is missing.

The list of types of supplemental oxygen and invasive mechanical ventilation can be 
extended depending on the medical review (see DPS part 2 or Excel sheet of the medical 
review)

The list of hospitalization terms (i.e.: ICU or WARD) can be extended depending on the 
medical review (see DPS part 2 or Excel sheet of the medical review).

If the Subjects has no HO data, the subject is considered to be in the hospital during the 
trial. All other aspect of the HRS will be evaluated according to the derivation below. 

In case the readiness for discharge (RDISHOSP) is assessed more than once per day 
(baseline visit) we consider the worst value: in case one of the values is ‘N’ then the final 
result of that day (or baseline visit) is ‘N’


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Some clarification is required for following categories:
6. Death
When DM.DTHDTC<=(date of assessment) 
5. Requiring invasive mechanical ventilation;
When CMSTDTC<=(date of assessment) <=CMENDTC where CMADMTP="INVASIVE 
MECHANICAL VENTILATION"
And CMADMDSC in (‘Through Endotracheal tube’ ‘Through Tracheostomy tube’ or ‘Through 
ECMO’ )
4. Admitted to the ICU;
From the HO data set:
          hostdy <=(day of assessment)<=hoendy
           hoterm = ‘ICU’ 
From the SS data set:
           SSTESTCD= ‘REQICU’ and SSSTRESC=’Y’
Or       SSTESTCD= ‘REASICU’ and SSSTRESC=’Y’
Or 
both REQICU and REAICU is missing and NOT (RDISHOSP = ‘Y’ on the day of 
assessment and RDISHOSP = ‘Y’ on the day (baseline visit) before)
OR
From the HO data set:
hostdy <=(day of assessment)<=hoendy
hoterm = ‘WARD’
From the SS data set:
SSTESTCD=’REASICU’ and SSSTRESC=’Y’
OR
SSTESTCD=’REQICU’ and SSSTRESC=’Y’
3. Non-ICU hospitalization, requiring supplemental oxygen
Non-ICU hospitalization:
hostdy <=(day of assessment)<=hoendy
hoterm = ‘Hospital inpatient Department (WARD)’ 
NOT (RDISHOSP=’Y’ on the day of assessment and RDISHOSP=’Y’ on day(baseline 
visit) before)
OR
hostdy <=(day of assessment)<=hoendy
hoterm = ‘ICU’ 
NOT (RDISHOSP=’Y’ on the day of assessment and RDISHOSP=’Y’ on day(baseline 
visit) before)
OR


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(day of assessment)=hoendy+1
RDISHOSP=’N’ on day(baseline visit) before
OR
In case re-hospitalization occurred (there is a day between the HOENDY of the previous 
record and HOSTDY of the next record)
(day of assessment) =HOSTDY (of the re-hospitalization)
NOT (RDISHOSP=’Y’ on the day of assessment and RDISHOSP=’Y’ on day(baseline 
visit) before)
AND
Requiring supplemental oxygen:
‘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.’
FAOBJ=CHRONIC OXYGEN USE and FAORRES=’N’
CMADMTP in (“Non-Invasive Mechanical Ventilation”, “Nasal Cannula”, “Venturi 
Mask”, “Simple Face Mask”, “Nonrebreathing Face Mask with Reservoir and One-
Way Valve”.)
CMTRT=SUPPLEMENTAL OXYGEN and CMSTDTC <= date of assessment <= 
CMENDTC
VSOXYSAT in (’N’ ‘NA’) at any time during the day of assessment (OR is missing)
OR
‘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.’
FAOBJ=CHRONIC OXYGEN USE and FAORRES=’Y’
CMARTN = ‘N’
CMADMTP in (“Non-Invasive Mechanical Ventilation”, “Nasal Cannula”, “Venturi 
Mask”, “Simple Face Mask”, “Nonrebreathing Face Mask with Reservoir and One-
Way Valve”.) and CMTRT=SUPPLEMENTAL OXYGEN and CMSTDTC <= date of 
assessment <= CMENDTC
      OR
‘Not receiving supplemental oxygen and Having a blood oxygen saturation of <94% 
when breathing room air for 15 minutes at any measurement on the day of assessment’ 


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No record in cm with oxygen supplementation
VSOXYSAT=’N’ at any time on the day of assessment OR [VSTESTCD=’OXYSAT’ 
and VSORRES<94% and VSOXSMRA=’Y’]
       OR
‘Not receiving supplemental oxygen and 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%.’
No record in cm with oxygen supplementation
VSEVINTX= PRE-INFLUENZA INFECTION and VSTESTCD=’OXYSAT and 
’VSORRES<94% and VSRMAIR=’Y’
VSORRES and VSTESTCD=OXYSAT (of day of assessment) < [ VSORRES and 
VSEVINTX= PRE-INFLUENZA INFECTION and VSTESTCD=’OXYSAT and 
VSRMAIR=’Y’ - 3 ]
2. Non-ICU hospitalization, not requiring supplemental oxygen
hostdy <=(day of assessment)<=hoendy
hoterm = ‘Hospital inpatient Department (WARD)’ 
NOT (RDISHOSP=’Y’ on the day of assessment and RDISHOSP=’Y’ on day(baseline 
visit) before)
hostdy <=(day of assessment)<=hoendy
hoterm = ‘ICU’ 
NOT (RDISHOSP=’Y’ on the day of assessment and RDISHOSP=’Y’ on day(baseline 
visit) before)
OR
(day of assessment)=hoendy+1
RDISHOSP=’N’ on day(baseline visit) before
OR
In case re-hospitalization occurred (there is a day between the HOENDY of the previous 
record and HOSTDY of the next record)
(day of assessment) =HOSTDY (of the re-hospitalization)
NOT (RDISHOSP=’Y’ on the day of assessment and RDISHOSP=’Y’ on day(baseline 
visit) before)


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1. Not hospitalized
Some examples
Discharge against medical advice
If a subject is discharged ‘against medical advice’ on the day prior to the day of assessment, the 
subject will be considered as hospitalized (evaluating the others aspects of the HRS to define the 
correct category, e.g.: requiring supplemental oxygen, on the day of assessment) 
We have a discharged against medical advice if on the day the subject is discharged (according 
to the HO dataset) the investigator indicated he is not ready and his SS status is discharged,
Day 3
Day 4
Day 5 
Day 6 
Day 7
Day 8
Status 
(HO)
Hospitalized
Hospitalized
Hospitalized
Discharged
Home
Home
Case 1
ready (SS)
Not ready
Not ready
Not ready
Not ready
--
--
Status(SS)
hospitalized
hospitalized
hospitalized
Hospitalized
discharged
--
Against 
medical 
advice?
NO
HRS
>1
>1
>1
>1
>1
HOME
Case 2
ready (SS)
Not ready
Not ready
Not ready
Not ready
Ready
--
Status(SS)
hospitalized
hospitalized
hospitalized
Hospitalized
discharged
--
Against 
medical 
advice?
NO
HRS
>1
>1
>1
>1
>1
HOME
Case 3
ready (SS)
Not ready
Not ready
Not ready
Not ready
Not ready
--
Status(SS)
hospitalized
hospitalized
hospitalized
Hospitalized
discharged
--
Against 
medical 
advice?
NO
HRS
>1
>1
>1
>1
>1
HOME
Case 4
ready (SS)
Not ready
Not ready
Not ready
Not ready
--
Status(SS)
hospitalized
hospitalized
hospitalized
Discharged


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
115
Approved, Date: 1 July 2020
Against 
medical 
advice?
YES
HRS
>1
>1
>1
>1
>1
Missing
Case 5
ready (SS)
Not ready
Not ready
Not ready
Ready
--
--
Status(SS)
hospitalized
hospitalized
hospitalized
discharged
Against 
medical 
advice?
NO
HRS
>1
>1
>1
>1
HOME
HOME
Case 6
ready (SS)
Not ready
Not ready
Not ready
Ready
--
--
Status(SS)
hospitalized
hospitalized
hospitalized
hospitalized
discharged
Against 
medical 
advice?
NO
HRS
>1
>1
>1
>1
HOME
HOME
Case 7
ready (SS)
Not ready
Not ready
Ready
Ready
--
--
Status(SS)
hospitalized
hospitalized
hospitalized
hospitalized
discharged
Against 
medical 
advice?
NO
HRS
>1
>1
>1
HOME
HOME
HOME
Case 8
ready (SS)
Not ready
Not ready
Not ready
--
--
--
Status(SS)
hospitalized
hospitalized
discharged
--
--
Against 
medical 
advice?
NO
HRS
>1
>1
>1
>1
HOME
HOME
Only in case 4 above we have a discharge against medical advice which would lead to missing 
values from day 8 onwards. The HRS on day 7 is defined by the other aspects of the HRS 
(requiring oxygen, ICU,..) on day 7 and not copied from day 6.


JNJ-63623872-ZCD  (Pimodivir)
Statistical Analysis Plan 63623872FLZ3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
116
Approved, Date: 1 July 2020
Requiring supplemental oxygen
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
supplemental oxygen (CM)
YES
YES
NO
NO
NO
NO
Chronic oxygen use
No
yes
Not used
Not used
Not used
Not used
returned to prior level?
Not used
N
Not used
Not used
Not used
Not used
pre influenza infection levels
Not used
Not used
Not used
Not used
Not used
93
Oxysat record < pre-influenza level at any 
moment during the day
Not used
Not used
Not used
Not used
Not used
yes
sustain >94% Oxy sat (VSOXYSAT)
N' missing 
or 'NA'
N' missing 
or 'NA'
N' at any 
time during 
the day
Missing or 
NA
YEs
Not used
Oxysat record <94% at any moment 
during the day
Not used
Not used
no
yes
yes
Not used
REQUIRING SUPPLEMENTAL 
OXYGEN?
YES
YES
YES
YES
YES
YES
To pay attention to
Case 7
Case 8
Case 9
Case 10
Case 11
Case 12
supplemental oxygen (CM)
YES
No
No
YEs
YEs
YEs
Chronic oxygen use
No
Not used
Yes
Yes
Yes
Yes
returned to prior level?
Not used
Not used
N
Missing
N
y
pre influenza infection levels
Not used
93
Not used
Not used
Not used
Not used
Oxysat record < pre-influenza level at any 
moment during the day
not used
yes
Not used
Not used
Not used
Not used
sustain >94% Oxy sat (VSOXYSAT)
missing
yes
Missing
Missing
Yes
Yes
Oxysat record <94% at any moment 
during the day
yes
Not used
Missing
Not used
Not used
yes
REQUIRING SUPPLEMENTAL 
OXYGEN?
NO
YES
NO
YES
YES
NO