Clinical trial NCT02532283
Conditions: Influenza A Virus
Keywords: Influenza A virus JNJ-63623872 Oseltamivir
Sponsor: Janssen Research & Development, LLC
Start date: 2015-12-11; Completion date: 2017-03-15
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the Pharmacokinetic parameters of JNJ-63623872 in combination with oseltamivir in elderly participants (aged 65 to \<= 85 years) compared to adults (aged 18 to \<= 64 years) with influenza A infection.

Detailed description:
This is a randomized (study medication assigned to participants by chance), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), placebo-controlled, multicenter (when more than one hospital or medical school team work on a medical research study) study to evaluate the effect of JNJ-63623872 in combination with oseltamivir in participants with influenza A infection. The study consists of 3 Phases: Screening visit (1 Day), participants who meet all eligibility criteria will be randomized in a 2:1 ratio to receive study drug in double-blind treatment Phase (7 Days) and follow up Phase (21 Days). The duration of participation in the study for each participant is approximately 28 Days. Primarily Pharmacokinetic parameters of JNJ-63623872 will be measured. Participants' safety will be monitored throughout the study.

Arms: arm 1: Participants will be administered JNJ-63623872 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. arm 2: Participants will be administered placebo tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Interventions: intervention 1: JNJ-63623872 intervention 2: Placebo intervention 3: Oseltamivir
Intervention descriptions: intervention 1: Participants will be administered JNJ-63623872 600 milligram (mg) tablets orally twice daily for 7 days. intervention 2: Participants will be administered placebo tablets orally twice daily for 7 days. intervention 3: Participants will be administered oseltamivir 75 mg capsules orally twice daily for 7 days.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 19 September 2016
Janssen Research & Development *
Clinical Protocol
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Pharmacokinetics, Safety, and Antiviral Activity of JNJ-63623872 in Combination With 
Oseltamivir in Adult and Elderly Hospitalized Patients With Influenza A Infection
Protocol 63623872FLZ2002; Phase 2
AMENDMENT 3   
JNJ-63623872  
*Janssen Research & Development is a global organization that operates through different legal 
entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen 
Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; 
Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; 
Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is 
used throughout the protocol to represent these various legal entities; the sponsor is identified on 
the Contact Information page that accompanies the protocol.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2015-003002-17
Status:
Approved
Date:
19 September 2016
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-106482090, 7.0
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.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
2
Approved, Date: 19 September 2016
Protocol History
63623872FLZ2002
Document Type and
File Name
Issued Date
Amendment
Type
Comments
Initial Clinical Trial Protocol
63623872FLZ2002_Protocol
05-Aug-2015
-
-
Protocol Amendment I
63623872FLZ2002_Protocol_Amend_1
23-Oct-2015
Substantial
For details, please refer to 
Section Amendment 1
Protocol Amendment II
63623872FLZ2002_Protocol_Amend_2
09-Dec-2015
Substantial
For details, please refer to 
Section Amendment 2
Protocol Amendment III
63623872FLZ2002_Protocol_Amend_3
This document
Substantial
For details, please refer to 
Amendment 3
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
3
Approved, Date: 19 September 2016
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 10
TIME AND EVENTS SCHEDULE – DURING HOSPITALIZATION (UP TO DISCHARGE) ..................... 17
TIME AND EVENTS SCHEDULE – AFTER DISCHARGE FROM HOSPITAL......................................... 19
ABBREVIATIONS ...................................................................................................................................... 21
1.
INTRODUCTION................................................................................................................................ 23
1.1.
Background .................................................................................................................................... 23
1.2.
Oseltamivir ..................................................................................................................................... 29
1.3.
Overall Rationale for the Study...................................................................................................... 30
1.4.
Benefits and Risks Management ................................................................................................... 31
1.4.1.
Known Benefits of JNJ-63623872 .............................................................................................. 31
1.4.2.
Potential Benefits of JNJ-63623872 ........................................................................................... 31
1.4.3.
Known Risks of JNJ-63623872 .................................................................................................. 31
1.4.4.
Potential Risks of JNJ-63623872 ............................................................................................... 32
1.4.5.
Overall Benefit/Risk Assessment ............................................................................................... 32
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 34
2.1.
Objectives ...................................................................................................................................... 34
2.2.
Hypothesis ..................................................................................................................................... 35
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 35
3.1.
Overview of Study Design.............................................................................................................. 35
3.2.
Study Design Rationale.................................................................................................................. 36
4.
SUBJECT POPULATION.................................................................................................................. 38
4.1.
Inclusion Criteria ............................................................................................................................ 38
4.2.
Exclusion Criteria ........................................................................................................................... 39
4.3.
Prohibitions and Restrictions ......................................................................................................... 41
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 42
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 43
7.
TREATMENT COMPLIANCE............................................................................................................ 43
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 44
9.
STUDY EVALUATIONS .................................................................................................................... 45
9.1.
Study Procedures........................................................................................................................... 45
9.1.1.
Overview..................................................................................................................................... 45
9.1.2.
Screening Phase ........................................................................................................................ 45
9.1.3.
Double-Blind Treatment Phase .................................................................................................. 46
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 47
9.1.5.
After discharge from the hospital................................................................................................ 47
9.2.
Pharmacokinetics........................................................................................................................... 48
9.2.1.
Evaluations ................................................................................................................................. 48
9.2.2.
Analytical Procedures................................................................................................................. 49
9.2.3.
Pharmacokinetic Parameters ..................................................................................................... 49
9.2.4.
Pharmacokinetic Endpoints ........................................................................................................ 49
9.2.5.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Evaluations.................................... 49
9.3.
Safety Evaluations ......................................................................................................................... 49
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
4
Approved, Date: 19 September 2016
9.3.1.
Adverse Events........................................................................................................................... 50
9.3.2.
Clinical Laboratory Tests ............................................................................................................ 50
9.3.3.
Electrocardiogram....................................................................................................................... 52
9.3.4.
Vital Signs (temperature, pulse/heart rate, respiratory rate, blood pressure, blood 
oxygen saturation, level of consciousness)................................................................................ 52
9.3.5.
Physical Examination.................................................................................................................. 53
9.3.6.
Specific Toxicities ....................................................................................................................... 53
9.4.
Efficacy........................................................................................................................................... 55
9.4.1.
Evaluations ................................................................................................................................. 55
9.4.1.1.
Patient-reported Outcomes ..................................................................................................... 55
9.4.1.2.
Viral Kinetics (Nasal MT Swabs) ............................................................................................. 56
9.4.2.
Efficacy Endpoints ...................................................................................................................... 57
9.5.
Resistance Evaluations.................................................................................................................. 57
9.5.1.1.
Viral Sequencing ..................................................................................................................... 57
9.5.1.2.
Phenotyping............................................................................................................................. 57
9.6.
Biomarkers ..................................................................................................................................... 57
9.7.
Sample Collection and Handling.................................................................................................... 57
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 58
10.1.
Completion ..................................................................................................................................... 58
10.2.
Discontinuation of Study Treatment............................................................................................... 58
10.3.
Withdrawal From the Study............................................................................................................ 58
11.
STATISTICAL METHODS................................................................................................................. 59
11.1.
Subject Information ........................................................................................................................ 59
11.2.
Sample Size Determination ........................................................................................................... 59
11.3.
Pharmacokinetic Analyses............................................................................................................. 62
11.4.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 64
11.5.
Safety Analyses ............................................................................................................................. 64
11.6.
Efficacy Analyses ........................................................................................................................... 66
11.7.
Biomarker Analyses ....................................................................................................................... 69
11.8.
Data Monitoring Committee ........................................................................................................... 69
12.
ADVERSE EVENT REPORTING ...................................................................................................... 69
12.1.
Definitions ...................................................................................................................................... 69
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 69
12.1.2.
Attribution Definitions.................................................................................................................. 71
12.1.3.
Severity Criteria .......................................................................................................................... 71
12.2.
Special Reporting Situations.......................................................................................................... 71
12.3.
Procedures..................................................................................................................................... 72
12.3.1.
All Adverse Events...................................................................................................................... 72
12.3.2.
Serious Adverse Events ............................................................................................................. 73
12.3.3.
Pregnancy................................................................................................................................... 74
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 74
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 74
13.1.
Procedures..................................................................................................................................... 74
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 75
14.
STUDY DRUG INFORMATION......................................................................................................... 75
14.1.
Physical Description of Study Drug(s) ........................................................................................... 75
14.2.
Packaging ...................................................................................................................................... 75
14.3.
Labeling.......................................................................................................................................... 75
14.4.
Preparation, Handling, and Storage............................................................................................... 75
14.5.
Drug Accountability ........................................................................................................................ 76
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 76
16.
ETHICAL ASPECTS ......................................................................................................................... 77
16.1.
Study-Specific Design Considerations........................................................................................... 77
16.2.
Regulatory Ethics Compliance....................................................................................................... 77
16.2.1.
Investigator Responsibilities ....................................................................................................... 77
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 77
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
5
Approved, Date: 19 September 2016
16.2.3.
Informed Consent ....................................................................................................................... 79
16.2.4.
Privacy of Personal Data ............................................................................................................ 79
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 80
16.2.6.
Country Selection ....................................................................................................................... 80
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 81
17.1.
Protocol Amendments.................................................................................................................... 81
17.2.
Regulatory Documentation ............................................................................................................ 81
17.2.1.
Regulatory Approval/Notification ................................................................................................ 81
17.2.2.
Required Prestudy Documentation............................................................................................. 81
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 82
17.4.
Source Documentation................................................................................................................... 82
17.5.
Case Report Form Completion ...................................................................................................... 83
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 84
17.7.
Record Retention ........................................................................................................................... 84
17.8.
Monitoring ...................................................................................................................................... 85
17.9.
Study Completion/Termination....................................................................................................... 86
17.9.1.
Study Completion ....................................................................................................................... 86
17.9.2.
Study Termination....................................................................................................................... 86
17.10.
On-Site Audits ................................................................................................................................ 86
17.11.
Use of Information and Publication................................................................................................ 86
REFERENCES............................................................................................................................................ 89
ATTACHMENTS......................................................................................................................................... 90
INVESTIGATOR AGREEMENT ............................................................................................................... 104
LAST PAGE.............................................................................................................................................. 104
LIST OF ATTACHMENTS
Attachment 1:
WHO Toxicity Grading Scale for Determining the Severity of Adverse 
Events (Feb 2003) .................................................................................................................... 90
Attachment 2:
Anticipated Events ......................................................................................................... 95
Attachment 3:
Influenza Intensity and Impact Questionnaire (Flu-iiQTM).............................................. 96
Attachment 4:
Additional Daily Diary Items to Flu-iiQTM........................................................................ 98
Attachment 5:
Flu-PRO Questionnaire.................................................................................................. 99
Attachment 6:
Additional Daily Diary Items to Flu-PRO...................................................................... 101
Attachment 7:
Cardiovascular Safety - Abnormalities......................................................................... 103
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Selected Single Dose JNJ-63623872 Pharmacokinetic Parameters ....................................... 26
Table 2:
Variability for Key Pharmacokinetic Parameters for JNJ-63623872 600 mg bid 
(Between-subjects %CV).......................................................................................................... 60
Table 3:
Precision of the LOESS Confidence Band Around the Prediction ........................................... 61
Table 4:
Upper Confidence Limits for any Event with a Zero Incidence................................................. 61
Table 5:
Risk Differences and Associated 95% Confidence Intervals for Potential 
Treatment-emergent Adverse Event Incidences ...................................................................... 62
Table 6:
Resolution Criteria for Vital Signs ............................................................................................. 66
Table 7:
Ordinal Scale on Day 8............................................................................................................. 67
FIGURES
Figure 1:
Example of LOESS Regression for a Simulated Data Set for Cmin (N=50) .............................. 61
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
6
Approved, Date: 19 September 2016
PROTOCOL AMENDMENTS
Amendment 3 (This document)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment:
Inconsistencies, corrections, and other edits within the protocol.
Rationale: Based on the conflict between Exclusion Criterion 8 and Section 10.2, Exclusion Criterion 8 was 
adapted to not allow subjects with chronic hepatitis C on treatment to enroll in the trial and the discontinuation 
criterion for hepatitis was removed from Section 10.2. In view of that, the discontinuation rules in Section 9.3.6
and Exclusion Criterion 7 were modified.
4.2 Exclusion Criteria
9.3.6 Specific Toxicities
10.2 Discontinuation of Study Treatment
Rationale: Toxicity management was updated to accommodate more severely ill patients in the hospital setting.
9.3.6 Specific Toxicities
Rationale: A second 300-mg tablet formulation containing the equivalent of JNJ-63623872 free base has been 
developed by the Sponsor. The formulation information was added to Section 14.1.
14.1 Physical Description of Study Drug(s)
Rationale: Exclusion Criterion 3 was modified to exclude severely immunocompromised subjects based on
CD4+ and absolute neutrophil counts. The discontinuation criterion for absolute neutrophil count was modified
in Section 9.3.6.
SYNOPSIS
4.2 Exclusion Criteria
9.3.6 Specific Toxicities
Rationale: Based on FDA feedback, swabbing for local virology testing was adapted to be done from both 
nostrils instead of one (if feasible).
TIME AND EVENTS SCHEDULE – During Hospitalization (Up to discharge)
TIME AND EVENTS SCHEDULE – After discharge From Hospital
9.1.2 Screening Phase
9.4.1.2 Viral Kinetics (Nasal MT Swabs)
Rationale: Based on investigator feedback, timing of second dose was allowed to be brought forward with a 
maximum of 4 hours from scheduled dosing (previously protocol language only allowed for movement of 
dosing back 4 hours).
6 DOSAGE AND ADMINISTRATION
Rationale: Based on investigator feedback, a footnote was added to the Time and Events Schedule to allow a 
historical ECG (prior to ICF sign-off) to be used for screening/baseline, with a window of 1 day. 
TIME AND EVENTS SCHEDULE – During Hospitalization (Up to discharge)
9.1.2 Screening Phase
9.3.3 Electrocardiogram
Rationale: Section 4.3 was updated following recent results of the oral contraceptive Phase 1 study (Study 
63623872FLZ1009), which demonstrated no significant drug interaction between JNJ-63623872 and estrogen-
and progesterone-based oral contraceptives.
1.1 Background
4.3 Prohibitions and Restrictions
Rationale: Based on results of the 14C-ADME study (Study 63623872FLZ1007), there is little (~5%) 
CYP3A-mediated metabolism in vivo and therefore strong inhibitors or inducers of CYP3A metabolism were
removed from the list of disallowed concomitant therapies.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
7
Approved, Date: 19 September 2016
Amendment 2 (09 December 2015)
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:
FDA feedback regarding (1) addition of a follow-up pregnancy test during treatment if pregnancy is a criterion 
for discontinuation of study drug and (2) addition of a hierarchal ordinal scale for clinical outcome as a 
secondary efficacy endpoint.
8 PRESTUDY AND CONCOMITANT THERAPY
Rationale: Clarification to Exclusion Criterion 12.
4.2 Exclusion Criteria
Rationale: Clarification to dose administration of oseltamivir based on the eGFR value.
SYNOPSIS
3.1 Overview of Study Design
6 DOSAGE AND ADMINISTRATION
9.1.3 Double-Blind Treatment Phase
Rationale: Clarifications and minor additions to Sections 11.5 and 11.6.
11.5 Safety Analyses
11.6 Efficacy Analyses
Rationale: Minor edits to below sections.
Front page
TIME AND EVENTS SCHEDULE – During Hospitalization (Up to discharge)
1.3 Overall Rationale for the Study
3.1 Overview of Study Design
3.2 Study Design Rationale
14.2 Packaging
Rationale: Based on feedback by the FDA, a urine pregnancy test (for females of childbearing potential) was 
added to Day 5 procedures.
TIME AND EVENTS SCHEDULE
9.1.3 Double-Blind Treatment Phase
9.3.2 Clinical Laboratory Tests
Rationale: Based on feedback by the FDA, a hierarchal ordinal scale for clinical outcome was added as a 
secondary efficacy endpoint.
SYNOPSIS
2.1 Objectives
11.6 Efficacy Analyses
Based on feedback by the FDA, standard-of-care was added as additional therapy to hospitalized patients 
outside this protocol (at the investigator's discretion).
9.1.3 Double-Blind Treatment Phase
Rationale: Based on recommendations related to contraception and pregnancy testing in clinical trials published 
by the Clinical Trial Facilitation Group, the double-barrier method of contraception was removed.
4.3 Prohibitions and Restrictions
Rationale: Based on practical considerations, sparse PK sampling was adjusted for Day 2 and Days 4-7 to: "On 
Day 2 and Days 4-7: predose (≤1 hour prior to dosing) and between 1.5 and 6 hours after the morning or 
evening dose (whichever is the most convenient)."
TIME AND EVENTS SCHEDULE
9.2.1 Evaluations
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
8
Approved, Date: 19 September 2016
Amendment 1 (23 October 2015)
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 FDA did not agree with the enrollment of adolescents because of 
insufficient Phase 2 safety and efficacy data in adults to support dosing in a pediatric population (Request for 
Additional Information 08 October 2015).
Rationale: Based on practical considerations and to align with the current Investigator Brochure (no food 
effect), the requirement of dosing with food was removed.
SYNOPSIS
3.1 Overview of Study Design
6 DOSAGE AND ADMINISTRATION
9.2.1 Evaluations
Rationale: Level of consciousness was added to the vital sign measurement. The level of consciousness will be 
measured according to the AVPU scale (alert, voice, pain, unresponsive). The National Early Warning Score 
(NEWS) will be derived based on vital signs and AVPU scale at baseline and during hospitalization.
TIME AND EVENTS SCHEDULE
9.1.2 Screening Phase
9.3.4 Vital Signs (temperature, pulse/heart rate, respiratory rate, blood pressure, blood oxygen saturation, level 
of consciousness)
11.5 Safety Analyses
REFERENCES
Rationale: Based on practical considerations, the limitation on regional recruitment was removed.
SYNOPSIS
3.1 Overview of Study Design
11.2 Sample Size Determination
Rationale: Minor edits were noted.
SYNOPSIS
TIME AND EVENTS SCHEDULE
ABBREVIATIONS
4.1 Inclusion Criteria
5 TREATMENT ALLOCATION AND BLINDING
9.2.1 Evaluations
9.2.2 Analytical Procedures
9.3.6 Specific Toxicities
12.1.1 Adverse Event Definitions and Classifications
12.3.1 All Adverse Events
14.1 Physical Description of Study Drug(s)
Attachment 2
Attachment 7
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
9
Approved, Date: 19 September 2016
Rationale: Based on the request by the FDA, all text regarding inclusion of the adolescent population was 
removed. Accordingly, the sample size justification was re-written.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.2 Oseltamivir
1.3 Overall Rationale for the Study
2.1 Objectives
3.1 Overview of Study Design
4 SUBJECT POPULATION
4.1 Inclusion Criteria
4.3 Prohibitions and Restrictions
9.1.2 Screening Phase
9.3 Safety Evaluations
11.2 Sample Size Determination
11.3 Pharmacokinetic Analyses
12.1.1 Adverse Event Definitions and Classifications
12.3.1 All Adverse Events
12.3.2 Serious Adverse Events
15 STUDY-SPECIFIC MATERIALS
16.1 Study-Specific Design Considerations
16.2.2 Independent Ethics Committee or Institutional Review Board
16.2.3 Informed Consent
17.2.2 Required Prestudy Documentation
Rationale: Re-wording was done to clarify exclusion criterion #3.
SYNOPSIS
4.2 Exclusion Criteria
Rationale: Minor errors were noted.
TIME AND EVENTS SCHEDULE
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
10
Approved, Date: 19 September 2016
SYNOPSIS
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Pharmacokinetics, 
Safety, and Antiviral Activity of JNJ-63623872 in Combination With Oseltamivir in Adult and 
Elderly Hospitalized Patients With Influenza A Infection
JNJ-63623872 (previously known as VX-787) is a non-nucleotide inhibitor of the influenza A virus 
polymerase and is currently in Phase 2 development as treatment for influenza A infection.
Oseltamivir is an influenza neuraminidase inhibitor indicated for the treatment of acute, 
uncomplicated influenza in patients 2 weeks of age and older who have been symptomatic for no 
more than 2 days and for prophylaxis of influenza in patients 1 year and older.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to evaluate the pharmacokinetic (PK) parameters of JNJ-63623872 in 
combination with oseltamivir in elderly subjects (aged 65 to ≤85 years) compared to adults (aged 
18 to ≤64 years) with influenza A infection.
Secondary Objectives
Secondary objectives include the assessment of the following parameters in the JNJ-63623872 
treatment arm compared to the control arm:
1.
Safety and tolerability.
2.
The time to influenza viral negativity based on quantitative reverse transcription polymerase 
chain reaction (qRT-PCR) and/or viral culture from nasal mid-turbinate (MT) swabs and, if 
applicable, based on PCR-based rapid molecular testing from nasal MT swabs.
3.
Viral load over time and rate of decline in viral load during treatment as measured by qRT-PCR 
and/or by viral culture.
4.
Area under the curve (AUC) of viral load as measured by qRT-PCR and/or by viral culture.
5.
Disease status and incidence of complications associated with influenza after the start of study 
treatment, and disease progression:

bacterial pneumonia (culture confirmed where possible),

other bacterial superinfections,

respiratory failure,

pulmonary disease (eg, asthma, chronic obstructive pulmonary disease [COPD]), 

cardiovascular and cerebrovascular disease (eg, myocardial infarction, congestive heart 
failure [CHF], arrhythmia, stroke).
6.
Change in duration and severity of clinical symptoms as measured by the Flu-PRO.
7.
Time to improvement of vital signs.
8.
Time to improvement of respiratory status. 
9.
Improvement on the ordinal scale.
10. Emergence of drug resistance as detected by genotype or phenotype.
11. Time to return to premorbid functional status.
12. Time to hospital discharge.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
11
Approved, Date: 19 September 2016
Exploratory Objectives
Exploratory objectives include the assessment of the following parameters in the JNJ-63623872 
treatment arm compared to the control arm:
1.
Use of antibiotics and/or corticosteroids during hospitalization.
2.
Number of subjects admitted to the Intensive Care Unit (ICU).
3.
Length of ICU stay for subjects transferred to the ICU after baseline.
4.
Correlation between the decline in viral load (measured by qRT-PCR and/or viral culture) and 
changes in clinical symptoms.
5.
PK/pharmacodynamic (PD) relationship (efficacy and safety).
Hypothesis
No formal hypothesis will be tested.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, multicenter Phase 2 study to evaluate the 
effect of JNJ-63623872 600 mg twice daily (bid) versus (vs.) placebo, both in combination with 
oseltamivir 75 mg bid in adult and elderly hospitalized subjects with influenza A infection. Up to 
90 subjects in total will be enrolled in this study. An effort will be made to enroll a minimum of 
approximately 24 subjects per age cohort.
Subjects who meet all eligibility criteria will be randomized in a 2:1 ratio to receive 1 of the following 
2 treatments:

JNJ-63623872 600 mg bid + oseltamivir 75 mg bid; OR

JNJ-63623872 placebo bid + oseltamivir 75 mg bid
All study drugs will be taken orally.
The study will consist of a screening/baseline visit, a double-blind treatment period of 7 days, and 
a follow-up period of 21 days.
The entire study duration for each subject will be 28 days with study assessments daily during the 
treatment period, and on Days 10, 14, and 28 of the follow-up period. The study is considered 
complete with the completion of the last study assessment for the last subject participating in the 
study.
SUBJECT POPULATION
In order to start treatment as soon as possible after the start of the influenza infection, screening will 
occur on Day 1, before randomization and the first administration of study drug.
Key Inclusion Criteria

Subject requires hospitalization to treat influenza infection and/or to treat complications of 
influenza infection.

Subject tested positive for influenza A infection within 1 day of signing of the informed consent 
form (ICF) using a PCR-based rapid molecular diagnostic assay.

Subjects must be capable of swallowing study medication tablets and capsules.

Male or female subject, 18 to 85 years of age (extremes included). 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
12
Approved, Date: 19 September 2016
Key Exclusion Criteria

Subject received more than 3 doses of the influenza antiviral medication oseltamivir, zanamivir, 
or peramivir since the start of the influenza symptoms, or ribavirin within 6 months prior to
screening.

Subject is unwilling to undergo regular nasal MT swabs or has any physical abnormality which 
limits the ability to collect regular nasal specimens.

Subject is known (considering lab results of the past 6 months) to be severely 
immunocompromised as defined by a CD4+ count <350 cells/mm3 or an absolute neutrophil 
count <750/mm3.

Subject is undergoing peritoneal dialysis, hemodialysis, or hemofiltration.

Subject has an estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m² according to the 
Modification of Diet in Renal Disease (MDRD) equation, assessed at screening or based on the 
most recent clinically relevant creatinine value if available.

Subject has known moderate (Child-Pugh class B) or severe hepatic impairment (Child-Pugh 
class C).
DOSAGE AND ADMINISTRATION
During the treatment period, all subjects will receive 1 of the following 2 dose regimens:

JNJ-63623872 600 mg bid + oseltamivir 75 mg bid on Days 1 through 7; OR

JNJ-63623872 placebo bid + oseltamivir 75 mg bid on Days 1 through 7.
Note: For subjects who receive only 1 dose on Day 1 (evening), dosing should continue until the 
morning of Day 8 so that all subjects receive 14 doses in total.
Oseltamivir dose should be reduced to 30 mg bid for subjects with an eGFR >30 and 
≤60 mL/min/1.73 m² according to the MDRD equation. Dose can be adjusted from 30 mg to 75 mg 
and vice versa during the course of treatment based on the eGFR value.
All study drugs will be taken orally. All subjects will take 2 tablets (JNJ-63623872 or placebo) and 
1 capsule (oseltamivir) bid. 
PHARMACOKINETIC EVALUATIONS
All evaluations will be performed as specified in the Time and Events Schedule.
All subjects will undergo intensive PK sampling for the measurement of plasma concentrations of 
JNJ-63623872 on Day 3, at 8 different time points within the dosing interval. The first sample should 
be collected before (preferably immediately prior to) study drug intake (≤1 hour prior to the morning 
dose). Samples 2 to 8 should be collected at 1, 2, 4, 6, 8, 10, and 12 hours after the morning dose (and 
prior to the evening dose). For subjects who are discharged before Day 3, no intensive PK sampling 
will be performed.
All subjects will undergo sparse PK sampling for the measurement of plasma concentrations of 
JNJ-63623872 at the time points specified in the TIME AND EVENTS SCHEDULE.
Measurement of plasma concentrations of oseltamivir and oseltamivir carboxylate may be done at the 
sponsor’s discretion.
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
A population PK and PK/PD analysis of plasma concentration-time data of JNJ-63623872 will be 
performed using the nonlinear mixed-effects modeling approach.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
13
Approved, Date: 19 September 2016
SAFETY EVALUATIONS
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards until 
the last study-related activity. The evaluations of safety and tolerability will include monitoring of 
adverse events (AEs)
(including complications
of influenza),
clinical laboratory tests, 
electrocardiograms (ECGs), vital sign measurements, physical examinations, pregnancy testing, and 
assessment of specific toxicities at the time points specified in the TIME AND EVENTS 
SCHEDULE.
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.
EFFICACY EVALUATIONS
Patient-reported Outcomes
The impact of influenza infection and its treatment (safety and efficacy) on patient-reported symptoms 
and functioning will be evaluated at the time points specified in the TIME AND EVENTS 
SCHEDULE using Flu-iiQTM and Flu-PRO.
Viral Kinetics
Influenza viral titer will be determined and quantified in nasal MT swabs taken at the time points 
specified in the TIME AND EVENTS SCHEDULE.
RESISTANCE EVALUATIONS
Viral Sequencing
Nasal MT swabs collected will be used for sequence analysis of the polymerase basic protein 2 (PB2) 
region of the influenza virus polymerase and the neuraminidase gene at the time points specified in 
the TIME AND EVENTS SCHEDULE. Exploratory sequencing of other regions of the influenza 
virus genome may also be performed.
Phenotyping
Nasal MT swabs will be used for analysis of phenotypic resistance against JNJ-63623872 and other 
antivirals at the time points specified in the TIME AND EVENTS SCHEDULE.
BIOMARKER EVALUATIONS
Blood samples will be collected at the time points specified in the TIME AND EVENTS SCHEDULE
for the exploration of blood biomarkers (eg, host ribonucleic acid [RNA], proteins including serum 
cytokines), on the premise that these markers may play a role in the blood concentrations, treatment 
response, or safety of JNJ-63623872 or oseltamivir, or the status and change of the influenza virus 
related disease. Where local regulations permit, an optional blood sample for exploratory host DNA 
research may also be collected.
In addition, nasal swabs collected for other testing may be used for biomarker analyses if available.
STATISTICAL METHODS
Since this is an exploratory study, no formal sample size calculation has been performed. 
Up to 90 subjects in total will be enrolled in this study. An effort will be made to include at least
24 subjects for each cohort, with the total of subjects allowed to be recruited across both cohorts. It is 
anticipated that it is feasible to recruit at least 60 subjects, which would lead to an acceptable 
precision for the primary objective.
For age cohorts it was assumed that the number of hospitalizations would be about equal for elderly 
and non-elderly adults. In case 60 subjects are enrolled, there are 40 subjects on active treatment and 
it is assumed that at least 16 subjects are on active treatment in each cohort. For the comparison of PK 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
14
Approved, Date: 19 September 2016
parameters of the cohort of elderly adults (test) vs. non-elderly adults (reference) with PK data in a 
16 to 24 ratio and a between-subject coefficient of variation (CV) of 60%, the 90% confidence 
interval (CI) of the geometric mean ratio (GMR) for minimum plasma concentration (Cmin) would be 
predicted to have a half-width of 35%, indicating that we can be 90% confident that the true GMR is 
in the interval observed GMR/1.35 to 1.35*GMR. If 90 subjects were enrolled with 60 on active 
treatment in a 24 to 36 ratio, the predicted half-width would be 28%.
For the safety objective of the study, the sample size of 40 to 60 subjects treated with JNJ-63623872 
can be characterized by assessing the precisions for (potentially) observed treatment-emergent AEs. 
For example, if no related treatment-emergent serious adverse event (SAE) is observed in a sample of 
60 subjects exposed to JNJ-63623872, it can be concluded with 95% confidence that the true 
incidence of related treatment-emergent SAEs will be less than 5%.
The primary PK analysis will be done on the PK-evaluable population, defined as all subjects who 
received active study treatment (JNJ-63623872 and oseltamivir), with evaluable PK measurements on 
Day 3.
Descriptive statistics will be used for all endpoints and will be tabulated by treatment arm and age 
cohort. No formal statistical hypothesis testing will be performed. Subgroup analyses may be 
summarized descriptively using baseline characteristics.
Primary Endpoint

PK parameters of JNJ-63623872 (ie, Cmin, Cmax, and AUC12h) established on Day 3.
Secondary Endpoints
1.
The proportion of subjects experiencing AEs, SAEs, and treatment-emergent grade 1-4 
laboratory abnormalities.
2.
Time to return to usual activity and usual health (Questions 5 and 9 of the additional items for the 
Flu-PRO). 
3.
Time to significant reduction in influenza symptom severity.
4.
Proportion of subjects with a significant reduction (to mild or none for all influenza symptoms) 
at each assessment.
5.
Disease status and incidence of complications associated with influenza after the start of study 
treatment, and disease progression: 

bacterial pneumonia (culture confirmed where possible), 

other bacterial superinfections,

respiratory failure,

pulmonary disease (eg, COPD), 

cardiovascular and cerebrovascular disease (eg, myocardial infarction, CHF, arrhythmia, 
stroke).
6.
Duration and severity of clinical symptoms as measured by the Flu-PRO.
7.
Time to improvement of vital signs. 
8.
Time to improvement of respiratory status.
9.
Improvement on the ordinal scale.
10. Time to hospital discharge.
11. The time to influenza viral negativity based on qRT-PCR and/or viral culture from nasal MT 
swabs and, if applicable, based on PCR-based rapid molecular testing from nasal MT swabs.
12. Viral load over time and the rate of decline in viral load during treatment as measured by 
qRT-PCR and/or viral culture.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
15
Approved, Date: 19 September 2016
13. AUC of viral loads as measured by qRT-PCR and/or viral culture. 
14. Resistance testing will be performed on all baseline samples as well as on qRT-PCR-positive 
post-baseline samples. Genotypic assays (sequencing of full length PB2 and other gene segments 
if applicable) will be used to determine resistance against JNJ-63623872. Phenotyping may be 
done at the sponsor’s discretion. Resistance testing for neuraminidase inhibitors will also be 
performed as applicable.
Exploratory Endpoints
1.
Length of ICU stay for subjects transferred to the ICU after baseline will be collected.
2.
Use of antibiotics and/or corticosteroids during hospitalization.
3.
Number of subjects admitted to the ICU.
4.
Correlation between the decline in viral load (measured by qRT-PCR and/or viral culture) and 
changes in clinical symptoms.
5.
PK/pharmacodynamic (PD) relationship (efficacy and safety).
An independent data monitoring committee (IDMC) will be established to monitor safety and efficacy 
data on a regular basis.
An interim analysis may be performed to support regulatory activities.
Pharmacokinetic Analyses
Descriptive statistics will be calculated for plasma concentrations of JNJ-63623872 at each sampling 
time point and for the derived plasma PK parameters. Statistics include sample size (n), mean, 
standard deviation (SD), %CV, geometric mean, median, minimum, and maximum.
For each subject treated with JNJ-63623872, JNJ-63623872 plasma concentration-time data will be 
graphically presented. Similarly, graphs of the mean plasma concentration-time profiles and overlay 
graphs with combined individual plasma concentration-time profiles will be produced. 
Pharmacokinetic parameters will be subjected to an exploratory graphical analysis in order to get a 
general overview.
Statistical analysis will be performed for the PK-evaluable population. Elderly adults (65 to 
≤85 years) will be compared to non-elderly adults (reference) to investigate the relative effect of age.
The primary PK parameters are Cmax, Cmin, and AUC12h. AUC12h will be omitted as primary parameter 
for an age cohort if more than half of the subjects of that age cohort do not have a reliable value.
Special attention will be paid to the plasma concentrations and PK parameters of those subjects who 
have discontinued the study for an AE, or who experienced an AE of at least grade 3, or an SAE.
Oseltamivir and oseltamivir carboxylate may be analyzed at the sponsor’s discretion.
Pharmacokinetic/Pharmacodynamic Analyses
The PK/PD relationship of JNJ-63623872 exposure (AUC12h, Cmax, or Cmin) with efficacy (ie, change 
in viral load from baseline and virologic response) and safety (including AEs and laboratory 
abnormalities) will be explored. Other exploratory analyses may be performed (eg, AUC of viral 
load).
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 drug received. Safety will be 
evaluated by means of AEs (including influenza complications), clinical laboratory tests, ECGs, vital 
signs, physical examinations, pregnancy testing, and specific toxicities. The safety analysis will be 
done using descriptive statistics for the Safety population and for each study phase separately 
(treatment, follow-up, and the combination of both).
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
16
Approved, Date: 19 September 2016
Efficacy Analyses
The efficacy endpoints will be analyzed on the Full Analysis Set, consisting of all subjects who were 
randomized, treated and had a confirmed influenza A infection, and will be analyzed by drug 
received. Descriptive statistics will be used for all efficacy endpoints and will be tabulated by 
treatment arm and by age cohort. For comparisons on defined endpoints of active vs. control 
treatment, appropriate pre-specified statistical analyses will be performed estimating the treatment 
difference including the associated 95% CI.
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 study subjects. Analyses may be conducted at the sponsor’s discretion 
and reported separately from this study.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
17
Approved, Date: 19 September 2016
TIME AND EVENTS SCHEDULE – DURING HOSPITALIZATION (UP TO DISCHARGE)
Phase
Screening
Treatment
Follow-up
Day
1a
2
3
4
5
6
7
10
14
28
Screening / 
Baselineb
Treatmentc
Safety Follow-up Visit / 
Final Study Visitd
Screening/Administrative
ICF
X
Inclusion/exclusion criteria
Xe
Medical history, demographics
X
Physical exam
X
X
Symptom-directed physical exam
Daily until discharge or until Day 14 (whichever comes first)
Height and weightf
X
12-lead ECG
Xw
Xg
X
Urine pregnancy test (female subjects of 
childbearing potential)
X
X
X
Study Drug Administration
Randomization
X
Administration of study drug (bid)
Xh
X
X
X
X
X
Xh
Virology Assessments
Nasal MT swabi for local PCR-based 
rapid molecular testing
Xk,l
The day before and/or the day of discharge from the hospitalk,m
Nasal MT swabj for central testing
Xk
Daily until discharge or until Day 14 (whichever comes first)k
Efficacy/Safety Assessments
Vital signs/pulse oximetryv
X
3X daily until discharge or until Day 14 (whichever comes first)n
X
Influenza symptoms and impact (Flu-
iiQTM)o
X
X
X
X
X
X
X
X
X
X
Influenza symptoms (Flu-PRO)p
X
X
X
X
X
X
X
X
X
X
Hematology, chemistry, coagulation, 
serology
Xq
Xr
Xr
Xr
Xr
Urinalysis
X
X
X
X
X
Pharmacokinetics
Xk,s
Xk,s
Xk,t
Xk,s
Xk,s
Xk,s
Xk,s
Blood biomarkers (proteins)
X
X
X
X
X
X
X
X
Blood biomarkers (mRNA)
X
X
X
X
X
Biomarkers (DNA)u
X
Adverse events (including 
complications of influenza)
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
Recording
X
X
X
X
X
X
X
X
X
X
a Day 1 encompasses signing of the informed consent form (ICF) approximately + 24 hours, and can be split over 2 calendar days if needed.
b All screening and baseline procedures should take place prior to the first study drug intake.
c Depending on the time of hospital admission and the timing of screening/baseline assessments, eligibility may only be established on the next calendar day, in which case the first study 
drug intake will be on that day, immediately after establishing eligibility.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
18
Approved, Date: 19 September 2016
d 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, or, at a minimum, to return to the site for a safety follow-up visit. Subjects who withdraw consent during the treatment or follow-up phase will be offered an optional safety 
follow-up visit.
e 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. Minimum criteria for the availability of documentation supporting the eligibility criteria are described in Section 17.4, Source Documentation.
f Height and body weight are only to be measured at screening if not already available in the subject’s chart and if practically feasible.
g Electrocardiogram (ECG) to be performed approximately 4 hours after the morning dose.
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 on 
Day 1 (evening), dosing should continue until the morning of Day 8 so that all subjects receive 14 doses in total.
i Local virology testing: Nasal mid-turbinate (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. Sampling should be done at approximately the same time when required. Sampling should be done according to the local testing requirements.
j Central virology testing: Nasal mid-turbinate (MT) swabs should be obtained from the left and the right nostrils and pooled into the same collection tube. Sampling should be done at 
approximately the same time each day throughout the study.
k At the time points where both nasal MT swabs and pharmacokinetic (PK) samples are obtained, these samples should be obtained as close together in time as possible. 
l An earlier sample within 1 day before signing of the ICF can be used in lieu of the baseline nasal swab requirement.
m Assessment to be performed on the day of discharge from the hospital and, if possible, the day before.
n Vital signs are to be measured 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).
o The Flu-iiQTM (and additional daily diary items) will be completed twice daily (preferably in the morning and in the evening) on Days 1 through 14 and once daily (preferably in the 
evening) on Days 15 through the Final Study Visit/Safety Follow-up Visit.
p The Flu-PRO (and additional daily diary items) will be completed once daily (preferably in the evening) throughout the study.
q Hepatitis A, B, and C serology testing will be done at screening for all subjects. Follicle-stimulating hormone (FSH) will be tested at screening for female subjects who are amenorrheic 
for 12 months or less.
r If feasible, safety blood samples will be collected after fasting for at least 10 hours.
s Sparse PK sampling will be performed as follows (for as long as subjects are hospitalized):

on Day 1: predose (≤1 hour prior to study drug intake), between 1.5 and 6 hours, and 12 hours after that same study drug intake (and prior to the next study drug intake). For 
subjects who start dosing in the morning of Day 1, a trough sample will be taken predose on Day 2 (≤1 hour prior to the morning dose).

on Day 2 and Days 4-7: predose (≤1 hour prior to dosing) and between 1.5 and 6 hours after the morning or evening dose (whichever is the most convenient).
t Intensive PK sampling will be performed over 12 hours: predose (≤1 hour prior to the morning dose) and 1, 2, 4, 6, 8, 10, and 12 hours after the morning dose (and prior to the evening 
dose). Note: For subjects who are discharged before or on Day 3, no intensive PK sampling will be performed.
u The pharmacogenomic (DNA) blood sample is optional and will preferably be collected at the baseline visit. However, if necessary eg, in case of a technical failure, it may be collected at 
a later time point without constituting a protocol deviation.
v Vital signs/pulse oximetry includes also assessment of level of consciousness (AVPU: alert, voice, pain, unresponsive).
w A historical ECG within 1 day before signing of the ICF can be used in lieu of the baseline ECG requirement.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
19
Approved, Date: 19 September 2016
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 9 would start with Day 10 procedures on this schedule). When 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 flowchart 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
Follow-up
Day
2/3/4b
5
+/-1 Day
6/7b
8c
+/-1 Day
10
+/-1 Day
14
+/-2 Days
28
+/-3 Days
Phone 
Follow-up
On-site/At 
home
Phone 
Follow-up
On-site/At 
home
On-site/At 
home
On-site/At 
home
Safety Follow-up Visit / 
Final Study Visitd
On-site
Study Drug Administration
Administration of study drug (bid)a
X
X
X
Virology Assessments
Nasal MT self-swabe for local PCR-based 
rapid molecular testing
Daily on days with no outpatient visit
Nasal MT swab for local PCR-based rapid 
molecular testinge
Xg
Xg
Nasal MT swab for central testingf
Xg
Xg
X
X
Efficacy/Safety Assessments
Vital signs/pulse oximetry
X
X
X
Physical exam
X
Symptom-directed physical exam
X
X
12-lead ECG
X
Urine pregnancy test (female subjects of 
childbearing potential)
X
X
Influenza symptoms and impact (Flu-
iiQTM)h
X
X
X
X
X
X
X
Influenza symptoms (Flu-PRO)i
X
X
X
X
X
X
X
Hematology, Chemistry, Coagulation
Xj
Xj
Xj
Urinalysis
X
X
X
Pharmacokinetics
Xg,k
Xg,k
Blood biomarkers (proteins and mRNA)l
X
X
X
Adverse events (including complications
of influenza)
X
X
X
X
X
X
X
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
20
Approved, Date: 19 September 2016
Phase
Treatmenta
Follow-up
Day
2/3/4b
5
+/-1 Day
6/7b
8c
+/-1 Day
10
+/-1 Day
14
+/-2 Days
28
+/-3 Days
Phone 
Follow-up
On-site/At 
home
Phone 
Follow-up
On-site/At 
home
On-site/At 
home
On-site/At 
home
Safety Follow-up Visit / 
Final Study Visitd
On-site
Concomitant medication 
Recording
X
X
X
X
X
X
X
a If the subject is discharged while on study treatment, he/she will receive study medication for at-home use.
b Subjects do not need to be seen on these days. A telephone contact is recommended to ensure compliance with study drug intake.
c For subjects who receive only 1 dose on Day 1 (evening), dosing should continue until the morning of Day 8 so that all subjects receive 14 doses in total.
d 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, or, at a minimum, to return to the study site for a safety follow-up visit. Subjects who withdraw consent during the treatment or follow-up phase will be offered an optional safety 
follow-up visit.
e Local virology testing: Nasal MT self-swabbing and swabbing by site staff should only continue for subjects for which the last sample before discharge was positive. Self-swabbing and 
swabbing by site staff should be continued until the subject is confirmed influenza negative or until Day 10 at the latest. Subjects will be instructed on how to self-swab at home and how 
to store the nasal samples at home until their next outpatient study visit. Nasal MT (self-)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. Sampling should be done at approximately the same time when required. Sampling should be done according to 
the local testing requirements.
f Central virology testing: Nasal MTswabs should be obtained from the left and the right nostrils and pooled into the same collection tube. Sampling should be done at approximately the 
same time when required. Nasal MT swabs for central testing should be continued for all subjects, at the indicated time points.
g 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.
h The Flu-iiQTM (and additional daily diary items) will be completed twice daily (preferably in the morning and in the evening) on Days 1 through 14 and once daily (preferably in the 
evening) on Days 15 through the Final Study Visit/Safety Follow-up Visit.
i The Flu-PRO (and additional daily diary items) will be completed once daily (preferably in the evening) throughout the study.
jIf feasible, safety blood samples will be collected after fasting for at least 10 hours.
k Sparse PK sampling will be performed as follows (if practically feasible): 

on Day 5: at any time during the visit.

on Day 8: at any time during the visit.
l Two blood samples will be taken.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
21
Approved, Date: 19 September 2016
ABBREVIATIONS
AE
adverse event
AUC
area under the plasma concentration-time curve
AUC0-∞
area under the plasma concentration-time curve from time 0 to infinity
ALP
alkaline phosphatase
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ASMP
Anticipated Events Safety Monitoring Plan
AST
aspartate aminotransferase
AUCth
area under the plasma concentration-time curve from time 0 to t hours after dosing
AVPU
alert, voice, pain, unresponsive
bid
bis in die; twice daily
BMI
body mass index
BUN
blood urea nitrogen
C0h
predose plasma concentration
CDC
Centers of Disease Control and Prevention
CHF
congestive heart failure
CI
confidence interval
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration 
COPD
chronic obstructive pulmonary disease
CPAP
clinical pharmacology analysis plan
CPK
creatine phosphokinase
Ctrough
plasma concentration just prior to the beginning or at the end of a dosing interval
CV
coefficient of variation
CYP
cytochrome P450
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
EC50
50% effective concentration
ECG
electrocardiogram
eCRF
electronic case report form
eDC
Electronic Data Capture
EENT
eyes/ears/nose/throat
eGFR
estimated glomerular filtration rate
(e)PRO
(electronic) patient reported outcome
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
GMR
geometric mean ratio
HbsAg
hepatitis B surface antigen
HCV
hepatitis C virus
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgM
immunoglobulin M
INR
international normalized ratio
IRB
International Review Board
IV
intravenous
IWRS
interactive web response system
LDH
lactate dehydrogenase
LS
least square
MCH
mean corpuscular hemoglobin
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
22
Approved, Date: 19 September 2016
MT
Mid-turbinate
NEWS
National Early Warning Score
NOAEL
no observed adverse effect level
OATP
organic anion transporting polypeptide
PB2
polymerase basic protein 2
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PQC
product quality complaint
PT
prothrombin time
qRT-PCR
quantitative reverse transcription 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
QTcL
QT correction derived by linear regression
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SBP
systolic blood pressure
SD
standard deviation
SUSAR
suspected unexpected serious adverse reaction
tmax
time to reach Cmax
UGT
uridine diphosphate-glucuronosyltransferases
USP
United States Pharmacopeia
vs.
versus
WBC
white blood cell
WHO
World Health Organization
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
23
Approved, Date: 19 September 2016
1.
INTRODUCTION
JNJ-63623872 (formerly known as VX-787) 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 2 development as treatment for influenza A infection.
For the most comprehensive nonclinical and clinical information regarding JNJ-63623872, refer 
to the latest version of the Investigator's Brochure for JNJ-63623872.6 Please consult the 
manufacturer’s prescribing information for oseltamivir (Tamiflu®) for full safety information.14,15
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 60.8 million cases, 274,000 hospitalizations, and over 
12,400 deaths.9 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, there exists an unmet need for new antiviral agents that are broadly 
effective.1
As well as ongoing vaccine development, several antiviral drugs have been developed for 
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, such as oseltamivir (Tamiflu), peramivir 
(RapivabTM), and zanamivir (Relenza®), and the viral M2 protein inhibitors, such as amantidine 
(Symmetrel®) and rimantadine (Flumadine®). Unfortunately, influenza strains have emerged that 
show resistance to both of these classes of drugs. In addition, these drugs have limitations in that 
they 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.
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. 
JNJ-63623872, an inhibitor of the viral replication complex, potentially meets all of these 
criteria.
Nonclinical Studies
JNJ-63623872 hemihydrate has a molecular formula of C20H19F2N5O2•HCl•0.5 H2O and a 
molecular weight of 399.39 Da.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
24
Approved, Date: 19 September 2016
Nonclinical Pharmacology
JNJ-63623872 is a non-nucleotide inhibitor of the PB2 subunit of the influenza A virus 
polymerase complex. JNJ-63623872 is a potent inhibitor of influenza A virus replication in vitro: 
using cytopathic effect-based methods in Madin-Darby canine kidney cells, the mean 50% 
effective concentration (EC50) of JNJ-63623872 was 1.1 nM for a panel of 36 influenza A 
strains, including contemporary and historical H1N1 strains, including 2009 pandemic strains, 
H3N2 strains, and the highly pathogenic H5N1 strain and H7N9 strains, as well as strains that 
were resistant to neuraminidase inhibitors. Little or no antiviral activity was seen against 
influenza B strains. JNJ-63623872 was also effective at inhibiting viral replication in ribonucleic 
acid (RNA) based assays and in experiments using normal human bronchial epithelial cells. 
Inhibition of viral replication was observed even when JNJ-63623872 was added after the 
initiation of viral infection, and the magnitude of viral replication inhibition was largely 
independent of multiplicity of infection.
In vitro synergy/antagonism experiments show synergy of JNJ-63623872 with the neuraminidase 
inhibitors oseltamivir and zanamivir, and additivity to synergy with favipiravir (an 
investigational nucleoside inhibitor).
In a murine model of pulmonary influenza infection, prophylactic treatment with JNJ-63623872 
administered at 3 or 10 mg/kg twice daily (bid) provided protection from influenza-induced 
mortality and morbidity; including when the start-to-treat window for JNJ-63623872 was 
delayed as long as 96 hours after influenza infection. JNJ-63623872 (up to 30 mg/kg) decreased 
lung viral titers (up to 1.8 log10 reduction) when administered to mice 24 hours after influenza A 
virus infection, and pharmacokinetic/pharmacodynamic (PK/PD) analysis suggested that the 
minimum plasma concentration (Cmin) was the PK parameter driving JNJ-63623872 antiviral 
activity. The predicted minimally efficacious therapeutic exposure assuming a 96-hour start-to-
treat window was an area under the plasma concentration-time curve from time 0 to 24 hours 
after dosing (AUC24h) of approximately 3,000 ng.h/mL, with an estimated Cmin of 30 ng/mL; 
based on improved efficacy at exposures associated with 10 mg/kg regimens in the mouse 
model, 100 ng/mL is targeted as the therapeutic Cmin.
Nonclinical Pharmacokinetics
In vitro studies indicate that JNJ-63623872 is highly permeable, subject to P-glycoprotein (P-gp)
transport, and is not an inhibitor of P-gp in vitro at 0.1 to 100 µM. JNJ-63623872 oral 
bioavailability was high in mice and rats, moderate in dogs, and low in monkeys.
JNJ-63623872 plasma protein binding ranged from 98% to >99.9% across species, and was 
concentration independent over a range of 1 to 10 μM. JNJ-63623872 was distributed widely 
throughout the body with the exception of the brain. There was no apparent melanin binding in 
pigmented skin or eyes.
JNJ-63623872 was metabolized in rat, dog, monkey, and human hepatocytes, and the metabolites 
detected in monkey cells were the most similar to those detected in human cells. JNJ-63623872 
elimination was governed by both Phase I cytochrome P450 (CYP) enzymes (namely CYP3A4) 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
25
Approved, Date: 19 September 2016
and aldehyde oxidase, as well as Phase II glucuronidation via uridine diphosphate-
glucuronosyltransferases (UGT) 1A3 and 1A9. The primary biotransformation pathways of 
JNJ-63623872 in rats are glucuronidation and oxidation. Based on in vitro results from CYP 
enzyme induction and inhibition studies, the potential for drug-drug interactions is expected to be 
low.
The estimated systemic clearance following intravenous (IV) administration of JNJ-63623872 
was approximately 51%, 44%, and 26% of hepatic blood flow in rats, dogs, and monkeys, 
respectively, with an elimination half-life ranging from 2.7 to 21 hours.
After oral administration of 14C-JNJ-63623872 to bile duct cannulated Sprague Dawley male 
rats, means of 79.1%, 13.7%, and 0.529% of the administered radioactivity were excreted in bile, 
feces, and urine, respectively, through 168 hours postdose.
JNJ-63623872 was found to inhibit organic anion transporting polypeptide (OATP) 1B1 with a 
50% inhibitory concentration (IC50) of 0.6 μM. JNJ-63623872 was also determined to be a 
substrate of OATP1B1.
Toxicology
No genotoxicity (mutagenicity, in vitro chromosomal aberration, or mammalian erythrocyte), 
phototoxicity (in vitro), safety pharmacology (battery of in vitro studies designed to evaluate 
effects of JNJ-63623872 against multiple cellular targets and a battery of in vivo cardiovascular, 
central nervous system, and respiratory systems), or reproductive (embryo-fetal, fertility, and 
early embryonic development) liabilities have been identified for JNJ-63623872. There were no 
toxicological effects in acute studies in mice and rats at doses up to 1,000 mg/kg. In studies 
where rats and monkeys were administered JNJ-63623872 at very high doses for 14 days, 
specific organ toxicity (liver, kidney, bone marrow, spleen, lymph nodes) and other toxicological 
findings were noted at doses of 250 mg/kg/day and above. 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 
(AUC0-24h basis) of 40-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 
JNJ-63623872 bid for 5 days.
Clinical Studies
At the time of protocol writing, data were available from 4 completed clinical studies: 
three Phase 1 studies and one Phase 2a challenge study. 
Human Pharmacokinetics
Food has a modest effect on bioavailability. When JNJ-63623872 was administered as either 
capsule or tablet with a high-fat meal, the AUC from time of dosing extrapolated to infinity 
(ACU0-∞) was similar compared to fasted conditions. However, the maximum plasma 
concentration (Cmax) was decreased by 9% for the capsule formulation and increased by 53% for 
the tablet formulation. The absolute bioavailability of the tablet is approximately 46%.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
26
Approved, Date: 19 September 2016
Following IV administration, the mean estimated volume of distribution at steady-state is 407 L, 
much larger than typical blood volume, suggesting JNJ-63623872 is extensively distributed.
Exploratory metabolite profiling suggested that JNJ-63623872 was the major component 
circulating in the plasma and only 1 glucuronide metabolite (<5%) was identified at steady-state.
Renal elimination of unchanged JNJ-63623872 is <1% following single oral doses.
Following single ascending doses of JNJ-63623872 capsules administered orally in the fasted 
state to healthy subjects, exposure (AUC) was slightly greater than dose proportional from 
200 mg to 800 mg, less than dose proportional from 800 mg to 1,200 mg, and slightly greater 
than dose proportional from 1,200 mg to 1,600 mg (study VX11-787-001) (Table 1). 
JNJ-63623872 plasma concentrations exhibit bi-phasic kinetics, eliminated initially at a more 
rapid rate, followed by a slower terminal elimination phase. The mean terminal elimination 
half-life (t1/2term) ranges from approximately 13 to 28 hours following single doses of 
JNJ-63623872.
Following a single 100 mg IV dose infused over 60 minutes, plasma concentrations of 
JNJ-63623872 declined more rapidly followed by a slower terminal elimination phase. The mean 
t1/2term was 20 hours, similar to oral doses.
Table 1:
Selected Single Dose JNJ-63623872 Pharmacokinetic Parameters
Mean (CV%)
Study
Dose
(mg)
Formulation
Fasted/Fed
Na,b
tmax
c
(h)
Cmax
(ng/mL)
AUC∞
(ng.h/mL)
t1/2term
(h)
001
200
Capsule
Fasted
6
1.25
(1.00, 2.00)
229 (49.6)
2,080 (50.9)
14.0 (32.3)
400
Capsule
Fasted
6
3.00
(1.00, 4.00)
602 (35.8)
5,690 (31.1)
12.9 (18.2)
800
Capsule
Fasted
6
1.50
(1.00, 6.00)
1,120 (61.8)
12,700 (41.2)
22.3 (26.9)
1,200
Capsule
Fasted
6
2.50
(1.00, 4.00)
1,580 (98.1)
12,500 (34.5)
17.1 (35.3)
1,600
Capsule
Fasted
6
2.50
(1.00, 6.00)
2,030 (83.2)
21,800 (42.8)
27.8 (60.9)
002
600
Capsule
Fasted
18
2.00
(1.00, 6.00)
558 (57.7)
7,856 (59.0)
20.9 (60.2)
600
Tablet
Fasted
18
3.00
(1.00, 6.00)
909 (45.2)
9,809 (50.5)
20.8 (78.2)
600
Tablet
Fed
18
2.00
(1.00, 12.00)
1,480 (71.2)
8,968 (42.8)
19.4 (16.1)
100
IV 60-minute 
infusion
8
0.75
(0.50, 1.00)
1,910 (15.3)
3,580 (56.6)
20.8 (63.8)
Source: studies VX11-787-001 and VX12-787-002
a AUC∞not reported for all subjects due to AUCextrap >25%
b terminal elimination half-life (t1/2term) not reported for all subjects due to t1/2 exceeding last sample collection
c median (range)
The mean accumulation index for AUC ranged from 1.6 to 2.5 following once daily doses of 
100 mg, 400 mg, and 800 mg for 10 days. There are no apparent time-dependency characteristics 
with repeat dosing. Steady-state is generally achieved after 3 days of dosing. Pharmacokinetic 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
27
Approved, Date: 19 September 2016
parameters observed in healthy subjects appear to be similar with or without prior inoculation of 
influenza A virus in a virus challenge model.
Clinical Efficacy
VX11-787-101 was a Phase 2a challenge study with a randomized, double-blind, placebo-
controlled design. Four dose regimens of JNJ-63623872 or placebo were administered orally at 
24 hours after viral inoculation and continued for 5 consecutive days: 100 mg once daily, 400 mg 
once daily, and single 900 mg or 1,200 mg loading dose followed by 600 mg once daily for 
5 days (capsule). A total of 106 healthy subjects were enrolled and inoculated, 104 subjects 
received study drug (n=72 JNJ-63623872; n=32 placebo).
Healthy subjects were inoculated intranasally with 1.0 mL of a 50% tissue culture infective dose 
of 5.0 to 5.5 log10/mL live influenza A/Wisconsin/67/2005 (H3N2) challenge strain virus on 
Day 0.
Results showed that JNJ-63623872 was effective in decreasing viral shedding in subjects with an 
active influenza A infection, with a concomitant reduction in symptoms.

A statistically significant dose response trend was observed on the AUC of viral shedding by 
tissue culture assay (p=0.036) and quantitative reverse transcriptase polymerase chain 
reaction (qRT-PCR) (p=0.031).

The 1,200/600-mg treatment group had a statistically significant reduction of the AUC of 
viral shedding by tissue culture (p=0.010) and by qRT-PCR (p=0.014) compared with 
placebo.

The 1,200/600-mg treatment group had a statistically significant reduction of the AUC 
(p=0.040), peak (p=0.034), and duration (p<0.001) of patient-reported influenza-like 
symptom scores compared with placebo.

The 1,200/600-mg treatment group had a statistically significant decrease in the duration 
(p=0.001) of patient-reported composite clinical symptom score compared with placebo.
These results suggest that JNJ-63623872 has the potential to be a novel treatment for patients 
with influenza A infection.
Clinical Virology
Population sequence analyses of the PB2 segment in subjects in study VX11-787-101 (healthy 
subjects challenged with influenza virus on Day 0, and treated with JNJ-63623872 for Days 1 
through 5) 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 JNJ-63623872 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 JNJ-63623872 in vitro (S324C, K376R, and M431L/R/V) were 
also observed in single JNJ-63623872 treated subjects.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
28
Approved, Date: 19 September 2016
Clinical Safety
JNJ-63623872 has been studied in single oral doses (studies VX11-787-001 and VX12-787-002), 
multiple oral doses (studies VX11-787-001 and VX-787FLZ1001), multiple oral doses 
coadministered with oseltamivir (study 63623872FLZ1001), and single IV doses (study 
VX12-787-002) in healthy subjects. In addition, JNJ-63623872 has been studied in multiple oral 
doses in subjects infected with a challenge dose of influenza A (study VX11-787-101). 
JNJ-63623872 was generally safe and well tolerated. There were no serious adverse events 
(SAEs) or adverse events (AEs) leading to discontinuation of study drug.
Safety in Phase 1 studies: In healthy subjects receiving single oral doses of JNJ-63623872 up to 
1,600 mg once daily, multiple oral doses of JNJ-63623872 up to 800 mg once daily for 10 days, 
and multiple oral doses up to 600 mg bid for 10 days, all AEs were mild in severity, except for a 
single case of moderate syncope (study VX12-787-002), and a single case of moderate diarrhea 
(study VX-787FLZ1001). The most frequently occurring AEs in healthy subjects administered 
single doses of JNJ-63623872 or placebo were headache (7.9% JNJ-63623872, 7.1% placebo) 
and diarrhea (6.6% JNJ-63623872, 7.1% placebo). The most frequently occurring AEs after 
multiple doses of JNJ-63623872 up to 800 mg once daily
were also headache 
(11.1% JNJ-63623872, 16.7% placebo) and diarrhea (11.1% JNJ-63623872, 0% placebo), as 
well as somnolence (11.1% JNJ-63623872, 0% placebo). The most frequently occurring AEs 
after multiple doses of JNJ-63623872 up to 600 mg bid for 10 days were gastrointestinal 
disorders, specifically diarrhea (58.3% JNJ-63623872, 0% placebo).
There were no AEs in healthy subjects receiving single IV doses of 100 mg JNJ-63623872 via a 
solution of 2 mg/mL JNJ-63623872.
Oral hormonal contraceptive is acceptable as a highly effective user-dependent contraceptive 
method (63623872FLZ1009).
Safety in Phase 2 studies: In 72 healthy subjects inoculated with a challenge dose of influenza A 
virus receiving multiple oral doses of JNJ-63623872 (up to 1,200 mg loading dose on the first 
day followed by 600 mg once daily for an additional 4 days) JNJ-63623872 was generally safe 
and well tolerated. Adverse events occurred in 63 of 72 (87.5%) subjects who received 
JNJ-63623872, and 28 of 32 (87.5%) subjects who received placebo. There were no SAEs or 
AEs leading to discontinuation of study drug:

Influenza-like illness was the most frequent AE (pooled placebo, 37.5%; pooled 
JNJ-63623872, 47.2%), as expected due to viral inoculation. Adverse events that occurred in 
≥10% of subjects and with ≥10% difference in the pooled JNJ-63623872 group than in the 
pooled placebo group were decreased blood phosphorus level (18.1% JNJ-63623872, 
0% placebo), rhinorrhea (4.2% JNJ-63623872, 18.8% placebo), and nasal congestion 
(1.4% JNJ-63623872, 15.6% placebo).
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
29
Approved, Date: 19 September 2016

The majority of AEs that occurred in subjects treated with JNJ-63623872 were mild or 
moderate in severity. Some of the AEs were severe; 8 severe AEs occurred in 5 subjects 
treated with JNJ-63623872: decreased blood phosphorus (n=4); increased blood creatine 
phosphokinase (CPK) (n=1); increased blood myoglobin (n=1); and severe headache (n=2). 
The most frequent AEs considered possibly related to study drug in the pooled 
JNJ-63623872 group were increased alanine aminotransferase (ALT, 12.5%), decreased 
blood phosphorus (12.5%), and increased aspartate aminotransferase (AST, 5.6%). Both 
ALT elevation and serum phosphorus decrease have been previously described in influenza 
and other upper respiratory tract infections.
1.2.
Oseltamivir
Oseltamivir (Tamiflu)
Oseltamivir is an influenza neuraminidase inhibitor indicated for the treatment of acute, 
uncomplicated influenza infection in patients 2 weeks of age and older who have been 
symptomatic for no more than 2 days and for prophylaxis of influenza in patients 1 year and 
older.
Clinical studies have shown that treatment with oseltamivir has clinical and virological benefit in 
patients with uncomplicated influenza when administered within 48 hours of onset of symptoms. 
Randomized studies in patients with severe influenza are lacking, but observational studies in 
patients admitted to hospital suggest that oseltamivir treatment, especially if it is given early, is 
associated with reduced mortality and shorter length of stay.3
Higher oseltamivir doses were tested in patients with uncomplicated influenza, but clinical or 
virological outcomes were found not significantly different compared to the standard dose. 
Despite a lack of evidence, several health authorities, including the United States Centers of 
Disease Control and Prevention (CDC) are recommending the use of double dose oseltamivir for 
severely ill or immunocompromised with influenza.13
There have been no studies specifically designed to evaluate the effectiveness of extending the 
duration of oseltamivir treatment beyond 5 days, however, it is reported in literature that over 
32% of hospitalized patients carry replicating virus beyond 7 days of illness onset.7 Using 
mathematical simulations to model an early or extended-duration oseltamivir therapy beyond 
5 days has shown an increased virological and symptom efficacy and a potential for reduced 
emergence of resistance. The available data from uncomplicated influenza studies are 
inconclusive whether reducing viral shedding leads to faster clinical improvement, but there are 
data supporting that lower viral load results in faster symptom resolution.7 Thus, there may be a 
possible benefit in using oseltamivir beyond 5 days in patients hospitalized with influenza.
For treatment of uncomplicated influenza in adults, oseltamivir is administered as 75 mg bid for 
5 days without respect to food.14,15 The dose is reduced in the presence of significant renal 
insufficiency. The most common AEs associated with oseltamivir (>1% and more common than 
with placebo) are nausea, vomiting, diarrhea, and abdominal pain. These events were generally 
mild to moderate and usually occurred on the first 2 days of administration. Subjects with 
influenza, including those receiving oseltamivir, may experience confusion and abnormal 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
30
Approved, Date: 19 September 2016
behavior early in the course of illness. Serious skin/hypersensitivity reactions may occur with 
oseltamivir. Less than 1% of subjects discontinued prematurely from clinical studies due to 
nausea and vomiting. 
Oseltamivir should not be administered until 2 weeks after intranasal live influenza 
immunization. Live influenza virus immunization should be delayed until 2 days after 
discontinuation of oseltamivir.
Oseltamivir is metabolized to oseltamivir carboxylate, which is pharmacologically active and 
entirely eliminated in the urine. Clinically significant drug interactions are unlikely. Plasma 
concentrations of the active metabolite are proportional to oseltamivir dose and display a small 
degree of inter-individual variability. Steady-state plasma concentrations were achieved within 
3 days of administration of multiple doses. On the basis of AUC, there is less than 2-fold 
accumulation of the active metabolite during twice daily administration. Pharmacokinetic 
parameters after 1 week of administration of multiple doses provided no indication of a temporal 
change in the disposition of the active metabolite over time.
Following doses of 600 mg of JNJ-63623872 bid for 10 days, mean Cmax and AUC12h of 
JNJ-63623872 were, respectively, 1.2-fold and 1.8-fold higher on Day 10 compared with Day 1.6
JNJ-63623872 600 mg bid administered alone or in combination with oseltamivir 75 mg bid for 
5 days resulted in generally comparable values for JNJ-63623872 predose plasma concentration 
(C0h) on Days 3, 4, and 5, indicating that near steady-state conditions had been achieved prior to 
Day 3. For JNJ-63623872 administered alone versus in combination with oseltamivir, Cmin and 
AUC12h of JNJ-63623872 were comparable, while JNJ-63623872 Cmax was 1.3-fold higher when 
administered in combination with oseltamivir, compared with administration of JNJ-63623872 
alone. The median time to reach Cmax (tmax) of JNJ-63623872 was 3.0 hours when JNJ-63623872 
was administered alone and 1.5 hours when administered in combination with oseltamivir. For 
oseltamivir administered alone versus in combination with JNJ-63623872, oseltamivir AUC12h
and oseltamivir carboxylate Cmin, Cmax, and AUC12h were comparable. Oseltamivir Cmin was 
1.1-fold higher and Cmax was 5% decreased when administered in combination with 
JNJ-63623872, compared with oseltamivir administered alone.6
For further information regarding oseltamivir refer to the manufacturer’s prescribing 
information.14,15
1.3.
Overall Rationale for the Study
Although generally a self-limited disease, infection with influenza A can cause significant 
morbidity and mortality, especially in certain patient populations such as those at the extremes of 
age, and may result in hospitalization. Currently available antiviral therapies (oseltamivir [oral], 
zanamivir [inhaled] and peramivir [IV]) are not indicated for influenza in hospitalized patients; 
however, they are used as de-facto standard of care as recommended by the CDC and the World 
Health Organization (WHO) for this patient population. Another class of influenza antiviral 
drugs, the adamantanes, is also available but is associated with high levels of antiviral resistance 
among circulating influenza viruses. 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
31
Approved, Date: 19 September 2016
The objective of antiviral therapy is to suppress viral replication rapidly and effectively, and thus 
provide a clinical benefit. Patients hospitalized with influenza are more severely ill and are 
reported to shed virus longer compared to patients with uncomplicated disease who are 
ambulatory. JNJ-63623872 has been demonstrated to neutralize a broad array of influenza A 
viruses both in in vitro and in vivo nonclinical models and has shown to reduce peak viral loads, 
AUC of viral shedding, and influenza-related clinical symptoms in an experimental human 
challenge model. A Phase 2b dose-ranging study evaluating JNJ-63623872 in adult subjects with 
uncomplicated seasonal influenza A infection is ongoing (VX14-787-103; 63623872FLZ2001). 
The purpose of the current study is to evaluate the pharmacokinetics (PK), safety, and antiviral 
effect of JNJ-63623872 in elderly hospitalized subjects (aged 65 to ≤85 years) as compared to
adult (aged 18 to ≤64 years) hospitalized subjects with influenza A following a 600 mg bid 7-day 
therapy.
In a mouse model of influenza infection, a concentration of 30 ng/mL was associated with effects 
on lung viral titers which were superior to those seen with oseltamivir, and 100 ng/mL was 
associated with even greater reductions in lung viral titers. Study 63623872FLZ1001 
(VX787FLZ1001), a healthy adult volunteer drug-drug interaction and PK study, showed, in-line 
with previous PK modeling data, that JNJ-63623872 at a dose level of 600 mg bid resulted in a 
median C12h of 161 ng/mL following the first dose and 310 ng/mL at steady-state. In this 
exploratory study, the dose regimen of 600 mg bid is expected to result in antiviral activity and a 
good safety profile.
1.4.
Benefits and Risks Management
Please see Section 1.2 and the manufacturer’s prescribing information14,15 for the benefits and 
risks of oseltamivir.
1.4.1.
Known Benefits of JNJ-63623872
The clinical benefit of JNJ-63623872 remains to be established.
1.4.2.
Potential Benefits of JNJ-63623872
Results from JNJ-63623872 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.
1.4.3.
Known Risks of JNJ-63623872
Every medication can have undesirable effects.
Adverse events in healthy subjects: Based on the data available, only headache and diarrhea 
were seen consistently in healthy subjects and were considered by the investigator to be possibly 
related to JNJ-63623872 treatment. These events were generally mild to moderate. The 
occurrences of headache were equally distributed among JNJ-63623872 and placebo, while 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
32
Approved, Date: 19 September 2016
diarrhea occurred more often after treatment with JNJ-63623872 compared to placebo. In 
subjects inoculated with influenza A virus in a challenge model of influenza A, transient 
elevations of liver transaminases, predominantly ALT, and decreased blood phosphorus were 
observed following JNJ-63623872 exposure.
1.4.4.
Potential Risks of JNJ-63623872
Reproductive Risk and Pregnancy
Based on preclinical studies, no reproductive (embryo-fetal, fertility and early embryonic 
development) liabilities have been identified for JNJ-63623872.
In the current study, subjects who are heterosexually active must follow the contraception 
requirements detailed in Section 4.3. Subjects who are pregnant, or breastfeeding, or planning to 
become pregnant during this study or within 90 days after receiving the last dose of study drug, 
or are unwilling to use an acceptable method of contraception are not allowed to enter this study 
(see Section 4.2). Subjects’ study treatment will be discontinued if they become pregnant (see 
Section 12.3.3).
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 JNJ-63623872 against multiple cellular targets and a battery of in vivo cardiovascular, 
central nervous system, and respiratory systems) liabilities have been identified for 
JNJ-63623872. There were no toxicological effects in acute studies in mice and rats at doses up 
to 1,000 mg/kg. In studies where rats and monkeys were administered JNJ-63623872 at very 
high doses for 14 days, specific organ toxicity (liver, kidney, bone marrow, spleen, lymph nodes) 
and other toxicological findings were noted at doses of 250 mg/kg/day and above. The 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 (AUC0-h basis) of 
40-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.
Based on human experience to date at high doses (up to 1,600 mg) no toxicology findings were 
observed, however this study will include study withdrawal criteria for individual subjects as a 
precaution (see Section 10.2, Discontinuation of Study Treatment).
1.4.5.
Overall Benefit/Risk Assessment
Based on the available data and proposed safety measures, the overall benefit/risk assessment for 
this study is acceptable for the following reasons:
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
33
Approved, Date: 19 September 2016

JNJ-63623872 has been studied in healthy subjects receiving single oral doses of 
JNJ-63623872 up to 1,600 mg (studies VX11-787-001 and VX12-787-002), multiple oral 
doses of JNJ-63623872 up to 800 mg once daily for 10 days (study VX11-787-001), 
multiple oral doses of JNJ-63623872 of 600 mg bid up to 10 days (study VX-787FLZ1001), 
and single IV doses of 100 mg JNJ-63623872 (study VX12-787-002), and in healthy 
subjects infected with a challenge dose of influenza A receiving multiple oral doses of 
JNJ-63623872 (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). JNJ-63623872 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, electrocardiogram [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:

A safety management plan is in place for subjects experiencing specific toxicities such 
as allergic reactions, clinical hepatitis, renal complications, nausea, and diarrhea.

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. Elevations of liver 
enzymes (eg, AST, ALT, bilirubin, gamma-glutamyltransferase [GGT], alkaline 
phosphatase [ALP]), hematological changes, serum creatinine elevations, and presence 
of proteinuria/albuminuria will be closely monitored.

Utilization of withdrawal criteria (see Section 10.2).

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.

Oseltamivir is a widely used medication for the treatment of influenza A infection in 
patients 2 weeks of age and older. Please see Section 1.2 and the manufacturer’s prescribing 
information14,15 for the benefits and risks of oseltamivir.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
34
Approved, Date: 19 September 2016
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to evaluate the PK parameters of JNJ-63623872 in combination with 
oseltamivir in elderly subjects (aged 65 to ≤85 years) compared to adults (aged 18 to ≤64 years)
with influenza A infection.
Secondary Objectives
Secondary objectives include the assessment of the following parameters in the JNJ-63623872 
treatment arm compared to the control arm:
1.
Safety and tolerability.
2.
The time to influenza viral negativity based on qRT-PCR and/or viral culture from nasal 
mid-turbinate (MT) swabs and, if applicable, based on PCR-based rapid molecular testing 
from nasal MT swabs.
3.
Viral load over time and rate of decline in viral load during treatment as measured by 
qRT-PCR and/or viral culture.
4.
AUC of viral load as measured by qRT-PCR and/or viral culture.
5.
Disease status and incidence of complications associated with influenza after the start of 
study treatment, and disease progression:

bacterial pneumonia (culture confirmed where possible),

other bacterial superinfections,

respiratory failure,

pulmonary disease (eg, asthma, chronic obstructive pulmonary disease [COPD]), 

cardiovascular and cerebrovascular disease (eg, myocardial infarction, congestive heart 
failure [CHF], arrhythmia, stroke).
6.
Change in duration and severity of clinical symptoms as measured by the Flu-PRO.
7.
Time to improvement of vital signs.
8.
Time to improvement of respiratory status.
9.
Improvement on the ordinal scale.
10. Emergence of drug resistance as detected by genotype or phenotype.
11. Time to return to premorbid functional status.
12. Time to hospital discharge.
Exploratory Objectives
Exploratory objectives include the assessment of the following parameters in the JNJ-63623872 
treatment arm compared to the control arm:
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
35
Approved, Date: 19 September 2016
1.
Use of antibiotics and/or corticosteroids during hospitalization.
2.
Number of subjects admitted to the Intensive Care Unit (ICU).
3.
Length of ICU stay for subjects transferred to the ICU after baseline.
4.
Correlation between the decline in viral load (measured by qRT-PCR and/or viral culture) 
and changes in clinical symptoms.
5.
PK/PD relationship (efficacy and safety).
2.2.
Hypothesis
No formal hypothesis will be tested.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind, placebo-controlled, multicenter Phase 2 study to evaluate the 
effect of JNJ-63623872 600 mg bid versus (vs.) placebo, both in combination with oseltamivir 
75 mg bid in adult and elderly hospitalized subjects with influenza A infection. Up to 90 subjects 
in total will be enrolled in this study. An effort will be made to enroll a minimum of 
approximately 24 subjects per age cohort (adults aged 18 to ≤64 years and elderly people aged
65 to ≤85 years).
Subjects who meet all eligibility criteria will be randomized in a 2:1 ratio to receive 1 of the 
following 2 treatments:

JNJ-63623872 600 mg bid + oseltamivir 75 mg bid; OR

JNJ-63623872 placebo bid + oseltamivir 75 mg bid
Oseltamivir dose should be reduced to 30 mg bid for subjects with an estimated glomerular 
filtration rate (eGFR) >30 and ≤60 mL/min/1.73 m² according to the Modification of Diet in 
Renal Disease (MDRD) equation. Dose can be adjusted from 30 mg to 75 mg and vice versa 
during the course of treatment based on the eGFR value.
All study drugs will be taken orally. 
The study will consist of a screening/baseline visit, a double-blind treatment period of 7 days, 
and a follow-up period of 21 days.
The entire study duration for each subject will be 28 days with study assessments daily during 
the treatment period, and on Days 10, 14, and 28 of the follow-up period. The study is 
considered complete with the completion of the last study assessment for the last subject 
participating in the study.
Full plasma concentration-time profiles of JNJ-63623872 will be determined over 12 hours after 
the morning dose of study drug on Day 3. For subjects who are discharged before Day 3, no 
intensive blood sampling will be performed. Sparse plasma samples for the measurement of 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
36
Approved, Date: 19 September 2016
plasma concentrations of JNJ-63623872 will be taken on Days 1, 2, 4 through 7 during 
hospitalization, and on Days 5 and 8 after discharge (see Section 9.2, Pharmacokinetics).
Measurement of plasma concentrations of oseltamivir and oseltamivir carboxylate may be done 
at the sponsor’s discretion.
Safety and tolerability will be assessed throughout the study from signing of the Informed 
Consent Form (ICF) until the subject’s last study-related activity. Safety evaluations will include 
the monitoring of AEs (including complications of influenza), clinical laboratory tests, 12-lead 
ECGs, vital sign measurements, (symptom-directed) physical examinations, pregnancy testing, 
and specific toxicities (see Section 9.3, Safety Evaluations). 
Influenza symptom score, impact of influenza, and functional status will be assessed, and 
samples for viral titers and viral sequencing will be collected (see Section 9.4.1, Evaluations).
Blood samples will be collected to allow for the exploration of blood biomarkers (see 
Section 9.5). Where local regulations permit, an optional biomarker sample may be collected at 
baseline for host deoxyribonucleic acid (DNA) genotyping (see Section 9.7, Sample Collection 
and Handling).
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. Refer 
to Section 11.8, Data Monitoring Committee, for details.
3.2.
Study Design Rationale
Blinding, Control, Study Phase/Periods, 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. 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. Blinded treatment will be used to reduce potential bias during data collection and 
evaluation of clinical endpoints.
Dose Selection
To date, three Phase 1 and one Phase 2 clinical studies have been completed. In the Phase 1 
studies, a total of 128 healthy subjects were exposed to JNJ-63623872, receiving: 

a single oral dose of JNJ-63623872 ranging from 50 to 1,600 mg (studies VX11-787-001 
and VX11-787-002, N=42), 

four single doses of 100 mg JNJ-63623872 (study VX11-787-001, N=16),

10-day multiple oral doses of JNJ-63623872 once daily ranging from 100 to 800 mg (study 
VX11-787-001, N=18), 

three single doses of 600 mg JNJ-63623872 (study VX12-787-002, N=18),
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
37
Approved, Date: 19 September 2016

single IV doses of 100 mg JNJ-63623872 (study VX12-787-002, N=8 previously exposed to 
single doses of 600 mg), 

5-day multiple oral doses of JNJ-63623872 600 mg bid, alone or in combination with 
oseltamivir 75 mg (study 63623872FLZ1001, N=18; 4 additional subjects received up to 4 
doses of 300 mg JNJ-63623872 twice daily), 

10-day multiple oral doses of JNJ-63623872 600 mg bid (study 63623872FLZ1001, N=12).
In the Phase 2 study, 72 healthy subjects challenged with influenza A received multiple oral 
doses of JNJ-63623872, with a loading dose up to 1,200 mg on the first day followed by up to 
600 mg once daily for an additional 4 days (study VX11-787-101). JNJ-63623872 was generally 
safe and well tolerated in these studies and no SAEs or AEs leading to discontinuation were 
observed. In addition, there were no clinically significant changes in standard 12-lead ECGs, 
vital signs, and clinical laboratory tests.
In an ongoing Phase 2b study (VX14-787-103; 63623872FLZ2001), the selected doses of 
JNJ-63623872 are 300 and 600 mg bid (without a loading dose). These doses were selected 
based on modeling and simulation.9 Target concentrations of 30 and 100 ng/mL have previously 
been identified based on efficacy data in a mouse model of influenza infection, in which 
30 ng/mL was associated with better efficacy compared to oseltamivir, and 100 ng/mL resulted 
in even greater reduction in viral load in the lungs. Simulations were performed to predict 
attainment of these target concentrations in patients. The probability of target attainment for 
simulated doses was compared to that of the highest dose evaluated in study VX11-787-101 
(1200/600 mg once daily), at which a statistically significant improvement in viral shedding and 
clinical symptom scores was observed compared to placebo. The median plasma concentration 
just prior to the beginning or at the end of a dosing interval (Ctrough) in the 1200/600 mg once 
daily dose group was approximately 130 to 150 ng/mL across the 5-day dosing duration. Twice 
daily doses were simulated with the goal of maintaining a higher Ctrough without increasing the 
overall exposure or AUC.
In the current proposed study, JNJ-63623872 600 mg bid will be administered for 7 days to 
subjects infected with influenza A.
Host DNA and Biomarker Collection
Blood samples will be collected to allow for the exploration of blood biomarkers (eg, proteins, 
host RNA) on the premise that these markers may play a role in the blood concentrations, 
efficacy or safety of JNJ-63623872 or oseltamivir, or help to explain interindividual variability in 
clinical outcomes or may help to identify population subgroups that respond differently to 
treatment. The biomarker analyses may also help to evaluate the PD of JNJ-63623872 and 
oseltamivir, and aid in evaluating the drug clinical response relationship. Where local regulations 
permit, an optional blood sample for exploratory host DNA research may also be collected.
DNA and biomarker samples may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies. 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
38
Approved, Date: 19 September 2016
4.
SUBJECT POPULATION
Signing of the ICF needs to be done before the first study-related activity.
Screening for eligible subjects will be performed on Day 1, before the randomization and the 
first administration of study drug. Note: Day 1 encompasses signing of the ICF approximately 
+ 24 hours, and can be split over 2 calendar days if needed. Depending on the time of hospital 
admission and the timing of screening/baseline assessments, eligibility may only be established 
on the next calendar day, in which case the first study drug intake will be on that day, 
immediately after establishing eligibility.
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 should consult with the appropriate sponsor representative before enrolling a subject 
in the study. 
For a discussion of the statistical considerations of subject selection, see Section 11.2, Sample 
Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1. Subject requires hospitalization to treat influenza infection and/or to treat complications 
of influenza infection.
2. Subject tested positive for influenza A infection within 1 day of signing of the ICF using 
a PCR-based rapid molecular diagnostic assay.
3. Subjects must be capable of swallowing study medication tablets and capsules.
4. Subject must be male or female 18 to 85 years of age, inclusive. 
5. Each subject (or their legally acceptable representative) must sign an ICF indicating that 
he or she understands the purpose of and procedures required for the study and is willing 
to participate in the study.
6. Subject must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol (see Section 4.3, Prohibitions and Restrictions).
7. Before randomization, a female subject must be either:
a.
Not of childbearing potential:
i. postmenopausal (>45 years of age with amenorrhea for at least 12 
months);
ii. permanently sterilized (eg, bilateral tubal occlusion [which includes tubal 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
39
Approved, Date: 19 September 2016
ligation procedures as consistent with local regulations], hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy);
iii. or otherwise incapable of pregnancy.
b. Of childbearing potential and 
i. practicing effective methods of birth control consistent with local 
regulations regarding the use of birth control methods for subjects 
participating in clinical studies
ii. and agrees to continue using two methods of birth control throughout the 
study and for at least 90 days after receiving the last dose of study drug 
(see Section 4.3, Prohibitions and Restrictions)
8. A female subject of childbearing potential must have a negative urine pregnancy test at
screening.
9. A female subject must agree not to donate eggs (ova, oocytes) for the purposes of 
assisted reproduction throughout the study and for at least 90 days after receiving the last 
dose of study drug (see Section 4.3, Prohibitions and Restrictions).
10. A male subject who is sexually active with a woman of childbearing potential and has not 
had a vasectomy must agree to use effective methods of birth control(see Section 4.3, 
Prohibitions and Restrictions), and all male subjects must also not donate sperm during 
the study and for 90 days after receiving the last dose of study drug.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1. Subject received more than 3 doses of the influenza antiviral medication oseltamivir, 
zanamivir, or peramivir since the start of the influenza symptoms, or ribavirin within 
6 months prior to screening.
2. Subject is unwilling to undergo regular nasal MT swabs or has any physical abnormality 
which limits the ability to collect regular nasal specimens.
3. Subject is known (considering lab results of the past 6 months) to be severely 
immunocompromised as defined by a CD4+ count <350 cells/mm3 or an absolute 
neutrophil count <750/mm3.
4. Subject is undergoing peritoneal dialysis, hemodialysis, or hemofiltration.
5. Subject has an eGFR ≤30 mL/min/1.73m² according to the MDRD equation, assessed at 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
40
Approved, Date: 19 September 2016
screening or based on the most recent clinically relevant creatinine value if available.
6. Subject has known moderate (Child-Pugh class B) or severe hepatic impairment (Child-
Pugh class C). 
7. 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 9.3.6) when screening a subject for 
enrollment.
8. Subject with known acute hepatitis A, B, or, C virus infection at screening, or known 
chronic hepatitis C infection undergoing antiviral therapy.
9. Subject has known allergies, hypersensitivity, or intolerance to JNJ-63623872 or its 
excipients (refer to the Investigator's Brochure6).
10. Subject has contraindications to the use of oseltamivir
per local prescribing 
information.14,15
11. Subject has 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.
12. Subject has a history of clinically significant heart arrhythmias, eg, unstable angina or 
myocardial infarction; uncontrolled, unstable atrial arrhythmia, or sustained ventricular 
arrhythmia, or a history of risk factors for Torsade de Pointes syndrome.
13. Subject has taken any disallowed therapies as noted in Section 8, Pre-study and 
Concomitant Therapy before the planned first dose of study drug.
14. Subject is an employee of the investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that investigator or study site, or a 
family member of an employee or the investigator, or an employee of the sponsor.
15. Female subject who is pregnant, or breastfeeding, or planning to become pregnant while 
enrolled in this study or within 90 days after the last dose of study drug, or female subject 
of childbearing potential who is unwilling to use an acceptable method of contraception 
as outlined in Section 4.3, Prohibitions and Restrictions.
16. Male subject who plans to father a child while enrolled in this study or within 90 days 
after the last dose of study drug.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
41
Approved, Date: 19 September 2016
17. 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.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Female subjects of childbearing potential who are heterosexually active must remain on 
effective methods of birth control throughout the study and for at least 90 days after the 
last dose of study drug, and all female subjects must also agree not to donate eggs (ova, 
oocytes) throughout the study and for 90 days after receiving the last dose of study drug. 
Effective methods of birth control include use of an intrauterine device or hormone-
based contraception in combination with a barrier contraceptive (eg, male condom, 
diaphragm with spermicidal gel, cervical cap, or female condom), or practice 
heterosexual abstinence. Female subjects of childbearing potential having a 
vasectomized partner are required to use one barrier contraceptive method throughout 
the study and for at least 90 days after the last dose of study drug when heterosexually 
active.
Note: A male and female condom should not be used together due to risk of breakage or 
damage caused by latex friction.
Note: If the childbearing potential changes after start of the study (eg, female subject 
who is not heterosexually active becomes active), the subject must use effective 
methods of birth control, as described above throughout the study and for 90 days after 
the last dose of study drug.
2.
Male subjects who are sexually active with a woman of childbearing potential and have 
not had a vasectomy must use effective methods of birth control as described above, and 
all male subjects must also not donate sperm throughout the study and for 90 days after 
receiving the last dose of study drug.
If the female sexual partner is postmenopausal for at least 2 years, is permanently 
sterilized (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or 
otherwise incapable of becoming pregnant, the birth control methods mentioned are not 
applicable. If the female sexual partner has had a tubal ligation, at least one 
contraceptive method should be used.
Male subjects who had a vasectomy and have a female partner of childbearing potential 
must agree to use a male condom throughout the study and for 90 days after receiving 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
42
Approved, Date: 19 September 2016
the last dose of study drugs.
Note: A male and female condom should not be used together due to risk of breakage or 
damage caused by latex friction.
3.
Subject should refrain from taking any disallowed therapies as noted in Section 8, Pre-
study and Concomitant Therapy.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment arms in a 2:1 ratio (active vs. placebo) based on a computer-generated 
randomization schedule prepared before the study by or under the supervision of the sponsor. 
The randomization will be balanced by using randomly permuted blocks and will be stratified by 
age cohort. An 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 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
43
Approved, Date: 19 September 2016
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 1 of the following 2 dose regimens:

JNJ-63623872 600 mg bid + oseltamivir 75 mg bid on Days 1 through 7; OR

JNJ-63623872 placebo bid + oseltamivir 75 mg bid on Days 1 through 7.
Note: For subjects who receive only 1 dose on Day 1 (evening), dosing should continue until the 
morning of Day 8 so that all subjects receive 14 doses in total.
Oseltamivir dose should be reduced to 30 mg bid for subjects with an eGFR >30 and 
≤60 mL/min/1.73 m² according to the MDRD equation. Dose can be adjusted from 30 mg to 
75 mg and vice versa during the course of treatment based on the eGFR value.
Study drugs (JNJ-63623872 or placebo + oseltamivir) will be administered according to the 
following guidelines:

All study drugs will be taken together orally. All subjects will take 2 tablets (JNJ-63623872 
or placebo) and 1 capsule (oseltamivir) bid.

The first dose of study drugs will be administered on Day 1 (ie, signing of the ICF 
approximately + 24 hours) at the study site after screening assessments and randomization
have been performed. Depending on the time of randomization and the time of first study 
drug intake on Day 1, subjects may receive 1 or 2 doses 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.

Subjects will swallow the study drug whole and will not chew the drug before swallowing. 
Opening capsules or crushing tablets in food or water is not permitted.

Study drug will be administered as described in the TIME AND EVENTS SCHEDULE. All 
intakes of study drug will take place at the study site for as long as subjects are hospitalized. 
Study-site personnel will instruct subjects on how to store study drug for at-home use in case 
subjects are discharged from the hospital during the treatment period. 
For subjects who are discharged before Day 3, no intensive PK sampling will be performed.
7.
TREATMENT COMPLIANCE
Missed doses (including those lost resulting from vomiting) 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 >6 hours past the scheduled dosing time, the missed 
dose should be skipped, and the next dose should be taken as scheduled.
Subjects who are discharged during the treatment period, will receive study medication for at-
home use. Compliance will be assessed at each visit by counting study drug dispensed and study 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
44
Approved, Date: 19 September 2016
drug returned. Discrepancies will be discussed with the subject and recorded in the source 
documents and the eCRF.
If a subject’s study drug intake 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
Prestudy therapies administered up to 7 days before the first dose of study drug must be recorded 
at screening.
Concomitant therapies must be recorded throughout the study beginning with the first dose of 
study drug until the Final Study Visit/Safety Follow-up Visit. Concomitant therapies should also 
be recorded beyond the Final Study Visit/Safety Follow-up Visit only 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:
1.
More than 3 doses of the influenza antiviral medication oseltamivir, zanamivir, or peramivir 
since the start of the influenza symptoms.
2.
Ribavirin within 6 months of screening until the end of the study.
3.
Substrates of OATP1B1 and/or OATP1B3, including atrasentan, bosentan, ezetimibe, 
glyburide, irinotecan, repaglinide, rifampin, telmisartan, valsartan, and olmesartan, from 
Day 1 through the last dose of study drug. Statins (ie, HMG CoA reductase inhibitors) 
may be continued, but subjects should be cautioned and observed for potential statin-related 
toxicity. 
4.
An investigational agent (small molecule) or investigational vaccine 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.
Before the start of the study, the acute (< 7 days) use of corticosteroids (inhaled or systemic) is 
permitted; chronic (≥14 days) use of corticosteroids is permitted for prednisone doses ≤15 mg (or 
equivalent).
All use of antipyretic and anti-inflammatory agents for the treatment of influenza symptoms will 
be recorded. Subjects should restrict their use of anti-pyretic/anti-inflammatory medications only 
to acetaminophen (paracetamol) during the conduct of the study, and only when necessary to 
control significant influenza symptoms. The dose is not recommended to exceed 500 mg 3 times 
a day, and should preferably be administered immediately after the assessment of influenza 
symptoms. The use of other medications for the relief of influenza symptoms is strongly 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
45
Approved, Date: 19 September 2016
discouraged. If the subject has an allergy or intolerance to acetaminophen (paracetamol), the 
investigator should recommend ibuprofen (at the lowest effective dose, but no more than 400 mg 
3 times a day) as a substitute medication for the relief of influenza symptoms. If ibuprofen 
cannot be used, the investigator may use his/her discretion in the choice of agent. 
For any concomitant therapy given as a treatment for a new condition or a worsening of an 
existing condition, the condition must be documented in the Adverse Event Section of the eCRF.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of PK sampling,
safety, efficacy, biomarker, and patient-reported outcome (PRO) measurements applicable to this 
study.
All visit-specific PRO assessments should be conducted/completed before any tests, procedures, 
or other consultations for that visit to prevent influencing subject perceptions.
If multiple assessments are scheduled for the same time point, it is recommended that procedures 
be performed in the following sequence: ECG, vital signs, blood sampling. Urine and 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 documents and eCRF.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
The total blood volume to be collected from each subject will be approximately 125 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
9.1.2.
Screening Phase
In order to start treatment as soon as possible after the start of the influenza infection, screening 
will occur on Day 1, before randomization and the first administration of study drug. Note:
Day 1 encompasses signing of the ICF approximately + 24 hours, and can be split over 2 
calendar days if needed. Depending on the time of hospital admission and the timing of 
screening/baseline assessments, eligibility may only be established on the next calendar day, in 
which case the first study drug intake will be on that day, immediately after establishing 
eligibility.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
46
Approved, Date: 19 September 2016
At the screening visit, after signing of the ICF (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. 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 will be recorded. A PCR-based rapid molecular diagnostic assay capable 
of distinguishing between influenza types A and B will be carried out as part of the screening 
procedures. Only those subjects testing positive for influenza A will be considered for 
enrollment. A physical examination (including height and body weight measurements if not 
already available and if practically feasible) will be conducted. A urine pregnancy test will be 
performed for all female subjects of childbearing potential.
Subjects will be requested to complete ePRO assessments (Flu-iiQTM, Flu-PRO and additional 
daily diary items) to assess influenza-related signs and symptoms and the impact of influenza on 
the conduct of daily activities (see Section 9.4.1 for more details).
Blood samples
(for hematology, biochemistry, blood coagulation parameters, drug 
concentrations, and biomarker analysis) and a urine sample (for urinalysis) will be taken. Where 
local regulations permit, an optional blood sample may be collected at baseline for host DNA 
genotyping. Nasal MT swabs will be obtained. Vital signs (systolic blood pressure [SBP], 
diastolic blood pressure [DBP], pulse rate, respiratory rate, body temperature, and level of 
consciousness) and blood oxygen saturation will be measured, and a 12-lead ECG will be 
performed. A historical ECG within 1 day before signing of the ICF can be used in lieu of the 
baseline ECG requirement.
9.1.3.
Double-Blind Treatment Phase
Subjects who meet all eligibility criteria will be randomized in a 2:1 ratio to receive 1 of the 
following 2 treatments:

JNJ-63623872 600 mg bid + oseltamivir 75 mg bid on Days 1 through 7; OR

JNJ-63623872 placebo bid + oseltamivir 75 mg bid on Days 1 through 7.
Note: For subjects who receive only 1 dose on Day 1 (evening), dosing should continue until the 
morning of Day 8 so that all subjects receive 14 doses in total.
Oseltamivir dose should be reduced to 30 mg bid for subjects with an eGFR >30 and 
≤60 mL/min/1.73 m² according to the MDRD equation. Dose can be adjusted from 30 mg to 
75 mg and vice versa during the course of treatment based on the eGFR value.
Subjects will undergo intensive PK sampling and sparse PK sampling at the time points specified 
in the TIME AND EVENTS SCHEDULE.
Throughout the treatment period, ePRO assessments will be completed before any other 
assessments for a specific visit; a symptom-directed physical examination, blood sampling (for 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
47
Approved, Date: 19 September 2016
hematology, biochemistry, blood coagulation parameters, drug concentrations, and biomarker 
analysis), urine sampling (for urinalysis), and a urine pregnancy test (for females of childbearing 
potential) will be performed; nasal MT swabs will be obtained; vital signs and blood oxygen 
saturation will be measured; and a 12-lead ECG will be performed at the time points specified in 
the TIME AND EVENTS SCHEDULE.
Subjects should be observed/interviewed for any AEs (including complications of influenza), 
concomitant medication will be reviewed, and AEs and concomitant medication will be 
recorded.
Subjects, who are discharged during the treatment phase, will receive study medication for 
at-home use. Local PCR-based rapid molecular diagnostic testing will be carried out on the day 
of discharge and, if possible, on the day before.
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, or, 
at a minimum, to return to the site for a safety follow-up visit. Subjects who withdraw consent
during the treatment phase will be offered an optional safety follow-up visit. 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. Under this protocol, there will be no 
option to extend study treatment for subjects who remain hospitalized and symptomatic at the 
end of the 7-day treatment period. A subject will be considered to have completed treatment after 
7-day therapy. It is up to the investigator’s discretion to administer standard of care to 
hospitalized patients who in their opinion need additional therapy, outside of this protocol.
9.1.4.
Posttreatment Phase (Follow-Up)
Subjects who prematurely discontinue the study for any reason (including withdrawal of consent) 
will be offered an optional safety follow-up visit. 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. 
The procedures to be completed during the follow-up phase are listed in the TIME AND 
EVENTS SCHEDULE.
9.1.5.
After discharge from the hospital
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 TIME AND EVENTS 
SCHEDULE. Every effort should be made to perform all of the assessments as outlined in the 
TIME AND EVENTS SCHEDULE (either on-site or at the subject’s home) if practically 
feasible. Telephone contact will be made on Days 2-4 and 6-7 to ensure compliance with study 
drug intake, remind subjects to complete the ePRO assessments (and to perform nasal self-
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
48
Approved, Date: 19 September 2016
swabbing if applicable), and to inquire about possible AEs and concomitant medication use. If 
the information on AEs and concomitant medications is obtained via telephone contact, written 
documentation of the communication must be available for review in the source documents. If 
the subject has died, the date and cause of death will be collected and documented in the eCRF.
9.2.
Pharmacokinetics
9.2.1.
Evaluations
Venous blood samples of approximately 1-2 mL will be collected for measurement of plasma 
concentrations of JNJ-63623872 (and, at the sponsor's discretion, for oseltamivir and oseltamivir 
carboxylate concentrations) at the time points specified in the TIME AND EVENTS 
SCHEDULE, and processed, handled and identified according to the laboratory manual, which 
will be provided before the start of the study. The exact dates and times of blood sampling and 
study drug intake must be recorded in the eCRF and/or laboratory requisition form. Measurement
of plasma concentrations of oseltamivir and oseltamivir carboxylate may be done at the 
sponsor’s discretion.
All hospitalized subjects will undergo intensive PK sampling on Day 3, at 8 different time 
points within the dosing interval. The first sample should be collected before (preferably 
immediately prior to) study drug intake (≤1 hour prior to the morning dose). Samples 2 to 8 
should be collected at 1, 2, 4, 6, 8, 10, and 12 hours after the morning dose (and prior to the 
evening dose). For subjects who are discharged before Day 3, no intensive PK sampling will be 
performed.
During hospitalization, sparse PK sampling will be performed as follows:

On Day 1: predose (≤1 hour prior to study drug intake), between 1.5 and 6 hours, and 
12 hours after that same study drug intake (and prior to the next study drug intake). For 
subjects who start dosing in the morning of Day 1, a trough sample will be taken predose 
on Day 2 (≤1 hour prior to the morning dose).

On Day 2 and Days 4-7: predose (≤1 hour prior to dosing) and between 1.5 and 6 hours 
after the morning or evening dose (whichever is the most convenient).
After discharge, sparse PK sampling will be performed as follows (if practically feasible):

On Day 5: at any time during the visit.

On Day 8: at any time during the visit.
As long as subjects are hospitalized, the following times need to be recorded in the eCRF:

Date and time of all study drug intakes,

Date and time of PK sampling, 

Date and start and stop times of food intake for all study drug intakes (if applicable). 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
49
Approved, Date: 19 September 2016
After discharge, the above-mentioned dates and times will only need to be recorded on days with 
PK sampling.
For details on study drug intake, see Section 6.
9.2.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of JNJ-63623872 using a validated, 
specific, and sensitive (LC-MS/MS) method by or under the supervision of the sponsor. 
Measurement of plasma concentrations of oseltamivir and oseltamivir carboxylate may be done 
at the sponsor’s discretion.
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 oseltamivir and oseltamivir carboxylate, protein binding, and metabolite 
profile.
9.2.3.
Pharmacokinetic Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of JNJ-63623872 will be 
derived using non-compartmental analysis.
For JNJ-63623872
On Day 3: 
Ctrough, Cmin, Cmax, tmax, and AUC12h
Additional PK parameters may be included if deemed appropriate. Actual sampling times will be 
checked for major aberrations. In case a major aberration occurs for an actual sampling time of 
>20.00% deviation from the scheduled time, this plasma concentration will be excluded from 
descriptive statistics in the plasma concentration table.
9.2.4.
Pharmacokinetic Endpoints
The PK endpoint, being the primary endpoint of this study is listed in Section 11.3.
9.2.5.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic 
Evaluations 
A population PK and PK/PD analysis of plasma concentration-time data of JNJ-63623872 will 
be performed using the nonlinear mixed-effects modeling approach. A more detailed description 
of the methodology to be followed will be given in the clinical pharmacology analysis plan 
(CPAP). Listings of JNJ-63623872 plasma concentration data from this study will be reported in 
the bioanalytical report for this study. Results of the population PK/PD analysis will be reported 
in a stand-alone document.
9.3.
Safety Evaluations
Details regarding the IDMC are provided in Section 11.8.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
50
Approved, Date: 19 September 2016
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards 
until the last study-related activity.
Any clinically relevant changes occurring during the study must be recorded in 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 SCHEDULE:
9.3.1.
Adverse Events
Adverse events (including influenza complications) will be reported by the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for the 
duration of the study. Adverse events will be followed by the investigator as specified in 
Section 12, Adverse Event Reporting.
Special attention will be paid to those subjects who discontinue the study for an AE, or who 
experience an AE of at least grade 3, or an SAE. 
9.3.2.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis 
will be collected. The investigator must review the laboratory report, document this review, and 
record 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.
In case a grade 3 or grade 4 laboratory abnormality occurs, 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
-red blood cell (RBC) count
*lymphocytes
-RBC parameters
*monocytes
*mean corpuscular hemoglobin (MCH)
*eosinophils
*MCH concentration
*basophils
*mean corpuscular volume
-platelet count
-white blood cell (WBC) count
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
51
Approved, Date: 19 September 2016
A WBC evaluation may include any abnormal cells, which will then be reported by the 
laboratory. Any RBC evaluation may include abnormalities in the RBC count and/or RBC 
parameters and/or RBC morphology, which will then be reported by the laboratory.

Serum Chemistry Panel
-sodium
-uric acid
-potassium
-eGFR
-chloride
-calcium
-bicarbonate
-calcium (corrected for albumin)
-blood urea nitrogen (BUN)
-phosphate
-creatinine
-serum albumin
-glucose
-total protein
-AST
-total cholesterol
-ALT
-high-density lipoprotein cholesterol
-GGT
-low-density lipoprotein cholesterol
-total, direct, and indirect bilirubin
-triglycerides
-ALP
-magnesium
-CPK
-lipase
-lactic acid dehydrogenase (LDH)
-pancreatic amylase
-α1-acid glycoprotein

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
-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, flow cytometry or microscopy will be used to measure sediment. In 
case of discordance between the dipstick results and the flow cytometric results, the sediment 
will be examined microscopically.
Dipstick and flow cytometric analysis of the urine samples will be performed in parallel, ie, in 
the same sample at the same time.

At screening, at Day 5, and at the Final Study Visit/Safety Follow-up Visit, a urine 
pregnancy test will be performed for female subjects of childbearing potential only.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
52
Approved, Date: 19 September 2016

At screening, follicle-stimulating hormone (FSH) will be tested for female subjects who are 
amenorrheic for 12 months or less.

At screening, hepatitis A, B, and C serologic testing will be performed.

At screening and at the time points indicated in the TIME AND EVENTS SCHEDULE, 
determination of the following coagulation parameters will be performed: prothrombin time 
(PT), activated partial thromboplastin time (aPTT), and fibrinogen. International normalized 
ratio (INR) will be calculated.
9.3.3.
Electrocardiogram
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 sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG, vital signs, blood draw. A historical ECG 
within 1 day before signing of the ICF 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.5, 10
Clinically relevant abnormalities occurring during the study should be recorded in the Adverse 
Event Section of the eCRF.
9.3.4.
Vital Signs (temperature, pulse/heart rate, respiratory rate, blood 
pressure, blood oxygen saturation, level of consciousness)
Vital signs including temperature, pulse/heart rate, respiratory rate, blood pressure, peripheral 
arterial blood oxygenation, and level of consciousness will be assessed once daily at screening 
and at the Final Study Visit/Safety Follow-up Visit. Vital signs will be assessed at least 3 times 
daily until the subject is discharged from the hospital or until Day 14 (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 will be measured once daily on Day 5 and Day 10, if practically 
feasible. 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. 
Temperature will be measured orally.
Blood oxygen saturation will be measured using standard pulse oximeter. Subjects should have 
nail polish removed and should be encouraged to sit still during the measurements.
Blood pressure, pulse/heart 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).
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
53
Approved, Date: 19 September 2016
Blood pressure, pulse/heart rate, respiratory rate, and temperature 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 AVPU scale (alert, voice, pain, 
unresponsive).8 Alert: The patient is fully awake (although not necessarily oriented). This patient 
will have spontaneously open eyes, will respond to voice (although may be confused), and will 
have bodily motor function. Voice: The patient 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. Pain: The patient 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 patient does not give any eye, voice 
or motor response to voice or pain. The National Early Warning Score (NEWS) will be derived 
based on vital signs and AVPU scale at baseline and during hospitalization.12
Clinically relevant abnormalities (as defined in Attachment 7) occurring during the study should 
be recorded in the Adverse Event Section of the eCRF.
9.3.5.
Physical Examination 
To evaluate the subject’s eligibility, a physical examination (including height and body weight 
measurement if not already available and if practically feasible) will be performed at screening. 
In addition, a symptom-directed physical examination will be performed at the time points 
provided in the TIME AND EVENTS SCHEDULE.
A physical examination includes a review of the following systems: head/neck/thyroid; 
eyes/ears/nose/throat (EENT); 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.
9.3.6.
Specific Toxicities
Subjects reporting allergic reactions, AST/ALT elevations, clinical hepatitis, renal 
complications, nausea, or diarrhea, and other laboratory parameter changes should be followed 
until resolution of the AE or toxicity and necessary standard management should be undertaken.
Refer to Section 10.2 for study drug discontinuation criteria.
Acute Systemic Allergic Reaction
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
54
Approved, Date: 19 September 2016
Subjects should be advised to contact the investigator immediately if there is any worsening of 
the acute systemic allergic reaction.
Subjects will be treated as clinically appropriate.
AST and ALT Elevation
Subjects should be followed until resolution (return to baseline) or stabilization of AST/ALT 
elevation (to be agreed upon with the sponsor).
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, 
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.
Renal Complications
If renal complications develop, subjects should be closely monitored for disturbances in serum 
creatinine and for abnormalities in urine analysis (eg, proteinuria). Additional investigations can 
be performed at the investigator´s discretion. Subjects must be treated as clinically appropriate.
Nausea (with or without Vomiting)
Subjects may be treated as needed with antiemetics given orally or rectally. The date and time of 
this AE should be recorded.
Diarrhea
Loperamide can be administered.
Other Laboratory Parameter Changes
If one (or more) of the following changes occurs, the subject should discontinue study drug and 
should be followed until resolution (return to baseline) or stabilization of change (to be agreed 
upon with the sponsor). The sponsor should be informed even if the change occurs outside of the 
treatment period (but before the end of the study).

Liver enzymes - screening/baseline

AST or ALT enzyme activity increases ≥5 x ULN

Direct bilirubin increases ≥2 x ULN

GGT and/or ALP enzyme activity increases ≥3 x ULN
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
55
Approved, Date: 19 September 2016

Liver enzymes - during treatment

AST or ALT enzyme activity increases ≥5 x ULN if the baseline value is normal

AST or ALT enzyme activity increases ≥5 x baseline if the baseline value is >ULN

ALT enzyme activity increases >15 x ULN

ALT enzyme activity increases >3 x ULN and total bilirubin increases >2 x ULN

Confirmed absolute neutrophil count <500/mm3

Hemoglobin <9 g/dL (female), <10.5 g/L (male)
9.4.
Efficacy 
9.4.1.
Evaluations
9.4.1.1.
Patient-reported Outcomes
Subjects should complete the PRO assessments (Flu-iiQTM, Flu-PRO and additional daily diary 
items) in their native language or if there is no version available in their native language, a 
version in a language in which the subject is fluent and literate. It is preferable that subjects are 
able to read and write to complete the assessments by themselves. If a subject is unable to read or 
has visual or other physical limitations that make it difficult to read or complete the assessments, 
trained study personnel may read the questions and responses aloud exactly as they appear on the 
assessment and record the subject’s responses during the hospitalization phase. Once the subject 
is discharged from the hospital, if the subject is unable to complete the PRO assessment unaided, 
a caregiver can read the questions and responses verbatim and record the subject's responses for 
the subject.
Study personnel will instruct subjects how to self-administer the PRO tool and will record in the 
eCRF whether the PRO assessments were performed during the study visit. If subjects will 
require assistance recording their responses post-hospital discharge, study personnel will instruct 
the caregiver how to administer the PRO assessments.
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, and instructed how to complete the PRO assessment on the ePRO device. 
When deciding which answer to report, subjects should not receive any help from 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.
Influenza Symptom Score (Flu-iiQTM Module 1)
Subjects will be asked to assess influenza-related signs and symptoms and other patient-reported 
outcomes and associated severity twice daily (preferably in the morning and in the evening) from 
study entry (Baseline, Day 1) through Day 14, and once daily (preferably in the evening) from 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
56
Approved, Date: 19 September 2016
Day 15 through the Final Study Visit/Safety Follow-up Visit, using the Flu-iiQTM influenza 
intensity and impact questionnaire (see Attachment 3) on an ePRO device.
Assessment of influenza symptoms will be recorded by the subjects or the site staff/caregiver if 
the subject requires assistance on the ePRO device and analyzed as an efficacy measure of 
treatment. Resolution of influenza symptoms will be the time since the start of treatment of the 
first of 2 evaluations (over 24 hours) in which all symptom scores for each of the 2 assessments 
are none or mild for all 7 primary influenza symptoms (cough, sore throat, headache, nasal 
stuffiness, feverishness or chills, muscle or joint pain, and fatigue).
Impact of Influenza (Flu-iiQTM Modules 2, 3, 4)
The impact of influenza on conduct of daily activities will be assessed in Module 2 of the 
Flu-iiQTM (see Attachment 3), scored on a 4-point scale, as above, for each of 6 activities. Scores
will be assessed twice daily, at the same times as when the symptom scale evaluation is 
performed, from study entry (Baseline, Day 1) through Day 14, and once daily from Day 15
through the Final Study Visit/Safety Follow-up Visit. Assessments along with the additional 
daily diary items (see Attachment 4) will be recorded on the ePRO device. Time to resumption 
of usual activities is the time at which all scores are reported as “no difficulty”.
Flu-PRO
The incidence and severity of symptoms (individual and composite) will be evaluated using the 
Flu-PRO questionnaire (see Attachment 5). Subjects will be asked to complete this questionnaire 
and additional daily diary items (see Attachment 6) on an ePRO device once daily (preferably in 
the evening) from study entry (Baseline, Day 1) through the Final Study Visit/Safety Follow-up 
Visit.
9.4.1.2.
Viral Kinetics (Nasal MT Swabs)
Influenza viral titer will be determined and quantified in nasal MT swab samples taken at 
scheduled times throughout the study as indicated in the TIME AND EVENTS SCHEDULE. 
Nasal MT swabs will be analyzed using qRT-PCR and/or viral culture, and PCR-based rapid 
molecular testing. Influenza A subtype will be determined from the baseline sample.
When subjects are discharged from the hospital and still positive for influenza A virus, they are 
encouraged to continue self-swabbing at home if practically feasible.
Details about the nasal MT (self-) swab sample collection, processing, and shipping will be 
provided in the laboratory manual or other instruction documents.
The nasal MT swabs for central testing should be obtained from the left and the right nostrils and 
pooled into the same collection tube. Nasal MT (self)swabs for local PCR-based rapid molecular 
testing 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. Sampling should be 
done at approximately the same time when required. The investigator should designate a limited 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
57
Approved, Date: 19 September 2016
number of trained study site personnel to collect the nasal MT swabs for the sake of consistency, 
and to train subjects on how to collect self-swabs if applicable.
9.4.2.
Efficacy Endpoints
The efficacy endpoints, being the secondary endpoints of this study are listed in Section 11.6.
9.5.
Resistance Evaluations
9.5.1.1.
Viral Sequencing
Samples collected as described in Section 9.4.1.2 will also be used for sequence analysis of the 
PB2 region of the influenza virus polymerase and the neuraminidase gene at the time points
specified in the TIME AND EVENTS SCHEDULE. Exploratory sequencing of other regions of 
the influenza virus genome may also be performed.
9.5.1.2.
Phenotyping
Nasal MT swabs will be used for the analysis of phenotypic resistance against JNJ-63623872 and 
other antivirals at the time points specified in the TIME AND EVENTS SCHEDULE.
Details about sample collection, processing, and shipping will be provided in the laboratory 
manual.
9.6.
Biomarkers 
Two blood samples will be collected at the time points specified in the TIME AND EVENTS 
SCHEDULE for the exploration of blood biomarkers (eg, host RNA, proteins including serum 
cytokines) on the premise that these markers may play a role in the blood concentrations, 
treatment response, or safety of JNJ-63623872 or oseltamivir, or the status and change of the 
influenza virus related disease. Where local regulations permit, an optional blood sample may be 
collected for host DNA genotyping. 
In addition, nasal MT swabs collected for other testing may be used for biomarker analyses if 
available.
Analyses of biomarkers (including DNA) may be conducted at the sponsor’s discretion and 
reported separately from this study.
Blood samples for pharmacogenomic evaluations will preferably be collected at the baseline 
visit. However, if necessary eg, in case of a technical failure, they may be collected at a later 
time point without constituting a protocol deviation.
9.7.
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 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
58
Approved, Date: 19 September 2016
sample collection, the cannula will be flushed with 0.9% sodium chloride, United States 
Pharmacopeia (USP) (or equivalent) sodium heparin of 10 U/mL and charged with a volume 
equal to the dead space volume of the lock.
Refer to the TIME AND EVENTS SCHEDULE for the timing and frequency of all sample 
collections.
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/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed all 
assessments of the Final Study Visit.
10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study.
A subject's study treatment should be discontinued if:

The investigator believes that for safety reasons (eg, AE) it is in the best interest of the 
subject to discontinue study treatment

The subject becomes pregnant

The subject undergoes mechanical ventilation

The subject requires peritoneal dialysis, hemodialysis, or hemofiltration

The subject has an eGFR ≤30 mL/min/1.73 m² according to the MDRD equation

The subject experiences any of the laboratory abnormalities as specified in Section 9.3.6, 
Specific Toxicities.
If a subject prematurely discontinues study treatment, follow-up assessments should be obtained 
and scheduled assessments should be continued. If a subject drops out due to withdrawal of 
consent, he or she will be offered an optional Safety Follow-up Visit.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
59
Approved, Date: 19 September 2016
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. 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.
A subject who withdraws from the study will have the following options regarding the optional 
research sample:

The collected sample will be retained and used in accordance with the subject's original 
separate ICF for optional research samples.

The subject may withdraw consent for optional research 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 
for the optional research samples and to request sample destruction. The sponsor study site 
contact will, in turn, contact the biomarker representative to execute sample destruction. If 
requested, the investigator will receive written confirmation from the sponsor that the 
sample has been destroyed.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (see 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.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
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, height, body weight, body mass index [BMI]) and 
other initial subject characteristics (physical examination, medical and surgical history, 
concomitant diseases, etc.) will be tabulated and analyzed descriptively.
11.2.
Sample Size Determination
Up to 90 subjects in total will be enrolled in this study. An effort will be made to include at least 
24 subjects for each cohort, with the total of subjects allowed to be recruited across both cohorts. 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
60
Approved, Date: 19 September 2016
It is anticipated that it is feasible to recruit at least 60 subjects, which would lead to an acceptable 
precision for the primary objective.
For the primary objective of evaluating the PK of JNJ-63623872 across age cohorts the PK 
parameters considered of major importance are Cmin, Cmax, and AUC12h. As there are no data 
available where Day 3 has been part of extensive PK sampling on the 600 mg bid dose, the 
variability on days with available data are presented in Table 2. Based on those data a between-
subjects CV of 60% was assumed as a reasonably conservative estimate for the current study.
Table 2:
Variability for Key Pharmacokinetic Parameters for JNJ-63623872 600 mg bid (Between-
subjects %CV)
Time point
N
Cmin
Cmax
AUC12h
Day 1
12
NA
65
56
Day 5
18
77
57
61
Day 5*
18
48
57
46
Day 10
12
56
44
43
Note: Based on study 63623872FLZ1001. 
*JNJ-63623872 600 mg bid + oseltamivir 75 mg bid. 
NA: Not applicable.
For age cohorts it was assumed that the number of hospitalizations would be about equal for 
elderly and non-elderly adults. In case 60 subjects are enrolled, there are 40 subjects on active 
treatment and it is assumed that at least 16 subjects are on active treatment in each cohort). For 
the comparison of PK parameters of the cohort of elderly adults (test) vs. non-elderly adults 
(reference) with PK data in a 16 to 24 ratio and a between-subject coefficient of variation (CV) 
of 60%, the 90% confidence interval (CI) of the geometric mean ratio (GMR) for Cmin would be 
predicted to have a half-width of 35%, indicating that we can be 90% confident that the true 
GMR is in the interval observed GMR/1.35 to 1.35*GMR. If 90 subjects were enrolled with 60
on active treatment in a 24 to 36 ratio, the predicted half-width would be 28%.
The precision was expressed as the half-width of the 90% confidence band around the predicted 
mean LOESS estimate (illustrated in a simulated situation presented in Figure 1, with circles as 
the individually simulated values for Cmin, as a solid line the predicted values and the shaded area 
the 90% confidence band for the prediction). With the anticipated numbers of subjects, the 
average half-widths and the maximum half-width are presented in Table 3 as percentages. The 
average half-width is the relative distance between the prediction and the 90% confidence band 
around that mean, averaged across the observed data points. Based on 40 to 60 subjects exposed 
to JNJ-63623872, the 90% confidence band for the planned LOESS regression was considered 
sufficiently precise (with average half-widths less than 25%) in order to evaluate the relationship 
between age and the major PK parameters.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
61
Approved, Date: 19 September 2016
Figure 1:
Example of LOESS Regression for a Simulated Data Set for Cmin (N=50)
Table 3:
Precision of the LOESS Confidence Band Around the Prediction
Cmin (CV=60%)
Number of subjects treated with JNJ-63623872
N=40
N=50
N=60
Mean half-width*
25%
22%
20%
Maximum half-width*
46%
40%
36%
*Expressed as the ratio of the upper 90% confidence band divided by the prediction derived from the LOESS 
regression. Expressed as a percentage, based on 10.000 simulations.
For the safety objective of the study the sample size of 40 to 60 subjects treated with 
JNJ-63623872 can be characterized by assessing the precisions for (potentially) observed 
treatment-emergent AEs. For example, if no related treatment-emergent SAE is observed in a 
sample of 60 subjects exposed to JNJ-63623872, it can be concluded with 95% confidence that 
the true incidence of related treatment-emergent SAEs will be less than 5%. Table 4 presents the 
one-sided upper confidence limits for a range of numbers of treated subjects.
Table 4:
Upper Confidence Limits for any Event with a Zero Incidence
Number of subjects treated with JNJ-63623872
N=40
N=50
N=60
Upper confidence limit*
7.2%
5.8%
4.9%
*Upper 95% confidence limit (one-sided) using the Clopper-Pearson method
Besides characterizing the precision for excluding significant side-effects, the current study also 
allows to assess the incidence of treatment-emergent AEs on JNJ-63623872 vs. placebo 
treatment. Table 5 presents the 95% CIs for the risk difference that may potentially be observed. 
Cmin (ng/mL)
0
100
200
300
400
500
600
700
800
900
Age
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
62
Approved, Date: 19 September 2016
For example, with 4 events (out of 60) vs. 1 event (out of 30) the risk difference (95% CI) would 
be 3.3% (-19%, 26%).
Table 5:
Risk Differences and Associated 95% Confidence Intervals for Potential Treatment-emergent 
Adverse Event Incidences 
Risk difference (95% CI) by sample size (active: placebo)
40:20
50:25
60:30
0% (-28%, 28%)
0% (-25%, 25%)
0% (-22%, 22%)
2.5% (-25%, 30%)
2.0% (-23%, 27%)
1.7% (-21%, 24%)
5.0% (-23%, 32%)
4.0% (-21%, 28%)
3.3% (-19%, 26%)
7.5% (-20%, 35%)
6.0% (-19%, 30%)
5.0% (-18%, 27%)
10.0% (-18%, 37%)
8.0% (-17%, 32%)
6.7% (-16%, 29%)
Based on exact 95% confidence intervals. Interval width only depends on risk difference. For zero events in both 
groups the confidence interval for the risk difference is not defined.
11.3.
Pharmacokinetic Analyses
Pharmacokinetic parameters will be used to assess the exposure of JNJ-63623872 on Day 3.
Refer to Section 9.2 for more details.
Primary Endpoint

PK parameters of JNJ-63623872 (ie, Cmin, Cmax, and AUC12h) established on Day 3.
Intensive Pharmacokinetic Sampling (Day 3)
All plasma concentrations below the lowest quantifiable concentration or missing data will be 
labeled as such in the concentration data presentations or SAS dataset. Concentrations below the 
lower quantifiable concentration will be treated as zero in the summary statistics. All subjects 
and samples excluded from the analysis will be clearly documented in the Clinical Study Report.
Descriptive statistics will be calculated for plasma concentrations of JNJ-63623872 at each 
sampling time point and for the derived plasma PK parameters. Statistics include sample size (n), 
mean, standard deviation (SD), %CV, geometric mean, median, minimum, and maximum.
For each subject treated with JNJ-63623872, JNJ-63623872 plasma concentration-time data will 
be graphically presented. Similarly, graphs of the mean plasma concentration-time profiles and 
overlay graphs with combined individual plasma concentration-time profiles will be produced. 
Pharmacokinetic parameters will be subjected to an exploratory graphical analysis in order to get 
a general overview.
Statistical analysis will be performed for the PK-evaluable population. Elderly adults (65 to 
≤85 years) will be compared vs. non-elderly adults (reference) to investigate the relative effect of 
age. The primary PK parameters are Cmax, Cmin, and AUC12h. AUC12h will be rejected as primary 
parameter for an age cohort if more than half of the subjects of that age cohort do not have a 
reliable value. For the primary PK parameters, the GMR of test vs. reference will be calculated 
including the associated 90% CI.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
63
Approved, Date: 19 September 2016
For the assessment of an age effect, regression techniques will be employed to describe and 
predict the relation between age and primary PK parameters. As the relationship need not be 
linear across age, LOESS regression will be used that allows for a nonlinear model fit. The 
LOESS model uses smoothing based on goodness of fit criteria; recognizing that marked local 
changes are not biologically plausible, smoothing will be restricted. In case important predictive 
covariates are identified a generalized additive model will be used to model the relation between 
age and PK parameters adjusted for covariates, including LOESS regression for age. Regression 
will be performed on the logarithm of the PK parameter, with the results of the regression being 
retransformed to the original scale, including the 90% confidence band around the regression 
line. For an effect of body weight on primary PK parameters a similar approach will be used as 
an exploratory analysis.
Special attention will be paid to the plasma concentrations and PK parameters of those subjects 
who have discontinued the study for an AE, or who experienced an AE of at least grade 3, or an
SAE.
Sparse Pharmacokinetic Sampling
Population PK analysis of plasma concentration-time data of JNJ-63623872 will be performed 
using nonlinear mixed-effects modeling. Data may be combined with those of other selected 
studies to support a relevant structural model. Available baseline subject characteristics 
(demographics, body weight, laboratory variables, genotypes, race, etc.) will be tested as 
potential covariates affecting PK parameters. Details will be given in a population PK analysis 
plan and the results of the population PK analysis will be presented in a separate report. 
A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected 
before this date will be analyzed for JNJ-63623872 and included in the population PK analysis. 
Samples collected after the snapshot date will be analyzed at a later date, and may be included in
a population PK re-analysis when they become available after database lock.
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 in the study report.
For each treatment arm, descriptive statistics, including sample size (n), arithmetic mean, SD, 
%CV, geometric mean, median, minimum, and maximum will be calculated for all individually
derived PK parameters including exposure information of JNJ-63623872.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
64
Approved, Date: 19 September 2016
11.4.
Pharmacokinetic/Pharmacodynamic Analyses
The PK/PD relationship of JNJ-63623872 exposure (AUC12h, Cmax, or Cmin) with efficacy (ie, 
change in viral load from baseline and virologic response) and safety (including AEs and 
laboratory abnormalities) will be explored. Other exploratory analyses may be performed.
11.5.
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 drug received. Safety will be 
evaluated by means of AEs (including complications of influenza), clinical laboratory tests, 
ECGs, vital signs, NEWS, physical examinations, pregnancy testing, and specific toxicities. The 
safety analysis will be done for the Safety population and for each study phase separately 
(treatment, follow-up, and the combination of both).
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are AEs 
with onset during the treatment phase or that are a consequence of a pre-existing condition that 
has worsened since baseline. All reported AEs will be included in the analysis. For each AE, the 
percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment arm. In addition, comparisons between treatment arms will be provided 
if appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or a 
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 
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.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
65
Approved, Date: 19 September 2016
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, QTcF, and QT correction 
derived by linear regression (QTcL).5,9
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of subjects with QTc interval >450 milliseconds, 
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of subjects 
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds.
All important abnormalities in ECG waveform that are changes from the baseline readings will 
be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
The percentage of subjects with abnormalities will be tabulated by treatment arm.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, blood pressure (systolic 
and diastolic) (supine), arterial oxygen saturation values, level of consciousness, and changes 
from baseline will be summarized at each scheduled time point. 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 will be summarized. For 
each subject, the NEWS will be derived based on the vital sign data. The average of the NEWS 
over time will be presented by treatment group.
Electrocardiogram data will be summarized by vital sign parameters (temperature, pulse/heart 
rate and blood pressure [systolic and diastolic]). 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.
Physical Examination
Descriptive statistics of changes from baseline will be summarized at each scheduled time point.
Physical examination findings will be summarized at each scheduled time point. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled time point. 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
66
Approved, Date: 19 September 2016
11.6.
Efficacy Analyses
The efficacy endpoints will be analyzed on the Full Analysis Set, consisting of all subjects who 
were randomized, treated and had a confirmed influenza A infection, and will be analyzed by 
drug received.
Descriptive statistics will be used for all efficacy endpoints and will be tabulated by treatment 
arm and by age cohort. No formal statistical hypothesis testing will be made.
Clinical outcomes
The incidence of influenza complications will be categorized in a hierarchical fashion. The 
overall category will consist of any complication, consisting of the following subcategories:

bacterial pneumonia (culture confirmed where possible), 

other bacterial superinfections,

respiratory failure,

pulmonary disease: asthma, chronic obstructive pulmonary disease [COPD]),

cardiovascular and cerebrovascular disease (eg, myocardial infarction, congestive heart 
failure [CHF], arrhythmia, stroke),

post-baseline ICU admission,

all-cause mortality
The incidences on Day 28 of each (sub) category will be analyzed using logistic regression; 
baseline characteristics that are predictive of the incidence of complications can be included 
based on goodness of fit criteria. Odds ratios and associated 95% CIs will be reported of active 
vs. control treatment.
The time to improvement of vital signs is defined as the time from first study treatment to when 
at least 4 of 5 symptoms (temperature, blood oxygen saturation, heart rate, SBP, respiration rate) 
are recovered, including normalization of temperature and blood oxygen saturation. 
Normalization is defined in Table 6. If subjects satisfy these criteria at entry they will be 
censored at that time (effectively they will be excluded from the analysis). The data will be 
presented using a Kaplan-Meier curve. The time to event data will be modeled using the 
accelerated failure time (if the data provide an acceptable model fit) or alternatively a Cox 
proportional hazards model (in case the hazards are proportional). Additionally, the time to event 
data will be analyzed using the Gehan-Wilcoxon method.
Table 6:
Resolution Criteria for Vital Signs
Assessment
Resolution Criterion
Temperature
≤ 37.2 °C or ≤ 37.8 °C rectal or tympanic
Oxygen saturation
≥ 92% on room air without supplemental oxygen
Respiration rate
≤ 24/min
Heart rate
≤ 100/min
Systolic blood pressure
≥ 90 mmHg
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
67
Approved, Date: 19 September 2016
Time to improvement of respiratory status is defined as normalization of blood oxygen saturation 
and respiration rate. Analysis performed will be analogous to the analysis for the time to 
improvement of vital signs.
The ordinal scale consists of 6 categories that are exhaustive, mutually exclusive, and ordered 
(Table 7). For all patients, the category at Day 8 will be established as the worst category on that 
day. For example, if someone is discharged on Day 8, the category will be non-ICU and no 
supplemental oxygen (if there was no supplemental oxygen given on that day). The analysis will 
be performed using a proportional odds model, modeling the common odds ratio of the 
improvement on the ordinal scale of active treatment versus control. Baseline covariates that are 
predictive of the ordinal scale may be added to the model to increase the model fit. In case of 
missing data (>10%), a multiple imputation method under the missing-at-random assumption 
will be employed. Details will be provided in the Statistical Analysis Plan.
Table 7:
Ordinal Scale on Day 8
Outcome
Death
Admitted to ICU or mechanically ventilated/ECMO
Non-ICU + supplemental oxygen
Non-ICU + no supplemental oxygen
Not hospitalized, but unable to continue activity
Not hospitalized and continues activities
ECMO = extracorporeal membrane oxygenation; ICU = Intensive Care Unit
Viral kinetics 
Measures of viral kinetics are performed for both qRT-PCR and viral culture of nasal MT swabs:

Duration of viral shedding defined as time to influenza A viral negativity

Viral AUC calculated from baseline to Day 14 

Rate of decline of viral load

Incidence of influenza A viral negativity by assessment

Peak viral shedding titer 
The time to influenza A viral negativity will be determined based on nasal MT swabs: a subject 
will be considered influenza A viral negative at the time point that the first negative nasal MT
swab was recorded (in days). A subject will be censored at the time of the last observed non-
negative swab + 1 day. The time to influenza A viral negativity will be summarized using a 
Kaplan-Meier curve. The accelerated failure time model will be used to compare the time to 
recovery for JNJ-63623872 vs. control treatment; the accelerated failure time model will use a 
Weibull, log-logistic, lognormal or gamma distribution based on goodness of fit criteria. 
Additionally, the time to event data will be analyzed using the Gehan-Wilcoxon method. The 
AUC will be estimated for each treatment arm using a mixed model for repeated measurements, 
ie, the AUC will not be calculated for each subject and then analyzed, but the AUC will be 
calculated for each treatment arm using the viral data over time of each subject. This approach 
ensures an optimal approach towards missing data. The rate of decline in quantitative viral load 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
68
Approved, Date: 19 September 2016
will be estimated through a pre-specified linear mixed model. The incidence of viral negativity 
will be analyzed using logistic regression. For the peak viral shedding titer a GMR will be 
derived using a general linear model. For each analysis the difference between the treatment 
arms will be presented including the associated 95% CI. Factors that are predictive of viral titers 
will be included as covariates.
Patient-reported Outcomes 
The time to resolution of influenza symptoms will be the time of the first of 2 evaluations (over 
24 hours) in which all symptom scores for each of the 2 assessments are none or mild for the 
7 primary influenza symptoms as recorded in the Flu-iiQ™ (cough, sore throat, headache, nasal 
stuffiness, feverishness or chills, muscle or joint pain, and fatigue).
The FLU-PRO and Flu-iiQ™ domain scores will be presented descriptively over time using 
descriptive statistics. A linear mixed model will be used to analyze composite symptom scores 
over time, per domain. For the Flu-iiQ™ a daily score will be derived averaging observed scores 
before the analysis. Baseline subject characteristics will be included (in particular baseline score) 
in case these provide to be predictive of post-baseline scores. Mean differences between 
treatment arms will be derived from this model using appropriate contrasts and will be presented 
including the associated 95% CI. For both measures, an AUC of composite symptom scores over 
a 7- and 14-day period per domain will be calculated and compared using a mixed model for 
repeated measurements.
Other PRO endpoints that will be analyzed are:
1.
Time to return to usual activity and usual health (Questions 5 and 9 of the additional items 
for the Flu-PRO). 
2.
Time to significant reduction in influenza symptom severity.
3.
Proportion of patients with a significant reduction (to mild or none for all influenza 
symptoms) at each assessment.
Other Outcomes
The length of overall hospital stay will be calculated from the date of first study drug intake up to 
the date of discharge. Subjects still hospitalized at the end of the study will be censored at the 
last contact. Data will be presented using Kaplan-Meier curves. For a comparison between 
treatment arms, the time to hospital discharge in days will be analyzed using an accelerated 
failure time model (if the data provide an acceptable model fit) or alternatively a Cox 
proportional hazards model (in case the hazards are proportional). Additionally, the time to event 
data will be analyzed using the Gehan-Wilcoxon method. The time to resumption of normal 
daily activities will be analyzed in an analogous fashion.
Resistance Analyses
The results of viral sequencing and phenotyping will be evaluated by the sponsor virologist. 
Additional exploratory characterization of the viral genotype and phenotype may be performed 
and will be reported accordingly.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
69
Approved, Date: 19 September 2016
11.7.
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 study subjects. Analyses may be conducted at the 
sponsor’s discretion and reported separately from this study.
The statistical approach for analyzing the exploratory host DNA research may depend on the 
objective of the analyses (treatment response, side effects, metabolism) and possibly relevant 
genes at the time of analysis. Analyses may be conducted, if deemed valuable, at the sponsor’s 
discretion and may be reported separately from this study.
11.8.
Data Monitoring Committee
An IDMC will be established to monitor data on an ongoing basis. The committee will meet 
periodically to review interim data. After the review, the IDMC will make recommendations 
regarding the continuation of the study.
An interim analysis may be performed to support regulatory activities.
The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The IDMC responsibilities, authorities, and procedures will be documented in its 
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
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH])
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
70
Approved, Date: 19 September 2016
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 (see Section 12.3.1, All 
Adverse Events, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

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 JNJ-63623872, since no adverse drug reactions are 
currently identified in the Investigator's Brochure, all related SAEs are considered unexpected 
for reporting purposes. For oseltamivir with a marketing authorization, the expectedness of an 
AE will be determined by whether or not it is listed in the manufacturer’s prescribing 
information.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
71
Approved, Date: 19 September 2016
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the general categorical descriptors outlined 
in the WHO Toxicity Grading Scale in Attachment 1.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
72
Approved, Date: 19 September 2016

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Special reporting situations should be recorded in the eCRF. Any special reporting situation 
that meets the criteria of an SAE should be recorded on the Serious Adverse Event page of 
the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF 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 electronically via Electronic Data Capture (eDC) or via facsimile (fax) when 
applicable 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 documents 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 documents and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). The investigator 
(or sponsor where required) must report SUSARs to the appropriate 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
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
73
Approved, Date: 19 September 2016

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
page of the eCRF, which must be completed and reviewed 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 
transmitted electronically via eDC or via fax when applicable.
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the subject for the duration of 
the treatment period.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
74
Approved, Date: 19 September 2016
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 
fulfill the SAE definition (see Section 12.1.1, Adverse Event Definitions and Classifications).
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the 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 electronically via eDC or via fax when applicable 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 by the study-site personnel within 24 hours of their 
knowledge of the event using the appropriate Pregnancy Notification Form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
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 (see Section 12.3.2, Serious Adverse Events). 
A sample of the suspected product should be maintained for further investigation if requested by 
the sponsor.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
75
Approved, Date: 19 September 2016
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The JNJ-63623872 supplied for this study is formulated as: 300-mg tablets for oral 
administration, containing JNJ-63623872, microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, povidone K30, sodium stearyl fumarate, Opadry II, white. 
A second formulation also containing the equivalent of 300 mg of JNJ-63623872 free base has 
been developed by the sponsor, which is also suitable for use in this study. The tablet contains
hypromellose, 
polysorbate 
20, 
crospovidone, 
silica 
colloidal 
anhydrous, 
silicified 
microcrystalline cellulose, microcrystalline cellulose, pregelatinized starch, sodium stearyl 
fumarate, Opadry II yellow.
JNJ-63623872 formulations are manufactured and provided under the responsibility of the 
sponsor. The JNJ-63623872 formulation to be used in each different country is determined by 
which one is approved by each respective health authority.
Matching JNJ-63623872 placebo tablets for each of the active formulations are available and will 
be provided for subjects randomized to the placebo group.
Commercially available supplies of oseltamivir will be used, formulated as: 75-mg capsules or 
30-mg capsules for oral administration, containing oseltamivir phosphate, pregelatinized starch, 
talc, povidone K30, croscarmellose sodium, and sodium stearyl fumarate.
14.2.
Packaging
The study drug (JNJ-63623872 or matching placebo tablets and oseltamivir capsules) will be 
provided on a blister card for each subject.
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.
Commercial oseltamivir capsules will be labeled with a study-specific label under the 
responsibility of the sponsor.
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.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
76
Approved, Date: 19 September 2016
Refer to the pharmacy manual/study site investigational product manual for additional guidance on 
study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The 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 legally acceptable representatives where applicable, must be instructed to return 
all original containers, whether empty or containing study drug. All study drugs 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 JNJ-63623872

Prescribing information for oseltamivir

Pharmacy manual/study site investigational product manual

Laboratory manuals (including procedures for collection of nasal swabs)

Contact information page(s)
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
77
Approved, Date: 19 September 2016

ePRO device and user manual

IWRS Manual 

eDC Manual

Sample ICF
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is considered to be within the normal range allowed for this 
subject population over this time frame.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
78
Approved, Date: 19 September 2016

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), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
79
Approved, Date: 19 September 2016
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF that are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, including permission to obtain information about his or 
her survival status, and agrees to allow his or her study physician to recontact the subject for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent disease-
related treatments, or to obtain information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
80
Approved, Date: 19 September 2016
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative)
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-
related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker and pharmacogenomic research is not conducted under standards
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand JNJ-63623872 and 
oseltamivir, to understand influenza A infection, to understand differential drug responders, and 
to develop tests/assays related to JNJ-63623872 and oseltamivir 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 for their samples to be 
stored for research (see Section 10.3, Withdrawal From the Study [Withdrawal From the Use of 
Samples in Future Research]).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
81
Approved, Date: 19 September 2016
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page[s] provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
82
Approved, Date: 19 September 2016
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of signed informed consent; dates of visits (including telephone follow-up 
calls, if applicable); 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.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
83
Approved, Date: 19 September 2016
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The following data will be recorded directly into the eCRF and will be considered source data: 

Race

History of smoking

Blood pressure and pulse/heart rate 

Height and weight 

Details of physical examination
The PRO assessments (Flu-iiQTM, Flu-PRO and additional daily diary items) will be completed 
by subjects on an ePRO device. The results will be recorded directly into the ePRO database and 
will be considered source data.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and Section 
4.2, Exclusion Criteria that specify a need for documented medical history are as follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format.
Electronic Data Capture will be used for this study. The study data will be transcribed by study-
site personnel from the source documents into the eCRF, and transmitted in a secure manner to 
the sponsor within the timeframe agreed upon between the sponsor and the study site. The 
electronic file will be considered to be the CRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into CRFs in 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
84
Approved, Date: 19 September 2016
English. Study site personnel must complete the eCRF as soon as possible after a subject visit, 
and the forms should be available for review at the next scheduled monitoring visit.
All 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 eCRFs 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 
investigator or study-site personnel must adjust the eCRF (if applicable) and complete the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's database, and 
direct transmission of PRO data to the ePRO vendor database and then into the sponsor’s 
database. Written instructions will be provided for collection, handling, storage, and shipment of 
samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources. 
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
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.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
85
Approved, Date: 19 September 2016
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will 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 hospital or clinic records (source 
documents) for completeness and accuracy, and perform source data verification to any source 
data captured on paper and entered in the system later. The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
eCRF are known to the sponsor and study-site personnel and are accessible for verification by 
the sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
86
Approved, Date: 19 September 2016
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit for the last subject participating in the 
study. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. 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 JNJ-63623872 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 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
87
Approved, Date: 19 September 2016
as a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of JNJ-63623872, and thus may be
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study, laboratory data from the 
selected laboratory that were transmitted to the sponsor’s database, and PRO data from the ePRO 
vendor database that were transmitted to the sponsor’s database. Recruitment performance or 
specific expertise related to the nature and the key assessment parameters of the study will be 
used to determine a coordinating investigator. Results of 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 
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
88
Approved, Date: 19 September 2016
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
89
Approved, Date: 19 September 2016
REFERENCES
1.
Bakker AJ. Detection of microalbuminuria. Receiver operating characteristic curve analysis favors albumin to 
creatinine ratio over albumin concentration. Diabetes Care 1999;22:307-313.
2.
Bazett HC. An analysis of the time-relationship of electrocardiograms. Heart. 1920;7:353-380.
3.
Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of 
randomised controlled trials. Lancet 2015;385:1729–1737.
4.
Dunning J, Baillie JK, Cao B, Hayden FG. International Severe Acute Respiratory and Emerging Infection 
Consortium (ISARIC). Antiviral combinations for severe influenza. Lancet Infect Dis 2014;14(12):1259-1270.
5.
Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for 
heart rate is better. J Am Coll Cardiol. 1983;1:694.
6.
JNJ-63623872 Investigator’s Brochure Edition 4.0 (June 2015).
7.
Lee N, Chan PKS, Hui DSC. Viral Loads and Duration of Viral Shedding in Adult Patients Hospitalized with 
Influenza. The Journal of Infectious Diseases. 2009;200:492–500.
8.
McNarry AF, Bateman DN. Simple bedside assessment of level of consciousness: comparison of two simple 
assessment scales with the Glasgow Coma scale. Anaesthesia. 2004;59: 34–37.
9.
Modeling VX-787 Brief Communication, 12 August 2014. Population pharmacokinetic and exposure-response 
analysis for an anti-influenza compound (VX-787) to support phase 2b dose selection in community infected 
patients. Document No. VRT103100.
10.
Sagie A, Larson MG, Goldberg RJ, Bengston JR, Levy D. An improved method for adjusting the QT interval 
for heart rate (the Framingham Heart Study). Am J Cardiol. 1992;70:797-801.
11.
Shrestha S, Swerdlow D, Borse R, et al. Estimating the Burden of 2009 Pandemic Influenza A (H1N1) in the 
United States (April 2009–April 2010). Clin Infect Dis 2011; 52 (suppl 1): S75-S82.
12.
Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. "The ability of the National Early 
Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit 
admission, and death". Resuscitation. 2013; 84: 465–470.
13.
South East Asia Infectious Disease Clinical Research Network. Effect of double dose oseltamivir on clinical 
virological outcomes in children and adults admitted to hospital with severe influenza: double blind 
randomized controlled trial. BMJ. 2013;346:1-16.
14.
Tamiflu SmPC. UK: Roche Registration Ltd; 2012. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000402/WC500033106.pdf
15.
Tamiflu USPI. Foster City, CA: Gilead Sciences, Inc; 2011. 
http://www.gene.com/download/pdf/tamiflu_prescribing.pdf
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
90
Approved, Date: 19 September 2016
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.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
91
Approved, Date: 19 September 2016
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-
glutamyltransferase
≥1.25 to ≤2.50 x 
ULN
>2.50 to ≤5.00 x 
ULN
>5.00 to ≤10.00 x 
ULN
>10.00 x ULN
Alkaline 
Phosphatase
≥1.25 to ≤2.50 x 
ULN
>2.50 to ≤5.00 x 
ULN
>5.00 to ≤10.00 x 
ULN
>10.00 x ULN
Amylase
≥1.1 to ≤1.5 x ULN
>1.5 to ≤2.0 x ULN
>2.0 to ≤5.0 x ULN
>5.0 x ULN
Chemistries
Hyponatremia
130-135 mEq/L
123-129 mEq/L
116-122 mEq/L
<116 mEq/L or 
mental status 
changes or 
seizures
Hypernatremia
146-150 mEq/L
151-157 mEq/L
158-165 mEq/L
>165 mEq/L or 
mental status 
changes or 
seizures
Hypokalemia
3.0-3.4 mEq/L
2.5-2.9 mEq/L
2.0-2.4 mEq/L or 
intensive 
replacement Rx 
required or 
hospitalization 
required
<2.0 mEq/L or 
paresis or ileus or 
life-threatening 
arrhythmia
Hyperkalemia
5.6-6.0 mEq/L
6.1-6.5 mEq/L
6.6-7.0 mEq/L
>7.0 mEq/L or 
life-threatening 
arrhythmia
Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
<30 mg/dL or 
mental status 
changes or coma
Hyperglycemia 
(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
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
92
Approved, Date: 19 September 2016
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
Creatinine
≥1.1 to ≤1.5 x ULN
>1.5 to ≤3.0 x ULN
>3.0 to ≤6.0 x ULN
>6.0 x ULN or 
required dialysis
Urinalysis
Proteinuria
1+ or <0.3% or 
<3g/L or 
200 mg – 1 gm 
loss/day
2-3+ or 0.3-1.0% or 
3-10 g/L or 
1-2 gm loss/day
4+ or >1.0% or 
>10 g/L or 
2-3.5 gm loss/day
nephrotic 
syndrome or 
>3.5 gm loss/day
Hematuria
microscopic only
gross, no clots
gross + clots
obstructive or 
required 
transfusion
Cardiac Dysfunction
Cardiac Rhythm
-
asymptomatic, 
transient signs, no 
Rx required
recurrent/persistent; 
no Rx required
requires Rx
Hypertension
transient inc. 
>20 mm; no Rx
recurrent, chronic, 
> 20 mm, Rx 
required
requires acute Rx; no 
hospitalization
requires 
hospitalization
Hypotension
transient orthostatic 
hypotension, no Rx
symptoms 
correctable with oral 
fluids Rx
requires IV fluids; no 
hospitalization 
required
requires 
hospitalization
Pericarditis
minimal effusion
mild/moderate 
asymptomatic 
effusion, no Rx
symptomatic 
effusion; pain; ECG 
changes
tamponade; 
pericardiocentesis 
or surgery 
required
Hemorrhage, Blood 
Loss
microscopic/occult
mild, no transfusion
gross blood loss; 
1-2 units transfused
massive blood 
loss; >3 units 
transfused
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
93
Approved, Date: 19 September 2016
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
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
94
Approved, Date: 19 September 2016
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
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
95
Approved, Date: 19 September 2016
Attachment 2:
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.
For the purposes of this study the following events will be considered anticipated events: 

Bacterial 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)
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as
described in Section 12.3.1, All Adverse Events. Any event that meets 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 (ASMP).
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
96
Approved, Date: 19 September 2016
Attachment 3:
Influenza Intensity and Impact Questionnaire (Flu-iiQTM)
This attachment provides a representative example of the Flu-iiQTM questionnaire that will be used in this study.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
97
Approved, Date: 19 September 2016
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
98
Approved, Date: 19 September 2016
Attachment 4:
Additional Daily Diary Items to Flu-iiQTM
This attachment provides a representative example of the additional daily diary items to Flu-iiQTM that will be used 
in this study.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
99
Approved, Date: 19 September 2016
Attachment 5:
Flu-PRO Questionnaire
This attachment provides a representative example of the Flu-PRO questionnaire that will be used in this study.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
100
Approved, Date: 19 September 2016
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
101
Approved, Date: 19 September 2016
Attachment 6:
Additional Daily Diary Items to Flu-PRO
This attachment provides a representative example of the additional daily diary items to Flu-PRO that will be used 
in this study.
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
102
Approved, Date: 19 September 2016
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
103
Approved, Date: 19 September 2016
Attachment 7:
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).
NCT02532283


JNJ-63623872
Clinical Protocol Amendment 3 63623872FLZ2002
104
Approved, Date: 19 September 2016
INVESTIGATOR AGREEMENT
I have read this document and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the document and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Lorant Leopold
Institution:
Janssen Research & Development
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
LAST PAGE
NCT02532283

SAP_001.pdf: 
63623872FLZ2002 
Statistical Analysis Plan 
Page 1 of 53 
Statistical Analysis Plan
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Pharmacokinetics, Safety, and Antiviral Activity of  
JNJ-63623872 in Combination With Oseltamivir in Adult and Elderly 
Hospitalized Patients With Influenza A Infection 
Protocol 63623872FLZ2002
JNJ-63623872
Issue/Report Date: 21 March 2017 
Version: 
2.0  
Document No.: 
EDMS-ERI-134078089 
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. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 2 of 53 
 
 
Abbreviations 
4 
Amendments 
5 
1. 
Study description 
6 
1.1. 
Study objectives .............................................................................. 6 
1.2. 
Study Design ................................................................................... 7 
1.3. 
Study population .............................................................................. 8 
1.4. 
Sample Size Justification ................................................................. 8 
1.5. 
Randomization and Blinding .......................................................... 10 
1.6. 
Changes to the planned analysis, not specified by protocol 
amendments before DB lock ......................................................... 11 
2. 
Interim and Final analysis 
12 
3. 
General analysis specifications 
13 
3.1. 
Visit Windows, Phase Definitions and Baseline ............................. 13 
3.1.1. 
Phase Definitions ............................................................. 13 
3.1.2. 
Use of Unscheduled Assessments .................................. 15 
3.1.3. 
Analysis visits ................................................................... 15 
3.1.4. 
Analysis timepoints .......................................................... 15 
3.1.5. 
Use of records in case more than 1 record per 
analysis visit/time point .................................................... 15 
3.1.6. 
Baseline Definitions.......................................................... 16 
3.2. 
Analysis sets ................................................................................. 16 
3.3. 
Definition of Subgroups ................................................................. 17 
3.4. 
Statistical Methods ........................................................................ 17 
4. 
Analyses 
19 
4.1. 
Subject Information ....................................................................... 19 
4.1.1. 
Subject disposition ........................................................... 19 
4.1.2. 
Summaries will be made overall and by age 
category, by treatment group (and 
overall).Demographics parameters and baseline 
disease characteristics ..................................................... 19 
4.1.3. 
Prior and Concomitant Medications ................................. 20 
4.1.4. 
Medical history ................................................................. 21 
4.1.5. 
Treatment Exposure and Compliance .............................. 21 
4.2. 
Efficacy .......................................................................................... 22 
4.2.1. 
Clinical Outcomes ............................................................ 22 
4.2.2. 
Viral Kinetics .................................................................... 25 
4.2.3. 
Influenza Symptom Score (FLU-iiQTM Module 1) ............. 28 
4.2.4. 
Impact of Influenza (Flu-iiQTM Modules 2, 3, 4) ................ 30 
4.2.5. 
FLU-iiQTM Additional Daily Diary Items ............................ 32 
4.2.6. 
Influenza Patient Reported Outcome Diary (FLU-
PRO) ................................................................................ 32 
4.2.7. 
FLU-iiQTM Additional Daily Diary Items ............................ 35 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 3 of 53 
 
 
4.2.8. 
Correlation between viral load, viral titer and 
changes in clinical symptoms ........................................... 35 
4.2.9. 
Other Outcomes ............................................................... 36 
4.3. 
Safety ............................................................................................ 36 
4.3.1. 
Adverse events ................................................................ 36 
4.3.2. 
Clinical laboratory tests .................................................... 38 
4.3.3. 
Electrocardiograms .......................................................... 39 
4.3.4. 
Vital Signs ........................................................................ 40 
4.3.5. 
NEW Score ...................................................................... 41 
4.3.6. 
Physical Examinations: .................................................... 41 
4.4. 
Virology ......................................................................................... 42 
4.4.1. 
Viral Phenotype ................................................................ 42 
4.4.2. 
Viral Genotype ................................................................. 42 
4.5. 
Health Care ................................................................................... 43 
References 
44 
Appendix 1 
Anticipated Events and Anticipated Event 
Groups 45 
Appendix 2 
WHO Toxicity Grading Scale for Determining the 
Severity of Adverse Events (Feb 2003) 
48 
Appendix 3 
WHO grading scale Vital Signs 
53 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 4 of 53 
 
 
Abbreviations  
AE 
Adverse event 
AUC 
area under the curve 
AUC24h 
area under the plasma concentration-time curve from time 0 to 24 hours 
bid 
bis in die; twice daily 
BMI 
body mass index 
C0h 
predose plasma concentration 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
CPAP 
Clinical Pharmacology Analysis Plan 
CTP 
clinical trial protocol 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
FAS 
Full Analysis Set 
GMR 
geometric mean ratio 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intent-To-Treat 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
Per Protocol 
PT 
preferred term 
qRT-PCR 
quantitative reverse transcription polymerase chain reaction 
RNA 
Ribonucleic Acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SI 
international system  
 
 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 5 of 53 
 
 
Amendments 
Amendment 1 
Changes compared to SAP version 1.0, dated 15 March 2017: 
Rationale: The original analysis of viral load qRT PCR assumed that both the 
limit of detection (LOD) and quantification  (LOQ) were the same (2.18 log10 
vp/mL). As this has been changed to two different limits: LOD of 2.05 log10 
vp/mL and LOQ of 2.18 log10 vp/mL, the analysis description had to be updated 
accordingly.  
Updates were made to Sections 3.2 (Analysis sets) and 4.2.2 (Viral Kinetics).    
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 6 of 53 
 
 
1. 
Study description 
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 JNJ-63623872. The SAP is to be interpreted in 
conjunction with the protocol. A detailed analysis plan for the pharmacokinetic 
data will be described in a Clinical Pharmacology Analysis Plan (CPAP). The 
Clinical Pharmacology Analysis Plan will include the primary endpoint and all 
secondary and exploratory endpoints related to PK and PK/PD for this study. 
JNJ-63623872 (formerly known as VX-787) 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 2 development as treatment for influenza A 
infection. 
1.1. 
Study objectives 
Please note this SAP does not cover the primary objective and the exploratory 
PK/PD relationship (efficacy and safety). These objectives will be analyzed and 
reported separately according to the clinical pharmacology analysis plan (CPAP). 
Primary Objective  
The primary objective is to evaluate the pharmacokinetic (PK) parameters of JNJ-
63623872 in combination with oseltamivir in elderly subjects (aged 65 to ≤85 
years) compared to adults (aged 18 to ≤64 years) with influenza A infection.  
Secondary Objectives  
Secondary objectives include the assessment of the following parameters in the 
JNJ-63623872 treatment arm compared to the control arm: 
■ Safety and tolerability. 
■ The time to influenza viral negativity based on qRT-PCR and/or viral 
culture from nasal mid-turbinate (MT) swabs and, if applicable, based on 
PCR-based rapid molecular testing from nasal MT swabs. 
■ Viral load over time and rate of decline in viral load during treatment as 
measured by qRT-PCR and/or viral culture. 
■ Area under the curve (AUC) of viral load as measured by qRT-PCR and/or 
viral culture. 
■ Disease status and incidence of complications associated with influenza 
after the start of study treatment, and disease progression: 
 
bacterial pneumonia (culture confirmed where possible), 
 
other bacterial superinfections, 
 
respiratory failure, 
 
pulmonary disease (eg, asthma, chronic obstructive pulmonary 
disease [COPD]), 
 
cardiovascular 
and 
cerebrovascular 
disease 
(eg, 
myocardial 
infarction, congestive heart failure [CHF], arrhythmia, stroke). 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 7 of 53 
 
 
■ Change in duration and severity of clinical symptoms as measured by the 
Flu-PRO. 
■ Time to improvement of vital signs. 
■ Time to improvement of respiratory status. 
■ Improvement on the ordinal scale. 
■ Emergence of drug resistance as detected by genotype and/or phenotype. 
■ Time to return to premorbid functional status (time to return to usual 
activities). 
■ Time to hospital discharge. 
Exploratory Objectives  
Exploratory objectives include the assessment of the following parameters in the 
JNJ-63623872 treatment arm compared to the control arm:  
■ Use of antibiotics and/or corticosteroids during hospitalization. 
■ Number of subjects admitted to the Intensive Care Unit (ICU). 
■ Length of ICU stay for subjects transferred to the ICU after baseline. 
■ Correlation between the decline in viral load (measured by qRT-PCR 
and/or viral culture) and changes in clinical symptoms.  
■ PK/PD relationship (efficacy and safety). 
1.2. 
Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter Phase 2 study 
to evaluate the effect of JNJ-63623872 600 mg bid versus (vs.) placebo, both in 
combination with oseltamivir 75 mg bid in adult and elderly hospitalized subjects 
with influenza A infection. Up to 90 subjects in total will be enrolled in this study. 
An effort will be made to enroll a minimum of approximately 24 subjects per age 
cohort. 
Subjects who meet all eligibility criteria will be randomized in a 2:1 ratio to 
receive 1 of the following 2 treatments: 
■ JNJ-63623872 600 mg bid + oseltamivir 75 mg bid; OR 
■ JNJ-63623872 placebo bid + oseltamivir 75 mg bid 
Oseltamivir dose should be reduced to 30 mg bid for subjects with an estimated 
glomerular filtration rate (eGFR) >30 and ≤60 mL/min/1.73 m² according to the 
Modification of Diet in Renal Disease (MDRD) equation. Dose can be adjusted 
from 30 mg to 75 mg and vice versa during the course of treatment based on the 
eGFR value. 
All study drugs will be taken orally. 
The study will consist of a screening/baseline visit, a double-blind treatment 
period of 7 days, and a follow-up period of 21 days. The entire study duration for 
each subject will be 28 days with study assessments daily during the treatment 
period, and on Days 10, 14, and 28 of the follow-up period. The study is 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 8 of 53 
 
 
considered complete with the completion of the last study assessment for the last 
subject participating in the study. 
1.3. 
Study population 
Eligibility will be reviewed and documented by an appropriately qualified 
member of the investigator’s team before subjects are enrolled. 
The inclusion and exclusion criteria for enrolling subjects in this study are 
described in section 4 of the Protocol. If there is a question about the inclusion or 
exclusion criteria, the investigator should consult with the appropriate sponsor 
representative before enrolling a subject in the study.  
1.4. 
Sample Size Justification  
Up to 90 subjects in total will be enrolled in this study. An effort will be made to 
include at least 24 subjects for each cohort, with the total of subjects allowed to be 
recruited across both cohorts. It is anticipated that it is feasible to recruit at least 
60 subjects, which would lead to an acceptable precision for the primary 
objective. 
For the primary objective of evaluating the PK of JNJ-63623872 across age 
cohorts the PK parameters considered of major importance are Cmin, Cmax, and 
AUC12h. As there are no data available where Day 3 has been part of extensive PK 
sampling on the 600 mg bid dose, the variability on days with available data are 
presented in Table 1. Based on those data a between-subjects CV of 60% was 
assumed as a reasonably conservative estimate for the current study. 
Table 1: Variability for Key Pharmacokinetic Parameters for JNJ-63623872 600 mg bid 
(Between-subjects %CV) 
Time point 
N 
Cmin 
Cmax 
AUC12h 
Day 1 
12 
NA 
65 
56 
Day 5 
18 
77 
57 
61 
Day 5* 
18 
48 
57 
46 
Day 10 
12 
56 
44 
43 
Note: Based on study 63623872FLZ1001. 
*JNJ-63623872 600 mg bid + oseltamivir 75 mg bid. 
NA: Not applicable. 
 
For age cohorts it was assumed that the number of hospitalizations would be 
about equal for elderly and non-elderly adults. In case 60 subjects are enrolled, 
there are 40 subjects on active treatment and it is assumed that at least 16 subjects 
are on active treatment in each cohort). For the comparison of PK parameters of 
the cohort of elderly adults (test) vs. non-elderly adults (reference) with PK data 
in a 16 to 24 ratio and a between-subject coefficient of variation (CV) of 60%, the 
90% confidence interval (CI) of the geometric mean ratio (GMR) for Cmin would 
be predicted to have a half-width of 35%, indicating that we can be 90% confident 
that the true GMR is in the interval observed GMR/1.35 to 1.35*GMR. If 90 
subjects were enrolled with 60 on active treatment in a 24 to 36 ratio, the 
predicted half-width would be 28%. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 9 of 53 
 
 
The precision was expressed as the half-width of the 90% confidence band around 
the predicted mean LOESS estimate (illustrated in a simulated situation presented 
in Figure 1, with circles as the individually simulated values for Cmin, as a solid 
line the predicted values and the shaded area the 90% confidence band for the 
prediction). With the anticipated numbers of subjects, the average half-widths and 
the maximum half-width are presented in Table 2 as percentages. The average 
half-width is the relative distance between the prediction and the 90% confidence 
band around that mean, averaged across the observed data points. Based on 40 to 
60 subjects exposed to JNJ-63623872, the 90% confidence band for the planned 
LOESS regression was considered sufficiently precise (with average half-widths 
less than 25%) in order to evaluate the relationship between age and the major PK 
parameters. 
Figure 1: Example of LOESS Regression for a Simulated Data Set for Cmin (N=50) 
 
 
Table 2: Precision of the LOESS Confidence Band Around the Prediction 
Cmin (CV=60%)  
 
Number of subjects treated with JNJ-63623872 
N=40 
N=50 
N=60 
Mean half-width*  
25%  
22%  
20% 
Maximum half-width*  
46%  
40%  
36% 
*Expressed as the ratio of the upper 90% confidence band divided by the prediction derived from 
the LOESS regression. Expressed as a percentage, based on 10.000 simulations. 
For the safety objective of the study the sample size of 40 to 60 subjects treated 
with JNJ-63623872 can be characterized by assessing the precisions for 
(potentially) observed treatment-emergent AEs. For example, if no related 
treatment-emergent SAE is observed in a sample of 60 subjects exposed to JNJ-
63623872, it can be concluded with 95% confidence that the true incidence of 
related treatment-emergent SAEs will be less than 5%. Table 3 presents the one-
sided upper confidence limits for a range of numbers of treated subjects.  
Cmin (ng/mL)
0
100
200
300
400
500
600
700
800
900
Age
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 10 of 53 
 
 
Table 3: Upper Confidence Limits for any Event with a Zero Incidence 
 
Number of subjects treated with JNJ-63623872 
 
N=40 
N=50 
N=60 
Upper confidence limit*  
7.2%  
5.8%  
4.9% 
*Upper 95% confidence limit (one-sided) using the Clopper-Pearson method 
Besides characterizing the precision for excluding significant side-effects, the 
current study also allows to assess the incidence of treatment-emergent AEs on 
JNJ-63623872 vs. placebo treatment. Table 4 presents the 95% CIs for the risk 
difference that may potentially be observed. For example, with 4 events (out of 
60) vs. 1 event (out of 30) the risk difference (95% CI) would be 3.3% (-19%, 
26%). 
Table 4: Risk Differences and Associated 95% Confidence Intervals for Potential Treatment-
emergent Adverse Event Incidences 
Risk difference (95% CI) by sample size (active: placebo) 
40:20 
50:25 
60:30 
0% (-28%, 28%) 
0% (-25%, 25%) 
0% (-22%, 22%) 
2.5% (-25%, 30%) 
2.0% (-23%, 27%) 
1.7% (-21%, 24%) 
5.0% (-23%, 32%) 
4.0% (-21%, 28%) 
3.3% (-19%, 26%) 
7.5% (-20%, 35%) 
6.0% (-19%, 30%) 
5.0% (-18%, 27%) 
10.0% (-18%, 37%) 
8.0% (-17%, 32%) 
6.7% (-16%, 29%) 
Based on exact 95% confidence intervals. Interval width only depends on risk difference. For zero 
events in both groups the confidence interval for the risk difference is not defined. 
1.5. 
Randomization and Blinding 
Central randomization will be implemented in this study. Subjects will be 
randomly assigned to 1 of 2 treatment arms in a 2:1 ratio (active vs. placebo) 
based on a computer-generated randomization schedule prepared before the study 
by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by age cohort. An 
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.  
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. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 11 of 53 
 
 
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. 
1.6. 
Changes to the planned analysis, not specified by protocol 
amendments before DB lock 
The protocol defines the improvement of vital signs using symptoms for 
temperature, blood oxygen saturation, heart rate, SBP and respiration rate.  In the 
resolution criterion for temperature the protocol defines rectal and tympanic 
temperatures. However, only oral temperatures are measured in the 
63623872FLZ2002 trial. Additionally the trial is stratified based on age categories 
for adults and elderly patients. It is known that older subjects have lower mean 
oral body temperatures. Taking these aspects into account the resolution criterion 
for temperature has been adapted to using oral temperature ≤ 36.5 °C for elderly 
and ≤ 37.2 °C for adults instead of rectal or tympanic temperature  ≤ 37.2 °C or ≤ 
37.8 °C respectively as specified in the protocol.  
 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 12 of 53 
 
 
2. 
Interim and Final analysis 
An IDMC will be established to monitor data on an ongoing 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 IDMC will consist of at least one medical expert in the relevant therapeutic 
area and at least one statistician. The IDMC responsibilities, authorities, and 
procedures will be documented in its charter.  
An interim analysis may be performed to support regulatory activities. In that case 
the same Statistical Analysis Plan (SAP) will be used for the interim and the final 
analysis.  
Should an interim analysis be performed this analysis will be based on the number 
of subjects randomized up to that timepoint. The interim analysis will be 
performed by a statistical support group independent of the study biostatistician 
team and any personnel directly involved in the conduct of the study. More details 
about their formation, roles, responsibilities and the level of unblinding of the 
different parties, can be found in the Interim Analysis Committee Charter (IAC 
Charter). 
 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 13 of 53 
 
 
3. 
General analysis specifications 
All analysis dataset preparations and statistical analyses will be performed using 
SAS® version 9.2. 
3.1. 
Visit Windows, Phase Definitions and Baseline 
The study is set up as shown in Figure 2. The phases will be constructed as shown 
in Table 5. 
Figure 2: Study time line. 
Day 
 
1 
2 
3 
4 
5 
6 
7 
 
10 
 
 
14 
 
 
 
28 
Arm 1 
Scr. 
JNJ-63623872 600 mg bid  
+ oseltamivir 75 mg bid* 
Follow-up 
 
Arm 2 
Scr. 
placebo bid  
+ oseltamivir 75 mg bid* 
Follow-up 
 
 * Oseltamivir dose should be reduced to 30 mg bid for subjects with an estimated glomerular 
filtration rate (eGFR) >30 and ≤60 mL/min/1.73 m² according to the Modification of Diet in Renal 
Disease (MDRD) equation. Dose can be adjusted from 30 mg to 75 mg and vice versa during the 
course of treatment based on the eGFR value. 
3.1.1. Phase Definitions 
 
Table 5: Construction of phases 
Trial phase 
Trial sub 
period*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 
medication intake  
Treatment  
 (phase 2) 
 
Datetime 
of 
first 
study 
medication intake  
Datetime 
of 
 
last 
investigational 
medication 
intake*5 + 24 hours 
Hospitalization 
(sub period 1)*2 
In case first intake of study 
medication occurred at the 
hospital*4: 
Datetime 
of 
first 
study 
medication intake  
The minimum of: 
• The last date of discharge 
from hospital*4 + timepart 
23:59 
• The Datetime of last 
investigational medication 
intake*5 + 24 hours 
Outpatient 
(sub period 2)*3 
In case first intake of study 
medication did not occur at 
the hospital*4: 
Datetime 
of 
first 
study 
medication intake  
In case first intake of study 
medication occurred at the 
hospital*4 and last discharge 
from the hospital occurred 
before the end of the treatment 
Datetime 
of 
 
last 
investigational 
medication 
intake*5 + 24 hours 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 14 of 53 
 
 
Trial phase 
Trial sub 
period*1 
Start date 
End date 
phase: 
End 
date 
hospitalization 
phase*4 + 1 minute  
Follow-up 
(phase 3) 
 
End of the  treatment phase  
+1 minute 
Trial termination date (date of 
last contact) or cut-off date 
for 
the 
Interim 
analysis, 
whichever comes first with 
23:59 as a timepart 
*1: A treatment period will be constructed in the derived datasets with the same start and end date 
as the treatment phase. 
*2: The hospitalization phase will not be made for subjects that took the first intake of study 
medication at home. 
*3: The Outpatient phase will not be made for subjects that are still in hospital at the end date of the 
treatment phase 
*4: the start date and end date of hospitalization will be derived from the eCRF Hospitalization 
page. If the start date is not available, the start date of hospitalization will be the date of first 
treatment (as being hospitalized is an inclusion criterion in the protocol). If the end date is not 
available the date will be derived from the subject exposure domain as the last visit that is not 
‘Outpatient’ (in case no outpatient visit available in the exposure domain, the subject is assumed to 
be hospitalized during the entire treatment phase). Should a subject be discharged and again 
hospitalized during the treatment phase, the entire period will be regarded in the hospitalization 
phase. 
*5: In case the time part of the last medication intake is missing the imputed time part will be used 
 
In case the time part of first medication intake is missing and visit time point is 
available, the time will be imputed with 8:00 if the first medication was taken in 
the morning or with 20:00 if the first medication was taken in the evening. In case 
the time of the last medication intake is missing, the time part will be imputed 
with 8:00 if the last medication was taken in the morning or with 20:00 if the last 
medication 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 (last contact) or the cut-off date in case the data are analyzed for 
an interim analysis (whichever comes first). 
For phase allocation of trial termination, 23:59 will be used as time of trial 
termination (on the trial termination date) in the allocation rule.  
Assessments will be assigned to phases based on their date time, but seconds will 
be ignored overall. If 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 0:00 of 
the day of the assessment (except for Adverse Events see details in section 4.3.1). 
If the day part of the end date of the assessment is present but the time part is 
missing, the assessment will be treated as if it happened at 23:59 of the day of the 
assessment. 
The number of days in the study (reldy) will be defined as:  
reldy = visit day – reference day+1 
for visits on or after the reference day, and  
reldy = visit day – reference day  
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 15 of 53 
 
 
for visits before the reference, where the reference day equals the date of first 
study medication intake. 
 
3.1.2. Use of Unscheduled Assessments 
All scheduled assessments after first administration of trial medication 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 dose unscheduled assessments will be taken into account for worst-case 
determination.  
3.1.3. Analysis visits 
In general, AVISIT will be derived as the day of a scheduled visit, assessment or 
self-assessment (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 the PRO post-baseline assessments of the FLU-iiQTM and FLU-PRO 
questionnaires, AVISIT and AVISITN will be derived from the number of days in 
the study relative to the start of study treatment (reldy). Post-baseline assessments 
taken from 00:00 until 03:00 will be assigned to the day before (e.g. a recording 
on day 4 at 01:00 will be assigned AVISIT= Day 3). 
3.1.4. Analysis timepoints 
In general, for parameters that were assessed more than once daily, the analysis 
time point (ATPT) will the time point as reported in the database. 
For the PRO assessments of the FLU-iiQTM, all post-baseline records from day 1, 
03:01 until day 15, 03:00 will be assigned to an analysis time point (ATPT) using 
the following windows: morning = from 3:01 until 15:00 and evening = from 
15:01 until 03:00. The measurements taken from 00:00 until 03:00 will be 
assigned to the evening of the day before (e.g. a recording on day 4 at 01:00 will 
be assigned AVISIT= Day 3, ATPT=Evening). For all records from day 15, 03:01 
until the final study visit/Safety follow-up visit the analysis time point is the 
analysis visit. 
3.1.5. Use of records in case more than 1 record per analysis visit/time point 
PRO assessments of FLU-iiQTM and FLU-PRO:  
-  Questionnaires that have too many missing items (> 50% or for the FLU-PRO 
see Minimal data requirement rules) will not be used in the anlysis. This will 
also be applied for the determining the baseline questionnaire. 
- 
For derivation of FLU-iiQTM composite symptom score, composite impact 
scores (modules 2-4) and total composite impact score; FLU-PRO domain 
scores (6 domains) and FLU-PRO total score: 
If two or more records, for which a compostie, total or domain score can be 
calculated, are available within an analysis visit/analysis time point, only the 
records from the worst questionnaire1 will be used for the analyses. The worst 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 16 of 53 
 
 
questionnaire is the questionnaire with the highest score on an individual item. 
If 2 or more questionnaires have the same highest score on an individual item, 
the one with the highest average score over all items will be used (ignoring 
missing items). If two or more questionnaires also have the same average 
score, the one which came last in time will be used. 
1A “questionnaire” is the combination of 7 symptom items for the FLU-iiQTM composite 
symptom score; 6, 4 and 5 items for composite impact scores of module 2, module 3 and 
module 4 respectively and all 15 impact score items for the total composite impact score. 
Similarly, for FLU-PRO a questionnaire is the combination of the items needed to calculate 
the 6 different FLU-PRO domains scores and all 32 items of FLU-PRO for the total FLU-
PRO score. 
- 
For the analysis of the additional questions of the FLU-iiQTM and FLU-PRO, 
if two or more records are available within an analysis visit/time point, the 
record to be used will be determined per individual question. Per question, 
only the record with the worst1 result will be used for the tabulations. If the 2 
or more records have the same worst result, the one which came last in time 
will be used. 
1”Worst” is defined as the lowest score for the FLU-iiQTM additional questions and for FLU-
PRO additional questions 7, 8 and 9. “Worst” is defined as the highest score for FLU-PRO 
additional questions 1-6. 
3.1.6. Baseline Definitions 
In general, the baseline record is defined as the last record before the first intake 
of the study drug. (For programming purposes the last record before intake 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 the FLU-iiQTM and FLU-PRO questionnaire assessments, if a baseline record 
is not available, the baseline record is defined as the first available assessment 
within 2 hours after first intake of study drug. 
3.2. 
Analysis sets 
Population of the analyses covered by this SAP will be:  
■ Randomized Analysis Set (RAND): All randomized subjects with a 
randomization date at or before the date of first intake of medication, or 
with a randomization date and no medication intake.  
■ Randomized and/or Treated Analysis Set (RT): All randomized subjects 
and/or all subjects who received at least 1 dose of study drug. 
■ Safety Set or All Subjects Treated (AST): All subjects who received at least 
1 dose of study drug, analyzed as treated. 
■ Full Analysis Set (FAS): All randomly assigned subjects who receive at 
least 1 dose of study drug and who have a confirmed infection with 
influenza A. Confirmation of Influenza A will be obtained from virology 
data. If there are no virology data available at cut-off of the interim 
analysis, then a subject will be considered infected with Influenza A and 
included in the FA set. If there are no virology data available at final 
analysis, then a subject will be excluded from the FA set. Analyses on the 
Full Analysis Set will be analyzed as treated. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 17 of 53 
 
 
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 testing1 (lbtestcd = 
'INFAVLD') at baseline or pre-baseline;  
else  
 at least two positive PCR results from central lab testing1 (lbtestcd = 
'INFAVLD') post-baseline;  
else 
 at least one positive PCR result from central lab testing1 (lbtestcd = 
'INFAVLD') post-baseline and one positive PCR result from local lab 
testing (lbtestcd = 'INFVSCR') post-baseline, provided that both are 
from a separate visit day; 
else   
 at least one positive PCR result from local lab testing (lbtestcd = 
'INFVSCR') at baseline or pre-baseline, provided that no central lab 
testing is available at baseline or pre-baseline. 
else 
 at least two positive PCR results from local lab testing (lbtestcd = 
'INFVSCR') post-baseline, provided that no central, or local lab testing 
is available at baseline or pre-baseline, and no central lab testing is 
available post-baseline.  
1Viral load results from central lab testing ( lbtestcd = 'INFAVLD') recorded as ‘TARGET 
NOT DETECTED’ will be considered as negative, all other results (‘<2.18’ and numeric 
results) as positive.  
 
The Randomized and/or Treated Analysis Set (RT) will be used in all listings. The 
Safety Set (AST) will be used to perform the evaluation of all safety variables. 
The Full Analysis Set (FAS) will be used to perform the evaluation of all efficacy 
variables. 
3.3. 
 Definition of Subgroups 
The following two age categories (>=18 - <65 years, >= 65 - <= 85 years) are 
strata in the study and will also be used as subgroups for the subject information, 
safety and the efficacy analyses. 
For demographics, baseline disease characteristics andvirology the influenza 
subtype category (A/H1N1, A/H3N2 and Other) will be used as subgroup. 
3.4. 
Statistical Methods 
This SAP covers the statistical analysis for Interim and Final analyses. Details of 
the single displays are described in the Data Presentation Specifications (DPS).  
■ The analysis population will be indicated in the titles of the displays.  
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 18 of 53 
 
 
■ The footnote of the displays for the interim analysis will report the cut-off 
date of the data snapshot or the locked database that have been used for the 
analysis. 
■ All results will be presented per treatment group. Tables on subject 
disposition, 
exposure, 
demographic 
data 
and 
baseline 
disease 
characteristics will include a ‘Total’ treatment group, pooling all subjects.  
■ Tables, listings and figures will be made by age category (stratum) and 
overall. 
■ Listings will be presented by treatment group and ordered by subject 
number and time point (if applicable). 
■ All outputs should be self-explanatory and therefore appropriate footnotes 
will be provided to clarify the contents of each listing, table or graph. 
■ In case the X-axis of a graph shows a time component, the distances 
between the time points will be proportional (not equidistant). 
Furthermore, when statistics are joined over time by a line, the actual 
statistics will be depicted by means of a symbol. 
■ Unless specified otherwise, continuous parameters will be summarized 
using the following statistics: number of observations, mean, standard 
deviation, minimum, median and maximum. The mean and median will be 
presented with one decimal place, while the standard deviation with two 
decimal places more than the decimal places of the raw data. The 
minimum and maximum will be presented to the same number of decimal 
places as the raw data. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 19 of 53 
 
 
4. 
Analyses 
4.1. 
Subject Information 
All general analyses will be done on the Full Analysis Set and the Safety Set 
unless specified otherwise for a specific display. 
4.1.1. Subject disposition 
Summaries will be provided for the following disposition information: 
 Number of subjects screened, screening failures, not randomized, randomized 
set, randomized and not treated, randomized and/or treated, safety set, treated 
but not Influenza A and full analysis set  
 Number of subjects who completed/discontinued treatment and/or the trial, 
with the reasons of discontinuation.  
 Number of subjects with a visit at each scheduled analysis time point by 
phase. 
4.1.2. Summaries will be made overall and by age category, by treatment group (and 
overall).Demographics parameters and baseline disease characteristics 
All demographics and baseline disease characteristics will be summarized overall 
and by age category, by treatment group (and overall); and by influenza subtype 
category, by treatment group (and overall) 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, Other). 
The specification of the category ‘Other’ will only be listed. 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Country  
• 
Geographic region (based on country: North America (to include 
Puerto Rico), Europe, Asia-Pacific, South America) 
• 
Age (years and categories: >=18 - <65 years, >= 65 - <= 85 years) 
• 
Weight at baseline (kg) 
• 
Height at baseline (cm) 
• 
BMI at baseline = Weight at baseline (kg) / (Height at baseline (m))2 
(rounded to 1 decimal. Although available in the raw data, BMI will 
be recalculated from last weight and height measurement before start 
of treatment)  
• 
Site ID 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 20 of 53 
 
 
• 
Tobacco use: cigarettes, cigars, patches/gum, pipes, smokeless 
tobacco (Yes, No: including ex-smokers) 
• 
Childbearing Potential (only listed)  
 
 Baseline disease characteristics: 
• 
Influenza subtype category (A/H1N1, A/H3N2, other) 
• 
Baseline influenza A viral load (log10 copies/mL), assessed by qRT-
PCR  
• 
Baseline influenza A viral titer (log10 TCID50/mL) assessed by viral 
culture 
• 
Composite symptom score of the seven primary influenza symptoms 
at baseline from the FLU-iiQTM (as defined in section 4.2.3) 
• 
Baseline FLU-PRO total score (as defined in section 4.2.6) 
• 
NEW Score at baseline 
• 
Respiration rate at baseline 
• 
Arterial oxygen saturation at baseline 
• 
Supplemental oxygen at baseline (Yes, No)  
• 
Oral temperature (°C) at baseline 
• 
Systolic blood pressure at baseline 
• 
Heart rate at baseline 
• 
Level of consciousness at baseline 
4.1.3. Prior and Concomitant Medications 
Medications taken up to 7 days before first dose of study drug and up to the Final 
Study Visit/Safety Follow-up Visit will be summarized by preferred term using 
the World Health Organization-Drug Dictionary for the FA Set and the Safety Set 
as frequency tables in 2 parts:  
1. Prior medication: medication that started before the first dose of study 
drug, regardless of when dosing of the medication ended  
2. Concomitant medication: medication received at or after the first dose of 
study drug, medication that was received before initial dosing and 
continued after initial dosing of study drug, or medication with missing 
stop date. 
(Medication that started before the first dose of study drug and continued after the 
first dose of study drug will be summarized as prior medication and separately as 
concomitant medication.) 
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 and corticosteroids by ATC class and by hospitalization status 
(Yes/No). Tabulations of concomitant corticosteroids and antibiotics administered 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 21 of 53 
 
 
because of adverse events reported as influenza complications will also be made. 
Separate frequency tabulations will be made for antipyretic medication and 
oxygen supplementation. Antipyretic medication will be categorized as 
Paracetamol, Ibuprofen, or other. The table showing oxygen supplementation will 
be tabulated per analysis visit and phase. 
All tabulations will be created overall and by age group, by treatment group (and 
overall). 
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 date/times, 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. 
4.1.4. Medical history 
Medical history will only be listed.  
The influenza vaccination status will be tabulated by previous season, current 
season and both previous and current season (for subjects who got vaccinated in 
both seasons), overall and by age category, by treatment group (and overall). 
The use of antiviral influenza medication prior to hospitalization will be tabulated 
separately, overall and by age category, by treatment group (and overall). 
Influenza history will be listed, including information on first acute respiratory 
symptoms, influenza vaccination and previous antiviral influenza therapy. Pre-
treatment Influenza complications will also be listed. 
4.1.5. Treatment Exposure and Compliance 
The treatment duration is defined as date/time of last study drug intake – date/time 
of first study drug intake + 12 hours.  
Note: treatment interruptions will not be taken into account for the above 
definition. 
Dosing compliance is calculated as the actual number of doses taken, as a 
percentage of the planned number of doses. The actual number of doses taken will 
be derived from the exposure information (EX domain) during hospitalization and 
from the drug accountability information (DA domain) after discharge from 
hospital.  
In the exposure information the amount of medication administered during 
hospitalization is given per visit and time point, the actual number of 
tablets/capsules during hospitalization is the sum of this amount per medication 
for the records that are not outpatient records.  
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 22 of 53 
 
 
The actual amount of tablets/capsules taken after discharge will be derived from 
the drug accountability information as the difference between the drug 
dispensation at discharge and the returned amount (in case both amounts are 
known).  
The actual number of doses taken during the study is the sum of the actual number 
of medication taken during hospitalization and after discharge, for Placebo or 
JNJ872 this number needs to be divided by 2 as the study uses 300 mg tablets. In 
total, the planned number of medication is 28 tablets of Placebo or JNJ872 and 14 
capsules of Oseltamivir. Hence the planned number of doses per medication 
equals 14 doses.  
Actual treatment duration and dosing compliance will be summarized 
descriptively overall and by age category, by treatment group (and overall). 
4.2. 
Efficacy  
All efficacy analyses will be done on the full analysis set. Descriptive statistics 
will be used for all efficacy endpoints and will be tabulated by treatment group 
and by stratum age category (>=18 - <65 years, >= 65 - <= 85 years, overall). 
Derived parameters will also be listed. No formal statistical hypothesis testing will 
be performed.  
4.2.1. Clinical Outcomes 
 Incidence of influenza complications 
The incidence of influenza complications from first intake up to Day 28 will 
be categorized in a hierarchical fashion. The overall category will consist of 
any complication, consisting of the following subcategories  
 bacterial pneumonia (culture confirmed where possible), 
 other bacterial superinfections, 
 respiratory failure, 
 pulmonary disease: asthma, chronic obstructive pulmonary disease 
[COPD]), 
 cardiovascular and cerebrovascular disease (eg, myocardial infarction, 
congestive heart failure [CHF], arrhythmia, stroke), 
 post-baseline ICU admission, 
 all-cause mortality 
The occurrence (yes/no) of influenza complications from first intake up to Day 
28 of each (sub) category will be analyzed using logistic regression with 
treatment group as covariate. In case influenza complications occur in both 
age categories, age category will also be added as a covariate and as an 
interaction with treatment group. If the model will not fit the age category and 
it’s interaction will be removed. Odds ratios and associated 95% CIs will be 
reported of active vs. control treatment and – if available – of elderly patients 
vs. patients <65 years. 
 Time to improvement of vital signs 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 23 of 53 
 
 
The time to improvement of vital signs is defined as the time (in hours) from 
first study treatment until the first assessment (actual date and time) of a 
successive series of 3 recordings (over 4 scheduled successive analysis time 
points, 1 missing time point is allowed) where at least 4 of 5 symptoms 
(temperature, blood oxygen saturation, heart rate, SBP, respiration rate) are 
recovered, with at least normalization of temperature and blood oxygen 
saturation. Normalization is defined in Table 6. If subjects satisfy these criteria 
at entry they will be censored at that time.  
Only vital signs assessments assessed during hospitalization and up to Day 14 
(during hospitalization) will be taken into account to determine time to 
improvement of vital signs. Assessments taken after hospital discharge or after 
day 14, 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 cases where there are no sufficient recordings of clinical stability as defined 
above, the endpoint will be censored. Censoring will be at the first time of clinical 
stability, if and only if after this observation there is no recording of non-resolved 
influenza symptoms (ignoring missing recordings). If there are no recordings of 
resolved symptoms satisfying this criterion, the time of censoring is the first 
possible time point an assessment could have been 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). There are two 
exceptions: in case the last available vital signs record is on the day of discharge 
in the evening or on day 14 during hospitalization in the evening. If at this record 
(last record for the subject to be taken into account for time to clinical stability) 
there is no clinical stability, the time of the last assessment (day of discharge, 
evening or day 14, evening) will be taken as the time of censoring. 
The data will be presented using a Kaplan-Meier curve and Kaplan-Meier 
estimates by treatment group, overall and by age group.The time to event data 
will be modeled using the accelerated failure time model. The model will use 
the parametric shape, selected based on the goodness of fit criterion (AIC), 
and may take a Weibull, log-logistic, lognormal, or gamma distribution. Age 
category, NEW Score at baseline and treatment group will be included as 
covariatesIf the data don’t provide an acceptable model fit, alternatively a Cox 
proportional hazards model can be used (in case the hazards are proportional). 
In case a Cox proportional hazards model is used a Log-log plot of survival 
will be added to check the proportional hazard assumption. Additionally, the 
time to event data will be analyzed using the logrank test and the Gehan-
Wilcoxon method. 
Table 6: Resolution Criteria for Vital Signs 
Assessment  
Resolution Criterion 
Temperature 
Oral temperature ≤ 36.5 °C for elderly and  ≤ 37.2 °C for adults 
Oxygen saturation 
≥ 92% on room air without supplemental oxygen* 
Respiration rate 
≤ 24/min 
Heart rate 
≤ 100/min 
Systolic blood pressure 
≥ 90 mmHg 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 24 of 53 
 
 
*On room air to be obtained from “Was oxygen saturation measured on room air?” on Vital 
Signs pages (SUPPVS.QVAL for SUPPVS.QNAM = ‘VSOXSMRA’ 
 Time to improvement of respiratory status 
Time to improvement of respiratory status is defined as the time (in hours) 
from first study treatment until the first assessment (actual date and time) of a 
successive series of 3 recordings (over 4 scheduled successive analysis time 
points, 1 missing time point is allowed) where normalization of blood oxygen 
saturation and respiration rate occurred (as defined in Table 6). Analysis 
performed will be analogous to the analysis for the time to improvement of 
vital signs. Note that the NEW Score at baseline should not be added as 
covariate in the models. 
 Clinical outcome on day 8 
The ordinal scale consists of 6 categories that are exhaustive, mutually 
exclusive, and ordered (Table 7). For all patients, the category at days 1 to 15 
will be established as the worst category on that day. The clinical outcome on 
day 8 will be further analyzed. 
The analysis of the clinical outcome on day 8 will be performed using a 
proportional odds model, modeling the common odds ratio of the 
improvement on the ordinal scale of active treatment versus control. Age 
category (>=18 - <65 years, >= 65 - <= 85 years) and baseline clinical 
outcome category will be added to the model. In case the model will not fit, 
age category and subsequently baseline category will be deleted.  
In case of missing data (>10%), multiple imputation under the missing-at-
random assumption will be employed as a sensitivity analysis. 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 15). The number of imputation datasets will be 
the same as the percentage of missing data (White et al. 2011). A monotone 
ordinal logistic regression imputation model will be used to complete the 
remaining missing clinical outcomes. 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.  
Additionally a Wilcoxon–Mann–Whitney test will be performed to compare 
the clinical outcome on day 8 between the two treatments.   
 
Table 7: Ordinal scale on Day 8 
Outcome 
Death 
Admitted to ICU or mechanically ventilated/ECMO 
Non-ICU + supplemental oxygen 
Non-ICU + no supplemental oxygen 
Not hospitalized, but unable to continue activity 
Not hospitalized and continues activities 
ECMO = extracorporeal membrane oxygenation; ICU = Intensive Care Unit 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 25 of 53 
 
 
4.2.2. Viral Kinetics 
Influenza viral load and viral titer will be determined and quantified in Nasal MT 
swab samples taken daily until discharge or until Day 14, whichever comes first. 
When subjects are discharged from the hospital and still positive for influenza A 
virus, they are encouraged to perform self-swabbing at home if practically 
feasible. All swabs will be analyzed using quantitative real time polymerase chain 
reaction (qRT-PCR) and/or viral culture (TCID50) and/or PCR-based rapid 
molecular testing (if applicable). 
All analyses described below, will be done on the qRT-PCR and viral culture 
results from central lab testing. As a sensitivity analysis, time to viral negativity 
will also be evaluated on a combination of the qRT-PCR results from central 
testing with the local rapid influenza test results (at home or on site) of days on 
which the results from central lab testing were missing. 
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 time point. As a 
consequence the results of a subject can be a combination of both methods (for 
example at baseline the NP ELISA result is used and at day 4 the 
Hemagglutination Inhibition Assay result is used). 
Viral load results recorded as ‘TARGET NOT DETECTED’ will be considered as 
negative, all other results (‘<2.18’ and numeric results) as positive. Viral titer 
results recorded as ‘<0.75’ will be considered as negative, all other results as 
positive. 
For analysis purposes the log10 qRT-PCR viral load will be imputed with 2.12 
when the result is ‘<2.18’ (i.e. below limit of quantification) and with 0 if result is 
‘TARGET NOT DETECTED’ (i.e. below limit of detection: <2.05). The log10 
TCID50 viral titer will be imputed with 0.375 when the result is ‘<0.750’.  
 Viral load and viral titer actual values and change from baseline 
Descriptive statistics and mean (SE) plots will be shown for the log10 values 
of viral load and viral titer (qRT-PCR and viral culture) and the changes from 
baseline calculated in log10 (vp/mL or TCID50/mL). 
 Incidence of influenza A viral negativity by assessment  
The proportion of subjects with a negative viral load and a negative viral titer 
will be tabulated at each time point.In addition, per parameter and time point a 
logistic model with baseline viral load/viral titer and age category (>=18 - <65 
years, >= 65 - <= 85 years) as covariates will be used to obtain the odds ratios 
(95% CI) for the comparison of the incidence of influenza A viral negativity 
of treatment versus placebo.   
Stacked barcharts of the percentage of subjects per response category will be 
made by day and treatment for viral load and viral titer. The following 
response categories will be used: 
 For viral load (log10 vp/mL) measurements: 
o Target not detected (<2.05 log10 vp/mL) 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 26 of 53 
 
 
o Target detected (<2.18 log10 vp/mL) 
o Quantifiable (≥2.18 log10 vp/mL) 
 For viral titer (log10 TCID50/mL) measurements: 
o Negative (<0.75 log10 TCID50/mL) 
o Positive (≥0.75 log10 TCID50/mL) 
 
 Time to influenza A viral negativity  
 
The time to influenza A viral negativity will be determined based on nasal MT 
swabs: a subject will be considered influenza A viral negative at the time point 
that the first confirmed negative nasal MT swab was recorded (in days) i.e. 
defined as time in days from start of treatment to first of assessments 
=’negative’ and the next assessed measurement is not =’positive’(ignoring 
missings, i.e. if first ‘negative’ is last available assessment or if next assessed 
result after first ‘negative’ is also ‘negative’). If this doesn’t occur, a subject 
will be censored at the time of the last observed nonnegative swab + 1 day. 
Note that at baseline every subject is considered positive.  
 
This will be done separately for viral load and viral titer assessments from 
central lab testing. As a sensitivity analysis, time to negativity will also be 
evaluated on a combination of qRT-PCR results from central lab testing and 
rapid influenza test results (from self or on site swabs). The available central 
lab qRT-PCR results (qualitative) will be complemented with the results of the 
rapid influenza tests that are available on days where central lab testing results 
are not available. 
 
The time to influenza A viral negativity will be presented using Kaplan-Meier 
curves and Kaplan-Meier estimates by treatment group, overall and by age 
group. For a comparison between treatment arms, the time to influenza A 
viral negativity will be analyzed using an accelerated failure time model. The 
accelerated failure time model will use a Weibull, log-logistic, lognormal or 
gamma distribution based on goodness of fit criteria (AIC). As covariates the 
baseline viral load and the age category (>=18 - <65 years, >= 65 - <= 85 
years) will be included. If the data don’t provide an acceptable model fit, 
alternatively a Cox proportional hazards model can be used (in case the 
hazards are proportional). In case a Cox proportional hazards model is used a 
Log-log plot of survival will be added to check the proportional hazard 
assumption. Additionally, the time to event data will be analyzed using the 
logrank test and Gehan-Wilcoxon method. 
 Viral AUC calculated from baseline to Day 8  
The viral AUC, calculated separately for viral load and viral titer, from 
baseline to Day 8 will be estimated for each treatment arm using a mixed 
model for repeated measurements, i.e., the AUC will not be calculated for 
each subject and then analyzed, but the AUC will be calculated for each 
treatment arm using log10 transformed viral load data over time of each 
subject. This approach ensures an optimal approach towards missing data.  
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 27 of 53 
 
 
Baseline and post-baseline mean viral load values over time (at time points 
Day 1 to 5 and Day 8) will be analyzed using a restricted maximum likelihood 
based repeated measures approach using a constrained longitudinal data 
analysis. The analysis model will include the fixed, categorical effects of visit, 
treatment-by-visit interaction, age category-by-visit interaction and treatment-
by-visit-by age category 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] 
The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom.  
The area under the viral load curve (viral AUC) will be based on the Full 
Analysis set. The model estimates from the model above will be used to 
estimate the viral AUC for each treatment and to derive the difference in the 
viral AUCs for active versus placebo, overall and by age category.  
A mean ±95% CI plot will also be provided for the estimated viral load and 
estimated viral titer over time. 
 Rate of decline of viral load and viral titer   
The rate of decline in quantitative viral load (log10 vp/mL per day) and 
quantitative viral titer (log10 TCID50/mL per day) will be estimated per 
treatment through a linear mixed model with repeated measures. Treatment 
and age group will be added as categorical effects, time will be added as a 
continuous covariate and the interactions between treatment and time, age 
group and treatment, and age group and time will also be added. The model 
will be fit with a random intercept and a random slope. In case the model will 
not fit, age category and interaction terms with age group will be deleted. 
 Peak viral load and peak viral titer  
The peak viral load/viral titer is defined as the highest value of viral load/viral 
titer during treatment and follow-up (including the baseline value) calculated 
as log10 (vp/mL or TCID50/mL). For the peak viral load/ viral titer a 
geometric mean ratio (GMR) will be derived using a general linear model 
including treatment group, age category and the interaction of both. 
Descriptive statistics will be provided by treatment group, overall and by age 
group. 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 28 of 53 
 
 
4.2.3. Influenza Symptom Score (FLU-iiQTM Module 1) 
The influenza symptom score (Flu-iiQTM Modules 1) will be assessed 2 times a 
day, from study entry (Baseline, Day 1) through Day 14, and once daily from 
Days 15 through Day 28 (Safety Follow-up Visit).  
 Composite symptom score 
The subject’s composite symptom score per datetime is defined as the mean of 
the corresponding non-missing 7 primary influenza symptoms of the Flu-
iiQTM (cough, sore throat, headache, nasal congestion, feeling feverish, body 
aches or pains, and fatigue (tiredness)) on a 0-3 scale calculated for each 
datetime the questionnaire was filled. For each time point a change from 
baseline will be calculated. 
An alternative composite symptom score will be calculated using all 10 
influenza symptoms included in Module 1 of the Flu-iiQTM instrument. 
If more than 50% of the items to construct a Composite symptom score are 
missing, the value for that composite score is coded as missing (i.e. 4 or more 
items missing for the primary symptom composite score and 6 or more items 
missing for the composite score based on all 10 items).  
The actual composite symptom scores and changes from baseline will be 
shown descriptively and by mean (SE) plots per analysis timepoint. 
 Daily average symptom score 
For the Flu-iiQ™ a daily average symptom score will be derived averaging 
the composite symptom scores (based on 7 primary and all 10 items 
respectively) per day over all post-baseline analysis timepoints. Also a total 
average symptom score over the daily averages of the composite symptom 
score will be calculated. The baseline value of the daily average symptom 
score will be the baseline score of the respective individual influenza 
symptom score or the composite symptom score..  
The daily averages of the composite symptom scores will be shown 
descriptively and by mean (SE) plots. The total average composite symptom 
score will be shown descriptively. 
 
 Time to Resolution of Influenza 
Resolution of influenza symptoms is defined as the first of a successive series 
of 2 recordings in which all symptom scores for each of the 2 assessments are 
0 or 1 for all 7 primary influenza symptoms of the Flu-iiQTM (cough, sore 
throat, headache, nasal congestion, feeling feverish, body aches or pains, and 
fatigue (tiredness)). If the first record of a successive series of 2 recordings of 
resolved influenza is before day 14 in the evening then the 2 successive 
recording should have been done over 3 scheduled successive analysis 
timepoints, 1 missing timepoint is allowed. If the first record of a successive 
series of 2 recordings of resolved influenza is at or after the evening record of 
Day 14 then the 2 successive recordings should have been done within 2 
scheduled successive analysis timepoints (no missing allowed).  
In cases where there are no sufficient recordings of resolved influenza as 
defined above, the endpoint will be censored. Censoring will be at the first 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 29 of 53 
 
 
time of resolved influenza symptoms, if and only if after this observation 
there is no recording of non-resolved influenza symptoms (ignoring missing 
recordings). If there are no recordings of resolved symptoms satisfying this 
criterion, the time of censoring is the first possible time point a diary entry 
could have been made after the last observation of the presence of influenza, 
which is 20:00 on the same day if the last observation was a morning diary 
entry (from 3:01 until 15:00), 8:00 the next day if the last entry was an 
evening diary (from 15:01 until 03:00) (Day 1 until Day 14, morning). If the 
last observation of the presence of influenza is on Day 14 in the evening or 
after day 14 then the time of censoring is the time of the last diary entry + 24 
hours. One exception is censoring at the Day 28 Visit (last study day for the 
subject). If the subject is not recovered on this day, the time of the last diary 
entry will be taken as the time of censoring. 
Subjects who discontinue the study before resolving influenza symptoms and 
have an adverse events being reported as influenzacomplication ongoing on 
the day of discontinuation of the study will be censored at day 28, 20:00.  
For this endpoint the difference of active dosing regimen versus placebo will 
be estimated using the accelerated failure time model. The model will use the 
parametric shape, selected based on the goodness of fit criterion (AIC), and 
may take a Weibull, log-logistic, lognormal, or gamma distribution. As 
baseline covariates the baseline composite score and age category (>=18 - <65 
years, >= 65 - <= 85 years) will be included. From this model the ratio of 
adjusted geometric means and the 95% confidence interval will be derived 
comparing the active treatment versus placebo. 
The Kaplan-Meier estimates will be tabulated and a figure with the Kaplan-
Meier curves of the time to resolution of influenza symptoms will be added by 
treatment group, overall and by age group. 
One stratified Cox proportional hazard model will be used to derive the 
Hazard Ratio for the active treatment in comparison to placebo. A Log (-Log) 
plot of survival will be added to check the proportional hazard assumption. 
Additionally, the time to event data will be analyzed using the logrank test 
and the Gehan-Wilcoxon method. 
All analyses of Time to Resolution of Influenza will also be repeated using all 
10 influenza symptoms included in Module 1 of the Flu-iiQTM instrument.  
Kaplan-Meier curves will also be provided for each individual influenza 
symptom separately. 
 Time to Definitive Resolution of Influenza 
Time to definitive resolution is defined as the first of a successive series of 2 
recordings in which all symptom scores for each of the 2 assessments are 0 or 
1 for all 7 primary influenza symptoms of the Flu-iiQTM (cough, sore throat, 
headache, nasal congestion, feeling feverish, body aches or pains, and fatigue 
(tiredness)) AND after which all following assessments also indicate 
resolution (all symptom scores 0 or 1 for all 7 primary influenza symptoms) or 
are missing.  
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 30 of 53 
 
 
Definitions for a successive series of 2 recordings over time are the same as 
for the Time to Resolution of Influenza. Also censoring will be done similarly 
as for the Time to Resolution of Influenza. 
The Time to Definitive Resolution of Influenza will be analyzed similarly as 
the Time to Resolution of Influenza. 
 Composite symptom score AUC:  
The composite symptom score AUC will be calculated using the daily average 
symptom scores, from baseline to Day 8 and will be estimated for each 
treatment arm using a mixed model for repeated measurements, ie, the AUC 
will not be calculated for each subject and then analyzed, but the AUC will be 
calculated for each treatment arm using the daily average symptom scores 
over time of each subject. This approach ensures an optimal approach towards 
missing data.  
Baseline and post-baseline daily average symptom scores over time will be 
analyzed using a restricted maximum likelihood based repeated measures 
approach and using a constrained longitudinal data analysis. The analysis 
model will include the fixed, categorical effects visit, treatment-by-visit 
interaction, age category-by-visit interaction and treatment-by-visit-by age 
category 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] 
The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom.  
The composite symptom score AUCs until Day 8 will be based on the Full 
Analysis set. The model estimates from the model above will be used to 
estimate the composite symptom score AUCs for each treatment and to derive 
the difference in the composite symptom score AUCs for active versus 
placebo overall and by age category.  
A mean ±95% CI plot will also be provided for the estimated average 
symptom scores over time. 
 
4.2.4. Impact of Influenza (Flu-iiQTM Modules 2, 3, 4) 
The impact of influenza (Flu-iiQTM Modules 2, 3, 4) will be assessed 2 times a 
day, from study entry (Baseline, Day 1) through Day 14, and once daily from 
Days 15 through Day 28 (Safety Follow-up Visit).  
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 31 of 53 
 
 
 Composite impact score 
Per datetime and per module (modules 2, 3 and 4) of the FLU-iiQTM 
questionnaire a composite impact score will be calculated as the mean of the 
non-missing items in each module respectively on a 0-3 scale. Additionally a 
“total composite impact score” will be calculated as the mean of all non-
missing items over all 3 impact score modules together (15 questions). For 
each time point and composite impact score (module 2, 3,4 and total) a change 
from baseline will be calculated.If more than 50% of the items to construct a 
Composite Impact Score are missing, then the value for that composite score 
for that individual and time point is coded as missing (i.e. 4 or more items 
missing for module 2, 3 or more items missing for module 3, 3 or more items 
missing for module 4 and 8 or more items missing for the total composite 
impact score). 
The composite impact scores will be shown descriptively and by mean (SE) 
plots per analysis time point. 
 Daily average impact score 
For the impact modules of the FLU-iiQTM questionnaire a daily average of the 
composite impact scores (for modules 2,3,4 and total) and a total average 
score over the daily averages of the composite impact scores (for modules 
2,3,4 and total) will be calculated similar to the daily average symptom scores 
above. 
The daily averages of the composite impact scores will be shown descriptively 
and by mean (SE) plots. The total average composite impact scores will be 
shown only descriptively. 
 Time to resumption of normal activities (usual activities,  emotional impact and 
impact on others)  
Per module of the FLU-iiQTM questionnaire on the impact of influenza a time 
to resumption of normal activities is defined as the time in hours from the first 
dose of investigational product till the first one of a successive series of 2 
recordings where all scores in the FLU-iiQ Module are reported as “no 
difficulty” (Module 2: usual activities), “not at all” (Module 3: emotional 
impact) or “not at all concerned” (Module 4: impact on others). If the first 
record of a successive series of 2 recordings of resumption of normal activities 
is before day 14 in the evening then the 2 successive recording should have 
been done over 3 scheduled successive analysis timepoints, 1 missing 
timepoint is allowed. If the first record of a successive series of 2 recordings 
of resumption of normal activities is at or after the evening record of Day 14 
then the 2 successive recording should have been done within 2 scheduled 
successive analysis time points.  
Censoring will be done similar to the time to resolution of influenza, taking 
into account the possible time points a diary entry could have been made after 
the last observation of difficulties in usual activities, which is 20:00 on the 
same day if the last observation was a morning diary entry and 8:00 the next 
day if the last entry was an evening diary entry (Day 1 until Day 14, morning). 
If the last observation of difficulties in usual activities is on Day 14 in the 
evening or after Day 14 then the time of censoring is the time of the last diary 
entry + 24 hours. One exception: if no resumption of usual activities is 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 32 of 53 
 
 
observed at Day 28, the time of the last diary entry will be taken as the time of 
censoring 
Data will be presented using Kaplan-Meier curves and Kaplan-Meier 
estimates by treatment group, overall and by age group. For a comparison 
between treatment arms, the time to parameters will be analyzed using an 
accelerated failure time model. The model will use the parametric shape, 
selected based on the goodness of fit criterion (AIC), and may take a Weibull, 
log-logistic, lognormal, or gamma distribution. As baseline covariates the 
respective baseline composite impact scores and age category (>=18 - <65 
years, >= 65 - <= 85 years) will be included. If the data don’t provide an 
acceptable model fit, alternatively a Cox proportional hazards model can be 
used (in case the hazards are proportional). In case a Cox proportional hazards 
model is used a Log-log plot of survival will be added to check the 
proportional hazard assumption. Additionally, the time to event data will be 
analyzed using the logrank test and Gehan-Wilcoxon method. 
4.2.5. FLU-iiQTM Additional Daily Diary Items 
For the 5 additional daily diary items of FLU-iiQTM frequency distributions of the 
number (%) of subjects per additional FLU-iiQTM  item and per response category 
will be shown at baseline and all post-baseline assessments, per treatment group. 
4.2.6. Influenza Patient Reported Outcome Diary (FLU-PRO) 
 FLU-PRO total score and FLU-PRO domain scores 
The FLU-PRO total score is computed as a mean score across 32 items 
contained by the instrument. Total scores can range from 0 (symptom free) to 
4 (very severe symptoms). 
Six FLU-PRO domain scores are computed, representing symptom severity in 
each of the following body areas: Nose, Throat, Eyes, Chest/Respiratory, 
Gastrointestinal and Body/Systemic. Each domain score is calculated as the 
mean of all items comprising the domain, see also Table 8. Each FLU-PRO 
domain score ranges from 0 to 4.  
These scores will be calculated at each time point a questionnaire was filled. 
A change from baseline will also be calculated. 
The FLU-PRO scores and changes from baseline will be presented 
descriptively over time. 
Table 8: FLU-PRO domain scores 
Domain 
Items 
Scoring and 
Minimum Data Requirement 
Nose 
Runny or dripping nose 
Congested or stuffy nose 
Sneezing  
Sinus pressure  
Arithmetic mean of 4 items  
Daily score for 3 of 4 items must be 
present to calculate domain score 
Throat 
Scratchy or itchy throat 
Sore or painful throat 
Difficulty swallowing 
Arithmetic mean of 3 items  
Daily score for 2 of 3 items must be 
present to calculate domain score 
Eyes 
Teary or watery eyes 
Sore or painful eyes 
Eyes sensitive to light 
Arithmetic mean of 3 items  
Daily score for 2 of 3 items must be 
present to calculate domain score 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 33 of 53 
 
 
Chest/Respiratory 
 
Trouble breathing 
Chest congestion 
Chest tightness 
Dry or hacking cough 
Wet or loose cough 
Coughing 
Coughed up mucus or phlegm 
Arithmetic mean of 7 items  
Daily score for 5 of 7 items must be 
present to calculate domain score 
Gastrointestinal 
Felt nauseous 
Stomach ache 
Vomit (frequency)  
Diarrhea (frequency) 
Arithmetic mean of 4 items  
Daily score for 3 of 4 items must be 
present to calculate domain score 
Body/Systemic 
Headache 
Head congestion 
Felt dizzy 
Lack of appetite 
Sleeping more than usual 
Body aches or pains 
Weak or tired 
Chills or shivering 
Felt cold 
Felt hot 
Sweating 
Arithmetic mean of 11 items  
Daily score for 8 of 11 items must be 
present to calculate domain score 
Total 
All above 32 items 
Arithmetic mean of all 32 items within 
FLU-PRO  
In the presence of missing data, the above 
conditions for the calculation of all domain 
scores must be met in order to calculate the 
FLU-PRO total score. 
Note: The FLU-PRO questionnaire handled according to the protocol is FLU-PRO version 1.0. 
The calculation of the Total score is done according to the FLU-PRO user manual version 1.1. 
Hence following questions from the FLU-PRO v1.0 questionnaire will not be used in the analysis: 
Swollen throat, Difficulty staying asleep, Difficulty falling asleep, Felt lightheaded, Felt 
uncomfortable (general discomfort). 
 
 FLU-PRO total score AUC  
The FLU-PRO total score AUC will be calculated using the FLU-PRO total 
scores, from baseline to Day 8 and will be estimated for each treatment arm 
using a mixed model for repeated measurements using a constrained 
longitudinal data analysis model, similarly as for the composite symptom 
score AUC in section 4.2.3.  
 Time to return to usual activity and time to return to usual health  
The time to return to usual activity and the time to return to usual health are 
defined as the time in hours from the first dose of investigational product till 
the first one of 2 successive cases where the response is ‘Yes’ on respectively 
FLU-PRO additional question 7 and FLU-PRO additional question 9. Missing 
data within the series are allowed as long as within three successive planned 
recordings there is at most 1 recording missing.   
 
In cases where there are no sufficient recordings of return to usual 
activity/health as defined above, the endpoint will be censored. Censoring will 
be at the first time of return to usual activity/health, if and only if after this 
observation there is no recording of difficulties in usual activities/health  
(ignoring missing recordings). If there are no recordings of return to usual 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 34 of 53 
 
 
activity/health satisfying this criterion, the time of censoring is the time of the 
last diary entry + 24 hours. One exception is censoring at the Day 28 Visit 
(last study day for the subject). If the subject is not returned to usual 
activity/health on this day, the time of the last diary entry will be taken as the 
time of censoring. 
Data will be presented using Kaplan-Meier curves and Kaplan-Meier 
estimates by treatment group, overall and by age group. For a comparison 
between treatment arms, the time to parameters will be analyzed using an 
accelerated failure time model. The model will use the parametric shape, 
selected based on the goodness of fit criterion (AIC), and may take a Weibull, 
log-logistic, lognormal, or gamma distribution. As baseline covariates the 
ordinal scale at baseline category (ICU, ward+O2, ward-O2) and the age 
category (>=18 - <65 years, >= 65 - <= 85 years) will be included.   If the data 
don’t provide an acceptable model fit, alternatively a Cox proportional hazards 
model can be used (in case the hazards are proportional). In case a Cox 
proportional hazards model is used a Log-log plot of survival will be added to 
check the proportional hazard assumption. Additionally, the time to event data 
will be analyzed using the logrank test and Gehan-Wilcoxon method. 
 Time to significant reduction in influenza symptom severity. 
The time to significant reduction in influenza symptom severity (to mild or 
none for all influenza symptoms) is defined as time in hours from the first 
dose of investigational product until the first of 2 successive recordings in 
which the total score for each of the 2 recordings are lower or equal to 1 and 
all the domain scores are lower or equal to 1. The 2 successive recordings 
should have been done within 3 scheduled successive analysis timepoints (one 
missing in between is allowed).  
Censoring will be done similar to the FLU-PRO time to return to usual activity 
and time to return to usual health as specified above. 
.  
Data will be presented using Kaplan-Meier curves and Kaplan-Meier 
estimates. For a comparison between treatment arms, the time to significant 
reduction in influenza symptom severity will be analyzed using an accelerated 
failure time model. The model will use the parametric shape, selected based 
on the goodness of fit criterion (AIC), and may take a Weibull, log-logistic, 
lognormal, or gamma distribution. As baseline covariate the age category 
(>=18 - <65 years, >= 65 - <= 85 years) and baseline FLU-PRO total score 
will be included. If the data don’t provide an acceptable model fit, 
alternatively a Cox proportional hazards model can be used (in case the 
hazards are proportional). In case a Cox proportional hazards model is used a 
Log-log plot of survival will be added to check the proportional hazard 
assumption. Additionally, the time to event data will be analyzed using the 
logrank test and Gehan-Wilcoxon method. 
 Proportion of patients with a significant reduction in influenza symptom 
severity.  
The proportion of subjects with a significant reduction in symptom severity 
(the total score for each of the 2 recordings are lower or equal to 1 and all the 
domain scores are lower or equal to 1) at each assessment will be tabulated. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 35 of 53 
 
 
4.2.7. FLU-iiQTM Additional Daily Diary Items 
For the 9 additional daily diary items of FLU-PRO frequency distributions of 
the number (%) of subjects per additional FLU-PRO   item and per response 
category will be shown at baseline and all post-baseline assessments, per 
treatment group. 
4.2.8. Correlation between viral load, viral titer and changes in clinical symptoms  
 Correlation between the decline in viral load, the decline in viral titer and 
clinical symptoms  
The time to influenza A viral negativity (see definition in section 4.2.2) 
measured by viral load and viral titer will be correlated with the following 
clinical measures (see definitions in sections 4.2.3 and 4.2.6):  
1. Time to resolution of symptoms (7 primary symptoms) 
2. Time to resolution of symptoms (All symptoms) 
3. Time to return to usual activity,  
4. Time to return to usual health and  
5. Time to significant reduction in influenza symptom severity  
 
Scatter plots with smoother curve will be shown per treatment group for the 
above mentioned correlations. An additional table will be provided showing 
the spearman correlation coefficients. 
 Correlation between the viral load, viral titer and severity of clinical 
symptoms  
The post-baseline log10 values of viral load and post-baseline log10 values of  
viral titer from day 2 to day 7 will be correlated with the following severity of 
clinical symptoms (see definitions in sections 4.2.3 and 4.2.6):  
1. Flu-iiQ™ daily average symptom score post-baseline from day 2 to 
day 7 
2. FLU-PRO total score post-baseline from day 2 to day 7 
Scatter plots with smoother curve will be shown per treatment group for the 
above mentioned correlations. An additional table will be provided showing 
the spearman correlation coefficients.  
 Correlation between baseline viral load, baseline viral titer and clinical 
symptoms  
The baseline viral load and baseline viral titer will be correlated with the 
following clinical measures (see definitions in sections 4.2.3 and 4.2.6):  
1. Time to resolution of symptoms (7 primary symptoms) 
2. Time to resolution of symptoms (All symptoms) 
3. Time to return to usual activity,  
4. Time to return to usual health and  
5. Time to significant reduction in influenza symptom severity  
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 36 of 53 
 
 
Scatter plots with smoother curve will be shown per treatment group for the 
above mentioned correlations. An additional table will be provided showing 
the spearman correlation coefficients. 
 
4.2.9. Other Outcomes 
 Time to hospital discharge 
The time to hospital discharge will be calculated from the date of first study drug 
intake during hospitalization up to the date of discharge. Subjects still hospitalized 
at the end of the study (end date of hospitalization missing or after trial 
termination) will be censored at the trial termination date.  
Data will be presented using Kaplan-Meier curves and Kaplan-Meier estimates. 
For a comparison between treatment arms, the time to hospital discharge in days 
will be analyzed using an accelerated failure time model. The model will use the 
parametric shape, selected based on the goodness of fit criterion (AIC), and may 
take a Weibull, log-logistic, lognormal, or gamma distribution. As baseline 
covariate the age category (>=18 - <65 years, >= 65 - <= 85 years) will be 
included. If the data don’t provide an acceptable model fit, alternatively a Cox 
proportional hazards model can be used (in case the hazards are proportional). In 
case a Cox proportional hazards model is used a Log-log plot of survival will be 
added to check the proportional hazard assumption. Additionally, the time to 
event data will be analyzed using the logrank test and the Gehan-Wilcoxon 
method. 
4.3. 
Safety 
All safety analyses will be done on the Safety Set. Analyses will be presented 
overall and by age category and by treatment group.  
 
4.3.1. Adverse events 
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 through the 28-day Safety Follow-up Visit. 
Adverse events with a start date and time recorded will be allocated based on their 
start date and time. If there is no time recorded for the start of the adverse event 
the adverse event that occurred on or after the day of first treatment intake and not 
after the 28-day safety follow up visit will be considered as treatment-emergent. 
Only adverse events that occur before the day of first medication intake and 
after/on the day of signing ICF will be considered as pre-treatment. 
In case the start date of an adverse event is partially or completely missing, a 
worst case allocation will be done using the available date and time information in 
the start and end date time of the adverse event (i.e. if possible based on the 
available information the adverse event will be allocated to the treatment phase 
and hospitalization sub period).    
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 37 of 53 
 
 
 
 Adverse events 
The variables related with adverse events are 
 
AE term (verbatim and MedDRA  preferred term and system organ class) 
 
Onset date, End date and duration of AE 
 
Serious AE (Yes/No) 
 
Severity (Mild, Moderate, Severe, Life threatening) 
 
Action taken towards study treatment (Dose increased, Dose not changed, 
Dose reduced, Dose interrupted, Drug withdrawn) 
 
Relation to study treatment (Not related, Doubtful, Possible, Probable, 
Very likely) 
 
Outcome of AE 
 
AE leading to death (Yes/No) 
 
Concomitant treatment taken (Yes/No) 
 
Influenza-related complication (Yes/No) 
 
Anticipated AE (Yes/No) 
 
Required hospitalization/prolonged hospitalization (Yes/No) 
 
The adverse events will be shown by MedDRA system organ class and preferred 
term, in order of descending overall frequency.  
Summaries of TEAEs will be presented overall and by the severity of the AE and 
relationship to the study drug.  
AEs leading to death, SAEs, AEs leading to dose interruption, and AEs leading to 
permanent discontinuation will be listed separately. All AEs through the Safety 
Follow-up Visit will be listed in an individual subject data listing, including pre-
treatment AEs. Spontaneous adverse events reported after the Safety Follow-up 
Visit, including unresolved, ongoing adverse events will be listed as well.  
 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. 
For the purposes of this study the following events will be considered anticipated 
events (see Appendix 1 for the classification of AEs into Anticipated Events and 
Anticipated Event Groups): 
 Bacterial 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) 
Frequency tabulations of anticipated events and anticipated event groups will be 
shown by treatment. The Incidence of Treatment Emergent anticipated events will 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 38 of 53 
 
 
be compared between active treatment versus placebo by a one-sided Fisher exact 
test (significance level < 0.10). 
 Influenza-related complications 
Adverse Events reported as influenza-related complications will be tabulated 
overall and by category and adverse event. A listing showing the AEs reported as 
influenza-related complications and complication information will be made 
linking the information to the AE listing. 
The categories of influenza related complications as recorded on the eCRF are: 
 Bacterial Pneumonia  
 Bacterial Superinfections, 
 Respiratory Failure, 
 Pulmonary Disease  
 Cardiovascular and Cerebrovascular Disease. 
 Other 
 
4.3.2. Clinical laboratory tests 
Laboratory parameters of hematology, serum chemistry and urinalysis will be 
investigated: All analyses will be done on SI-converted values as available in the 
database. 
In case a laboratory test result is censored (no numeric value is available, but only 
a verbatim term), the following rules are applied: 
● ‘<x’ or ‘>x’: a numeric value will be imputed by a value exceeding 
the cut-off value with one unit 
● ‘≤x’ or ‘≤x’: imputation by x. 
The laboratory abnormalities will be determined according to the criteria specified 
in the WHO grading table (see Appendix 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 the following rules are applied: 
• Worst grades/abnormalities are determined over the whole observational 
period for each trial phase separately, including all post-reference 
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-reference, both abnormalities are 
shown in the tables. (This means that the sum of the percentages can be 
more than 100%) 
• If, for a specific test, the grading list provides distinct limits for 
abnormally low (=hypo) values as well as for abnormally high (=hyper) 
values, this test should be repeated for hyper and hypo limits separately in 
cross-tabulations. 
Actual values and change from baseline will be summarized by treatment group at 
each scheduled time point. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 39 of 53 
 
 
An abnormality (toxicity grade or abnormality based on normal ranges) will be 
considered treatment-emergent in a particular phase if it is worse than the 
reference corresponding to this phase. If the reference is missing, the abnormality 
is always considered as treatment-emergent.  A shift from “abnormally low” at 
reference to “abnormally high” post reference (or vice versa) is also treatment-
emergent. The treatment emergent definition is applicable in both, the treatment 
and follow-up phase. 
The number and percentage of subjects will be shown in a cross-tabulation of the 
toxicity/abnormality post-baseline versus baseline at each scheduled time point. 
Additionally, a cross-tabulation of the worst toxicity/abnormality versus baseline 
will be presented per phase (Treatment phase, Follow-up phase) and for the 
combination of Treatment and follow-up phase. This table will also show the 
number and percentage of subjects per worst toxicity/abnormality, the number and 
percentage of subjects per treatment-emergent worst toxicity/abnormality, and the 
cumulative number of subjects per treatment-emergent toxicity/abnormality or 
worse. 
Mean ± SE graphs over time for the actual values and changes from reference will 
be generated for all tests performed.   
A listing of abnormal individual subject hematology and clinical chemistry values 
from scheduled and unscheduled time points will be provided. This listing will 
include all other time points for the corresponding subject/parameter. 
Grade 2 or higher toxicity laboratory values will be listed separately. 
Urinalysis results will be listed. Proteinuria and urine WBCs will be summarized. 
4.3.3. Electrocardiograms 
PR duration, QT duration,, QRS duration, Heart Rate and QTc intervals using 
Bazett’s correction formula and Fridericia's correction formula will be 
investigated. QTc values will be used as reported, they will not be recalculated. 
The actual values of QT/QTc will be categorized into abnormalities using the 
boundaries defined in the table below: 
 
Abnormalities on the change from reference will be defined for QT/QTc, as 
follows  
 
< 30 ms (Normal)  
 
[30; 60] ms 
 
> 60 ms. 
Only increases by ≥ 30 ms will be considered as abnormalities. (Note: the QTc 
definitions for abnormalities follow the ICH E14 guidance.)  
Abnormality codes: 
QT/QTcorrected 
“Normal” 
≤450 ms 
“]450 ms, 480 ms]” 
450 ms< QTc ≤ 480 ms 
“]480 ms, 500 ms]” 
480 ms< QTc ≤ 500 ms  
“More than 500 ms” 
QTc > 500 ms 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 40 of 53 
 
 
Worst abnormalities are determined over the whole observational period for each 
trial phase separately, including all post-reference scheduled and unscheduled 
measurements of that phase. 
An abnormality will be considered treatment-emergent in a particular phase if it is 
worse than the reference corresponding to this phase. If the reference is missing, 
the abnormality is always considered as treatment-emergent. Abnormalities on 
changes from reference are always defined as treatment-emergent. 
Actual values and change from baseline will be summarized by treatment group at 
each scheduled time point. 
The number and percentage of subjects will be shown in a cross-tabulation of the 
toxicity/abnormality post-baseline versus baseline at each scheduled time point. 
Additionally, a cross-tabulation of the worst toxicity/abnormality versus baseline 
will be presented per phase (Treatment phase, Follow-up phase) and for the 
combination of Treatment and follow-up phase. This table will also show the 
number and percentage of subjects per worst toxicity/abnormality, the number and 
percentage of subjects per treatment-emergent worst toxicity/abnormality, and the 
cumulative number of subjects per treatment-emergent toxicity/abnormality or 
worse. 
Mean ± SE graphs over time for the actual values and changes from reference will 
be generated for all tests performed.   
A tabulation of the worst QT/QTc change versus baseline per treatment per phase 
will be presented. 
Abnormal individual subject ECG values or abnormalities on the changes will be 
listed. 
4.3.4. Vital Signs 
Systolic and Diastolic blood pressure, oral temperature, pulse rate, respiratory 
rate, arterial oxygen saturation and level of consciousness will be investigated.  
Vital Signs abnormalities will be determined according to the WHO grading scale 
and the boundaries defined in Appendix 3.  
Worst toxicities are determined over the whole observational period for each trial 
phase separately, including all post-reference scheduled and unscheduled 
measurements of that phase.   
Actual values and change from baseline will be summarized by treatment group at 
each scheduled time point. A toxicity will be considered treatment-emergent in a 
particular phase if it is worse than the reference corresponding to this phase. If the 
reference is missing, the abnormality is always considered as treatment-emergent. 
The number and percentage of subjects will be shown in a cross-tabulation of the 
toxicity/abnormality post-baseline versus baseline at each scheduled time point. 
Additionally, a cross-tabulation of the worst toxicity/abnormality versus baseline 
will be presented per phase (Treatment phase, Follow-up phase) and for the 
combination of Treatment and follow-up phase. This table will also show the 
number and percentage of subjects per worst toxicity/abnormality, the number and 
percentage of subjects per treatment-emergent worst toxicity/abnormality, and the 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 41 of 53 
 
 
cumulative number of subjects per treatment-emergent toxicity/abnormality or 
worse. 
Mean ± SE graphs over time for the actual values and changes from reference will 
be generated for all tests performed.   
A listing of abnormal individual subject VS values will be provided. 
4.3.5. NEW Score 
The NEW Score is an aggregated score with a range from 0 to 20 calculated as the 
sum of the scores per parameter (see Table 9). In case information for a parameter 
is missing the NEW score cannot be calculated. Descriptive statistics of the NEW 
score and the change from baseline will be shown by analysis time point. 
Additionally a mean +/- SE graph of the scores over time will be provided. 
The NEW score will be categorized into its clinical risk according to the 
following categories: 
 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) 
 
A tabulation of the clinical risk categories will be made per analysis time point.  
Table 9: 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 
 
4.3.6. Physical Examinations: 
Abnormal physical examination results will be listed only. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 42 of 53 
 
 
4.4. 
Virology  
4.4.1. 
Viral Phenotype 
The JNJ-63623872 EC50 and Oseltamivir IC50 with their fold change values will 
be analyzed at baseline and at the subject’s last study visit (FC = fold change in 
EC50 (IC50) value).  
● The last study visit is defined as the last time point for which an 
EC50 and/or IC50 result is available.  
● FC is calculated as the EC50 (or IC50) divided by the reference. If 
the patient EC50 (or IC50) is censored, the fold change value get the 
same censor, e.g. patient EC50 = >20 nM, reference EC50 = 4nM, 
Fold Change value >5. 
The following output will be provided overall and by influenza subtype category: 
■ Emerging phenotypic resistance: descriptive statistics for FC in EC50 and IC50 
value for JNJ-63623872 and oseltamivir respectively at baseline and the last 
study visit. The number (%) of subjects by treatment arm with censored 
phenotype data at baseline and the last study visit will also be shown. 
■ Descriptive statistics for fold change ratio of last study visit 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 time 
points including screening/baseline. 
4.4.2. 
Viral Genotype 
Assessment of viral sequences will be done to determine amino-acid sequence 
changes that may be associated with resistance to JNJ-63623872 and/or 
oseltamivir. To that end, genotypic data for PB2, NA and optionally other genome 
segments of the influenza virus will be gathered. 
All positions in the gathered regions will be analyzed. 
The following 12 amino-acid positions in PB2 are of interest: Q306, F323, S324, 
F325, S337, H357, F363, K376, F404, Q406, M431, and N510. 
The following resistance associated mutations in NA 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 time point.  
The baseline is the collection of all polymorphisms present at any time point up to 
the first intake of study. 
Data will be summarized using frequency tabulations (n and %). Displays and 
individual mutations should be presented overall and by influenza subtype 
category and for PB2 and NA separately. The following output will be provided: 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 43 of 53 
 
 
■ 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 time points including 
screening/baseline including viral load data (include influenza subtype and 
influenza subtype category).  
4.5. 
Health Care 
The number of subjects admitted to the Intensive Care Unit (ICU) after baseline 
will be tabulated.  
The length of ICU stay for subjects transferred to the ICU after baseline is 
calculated as: 
 End date in ICU – Start date in ICU +1.  
If a subject has multiple periods in the ICU the durations for these separate stays 
in the ICU will be summed.  
Descriptive statistics of the duration in the ICU will be shown for all subjects that 
were admitted to the ICU after baseline.  
 
 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 44 of 53 
 
 
References 
Bacci E.D., Kim K., Stringer S., Leidy N.K. (18 Dec 2015 v1.1) User Manual for the 
InFLUenza Patient-Reported Outcome (FLU-PRO) Diary, Leidos Biomedical Research 
in support of the National Institute of Health, National Institute of Allergy and Infectious 
diseases, Division of Clinical Research 
Royal College of Physicians of London. (2012) National early warning score (NEWS): 
standardising 
the 
assessment 
of 
acute-illness 
severity 
in 
the 
NHS.. 
www.rcplondon.ac.uk/resources/national-earlywarning-score-news 
Guideline, I. H. T. (2006). The clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs E14. Recommended for adoption at 
Step, 4 
White, I. R., Royston, P., & Wood, A. M. (2011). Multiple imputation using chained 
equations: issues and guidance for practice. Statistics in medicine, 30(4), 377-399. 
World Health Organization. (2003) "WHO toxicity grading scale for determining the 
severity of adverse events." 
 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 45 of 53 
 
 
Appendix 1 Anticipated Events and Anticipated Event Groups 
Table 10 shows an overview of the anticipated event groups with group number.  
Table 11 indicates which adverse event preferred terms (MedDRA PT) are Anticipated Events (AnE) and Closely Related Medical Events (ME). 
These adverse events will be classified as an Anticipated Event according to the protocol term and are grouped into Anticipated Event Groups. 
One adverse event can be added to one or two groups according to Table 11.  
 
Table 10: Anticipated Event groups 
Group Number 
Grouped Term  
Group 1  
Infections and infestations 
Group 2 
Bacterial Pneumonia 
Group 3 
Bronchitis 
Group 4 
Sinus infection 
Group 5 
Ear infection 
Group 6 
Worsening of asthma, asthma attack 
Group 7 
COPD exacerbation  
Group 8 
Complications of sickle cell disease, sickle cell crisis 
Group 9 
Diabetic complications 
Group 10 
Acute Respiratory Distress Syndrome (ARDS) 
 
Table 11: Anticipated Events (AnE) and Closely Related Medical Events (ME).  
Protocol Term Anticipated Event 
AnE  
ME 
MedDRA PT  
MedDRA 
Code* 
Anticipated Event Grouped Term 
Group 
Number 
Bacterial pneumonia 
☒ 
☐ 
Pneumonia bacterial 
10060946 
Infections and infestations/Bacterial Pneumonia 
1/2 
Bacterial pneumonia 
☐ 
☒ 
Enterobacter pneumonia 
10054218 
Infections and infestations/Bacterial Pneumonia 
1/2 
Bacterial pneumonia 
☐ 
☒ 
Pneumonia haemophilus 
10035702 
Infections and infestations/Bacterial Pneumonia 
1/2 
Bacterial pneumonia 
☐ 
☒ 
Pneumonia staphylococcal 
10035734 
Infections and infestations/Bacterial Pneumonia 
1/2 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 46 of 53 
 
 
Bacterial pneumonia 
☐ 
☒ 
Pneumonia streptococcal 
10035735 
Infections and infestations/Bacterial Pneumonia 
1/2 
Bronchitis 
☒ 
☐ 
Bronchitis 
10006451 
Infections and infestations/Bronchitis 
1/3 
Bronchitis 
☐ 
☒ 
Bronchitis bacterial 
10061736 
Infections and infestations/Bronchitis 
1/3 
Bronchitis 
☐ 
☒ 
Bronchitis haemophilus 
10006460 
Infections and infestations/Bronchitis 
1/3 
Sinus infection 
☒ 
☐ 
sinusitisa 
10040753 
Infections and infestations/Sinus infection 
1/4 
Sinus infection 
☐ 
☒ 
Acute sinusitis1 
10001076 
Infections and infestations/Sinus infection 
1/4 
Sinus infection 
☐ 
☒ 
Chronic sinusitis 
10009137 
Infections and infestations/Sinus infection 
1/4 
Sinus infection 
☐ 
☒ 
Viral sinusitis 
10051513 
Infections and infestations/Sinus infection 
1/4 
Ear infection 
☒ 
☐ 
Ear infection  
10014011 
Infections and infestations/ Ear infection 
1/5 
Ear infection 
☐ 
☒ 
Middle ear effusion 
10062545 
Infections and infestations/ Ear infection 
1/5 
Ear infection 
☐ 
☒ 
Otitis externa 
10033072 
Infections and infestations/ Ear infection 
1/5 
Ear infection 
☐ 
☒ 
Otitis media 
10033078 
Infections and infestations/ Ear infection 
1/5 
Ear infection 
☐ 
☒ 
Otitis media acute 
10033079 
Infections and infestations/ Ear infection 
1/5 
Worsening of asthma, asthma attackb  
☒ 
☐ 
Asthma 
10003553 
Worsening of asthma, asthma attack 
6 
Worsening of asthma, asthma attack2 
☐ 
☒ 
Asthmatic crisis 
10064823 
Worsening of asthma, asthma attack 
6 
COPD exacerbation c 
☐ 
☒ 
Chronic obstructive 
pulmonary disease 
10009033 
COPD exacerbation  
7 
COPD exacerbation 3 
☐ 
☒ 
Emphysema 
10014561 
COPD exacerbation  
7 
Complications of sickle cell disease, sickle 
cell crisisd  
☐ 
☒ 
Sickle cell anaemia 
10040641 
Complications of sickle cell disease, sickle cell crisis 
8 
Complications of sickle cell disease, sickle 
cell crisis4 
☐ 
☒ 
Acute chest syndrome 
10051895 
Complications of sickle cell disease, sickle cell crisis 
8 
                                                 
a Infectious etiology only 
b 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. 
c 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. 
d 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. 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 47 of 53 
 
 
Complications of sickle cell disease, sickle 
cell crisis4 
☐ 
☒ 
Pain 
10033371 
Complications of sickle cell disease, sickle cell crisis 
8 
Complications of sickle cell disease, sickle 
cell crisis4 
☐ 
☒ 
Ischaemic stroke 
10061256 
Complications of sickle cell disease, sickle cell crisis 
8 
Complications of sickle cell disease, sickle 
cell crisis4 
☐ 
☒ 
Embolic stroke 
10014498 
Complications of sickle cell disease, sickle cell crisis 
8 
Complications of sickle cell disease, sickle 
cell crisis4 
☐ 
☒ 
Deep vein thrombosis 
10051055 
Complications of sickle cell disease, sickle cell crisis 
8 
Complications of sickle cell disease, sickle 
cell crisis4 
☐ 
☒ 
Pulmonary embolism 
10037377 
Complications of sickle cell disease, sickle cell crisis 
8 
Complications of diabetes mellitus, diabetic 
ketoacidosise 
☒ 
☐ 
Diabetic complications  
10061104 
Diabetic complications 
9 
Complications of diabetes mellitus, diabetic 
ketoacidosis5 
☐ 
☒ 
Diabetic ketoacidosis 
10012671 
Diabetic complications 
9 
Complications of diabetes mellitus, diabetic 
ketoacidosis5 
☐ 
☒ 
Diabetes mellitusf 
10012601 
Diabetic complications 
9 
Complications of diabetes mellitus, diabetic 
ketoacidosis5 
☐ 
☒ 
Diabetic ketoacidotic 
hyperglycaemic coma 
10012672 
Diabetic complications 
9 
Complications of diabetes mellitus, diabetic 
ketoacidosis5 
☐ 
☒ 
Hypoglycaemia 
10020993 
Diabetic complications 
9 
Acute Respiratory Distress Syndrome 
(ARDS) 
☒ 
☐ 
Acute respiratory distress 
syndrome 
10001052 
Acute Respiartory Distress Syndrome (ARDS) 
10 
Acute Respiratory Distress Syndrome 
(ARDS) 
☐ 
☒ 
Acute respiratory failureg 
10001053 
Acute Respiartory Distress Syndrome (ARDS) 
10 
                                                 
e 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. 
f Please note that diabetes mellitus aggravated and diabetes mellitus exacerbated codes to a PT of diabetes mellitus 
g This event will be considered anticipated only if it occurs in the context of ARDS 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 48 of 53 
 
 
Appendix 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. 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 49 of 53 
 
 
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 
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 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 50 of 53 
 
 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
Hypomagnesemi
a 
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 
Creatinine 
≥1.1 to ≤1.5 x 
ULN 
>1.5 to ≤3.0 x 
ULN 
>3.0 to ≤6.0 x 
ULN 
>6.0 x ULN or 
required 
dialysis 
Urinalysis 
Proteinuria 
1+ or <0.3% or 
<3g/L or  
200 mg – 1 gm 
loss/day 
2-3+ or 0.3-1.0% 
or 3-10 g/L or  
1-2 gm loss/day 
4+ or >1.0% or 
>10 g/L or  
2-3.5 
gm 
loss/day 
nephrotic 
syndrome 
or 
>3.5 gm 
loss/day 
Hematuria 
microscopic only 
gross, no clots 
gross + clots 
obstructive 
or 
required 
transfusion 
Cardiac Dysfunction 
Cardiac Rhythm 
- 
asymptomatic, 
transient 
signs, 
no Rx required 
recurrent/persiste
nt; 
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 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 51 of 53 
 
 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Pericarditis 
minimal effusion 
mild/moderate 
asymptomatic 
effusion, no Rx 
symptomatic 
effusion; 
pain; 
ECG changes 
tamponade; 
pericardiocente
sis or surgery 
required 
Hemorrhage, 
Blood Loss 
microscopic/occul
t 
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 
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 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 52 of 53 
 
 
Item 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neuro 
Control 
(ADL 
= 
activities of daily 
living) 
mild 
difficulty 
concentrating; no 
Rx; 
mild 
confusion/agitati
on; 
ADL 
unaffected 
moderate 
confusion/agitatio
n 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 
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 
 
NCT02532283


63623872FLZ2002 
Statistical Analysis Plan 
 
Page 53 of 53 
 
 
Appendix 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 
 
 
NCT02532283