Trial Outcomes & Findings for A Study to Evaluate the Pharmacokinetics, Safety, and Antiviral Activity of JNJ-63623872 in Combination With Oseltamivir in Adult, and Elderly Hospitalized Participants With Influenza A Infection (NCT NCT02532283)

Last Updated: 2020-03-27

Results Overview

Cmax is the maximum observed plasma concentration. As per planned analysis, results are presented by age groups (65 to less than or equal to \[\<=\] 85 years and 18 to \<=64 years).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

102 participants

Primary outcome timeframe

Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3

Results posted on

2020-03-27

Participant Flow

In total, 102 participants were randomized. 3 participants were randomized but not treated due to withdrawal of consent before treatment start. Therefore, the Safety Set, comprising all participants who received at least 1 dose of study drug(s), consisted of 99 participants.

Participant milestones

Participant milestones
Measure	Pimodivir 600 mg Plus Oseltamivir 75 mg Participants received pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated-glomerular filtration rate (eGFR) value.	Placebo Plus Oseltamivir 75 mg Participants received matching placebo tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.
Overall Study STARTED	64	35
Overall Study Full Analysis Set	63	32
Overall Study COMPLETED	55	30
Overall Study NOT COMPLETED	9	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Pimodivir 600 mg Plus Oseltamivir 75 mg Participants received pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated-glomerular filtration rate (eGFR) value.	Placebo Plus Oseltamivir 75 mg Participants received matching placebo tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.
Overall Study Adverse Event	0	1
Overall Study Death	1	0
Overall Study Lost to Follow-up	0	1
Overall Study Withdrawal by Subject	8	3

Baseline Characteristics

A Study to Evaluate the Pharmacokinetics, Safety, and Antiviral Activity of JNJ-63623872 in Combination With Oseltamivir in Adult, and Elderly Hospitalized Participants With Influenza A Infection

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pimodivir 600 mg Plus Oseltamivir 75 mg n=64 Participants Participants received pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated-glomerular filtration rate (eGFR) value.	Placebo Plus Oseltamivir 75 mg n=35 Participants Participants received matching placebo tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.	Total n=99 Participants Total of all reporting groups
Age, Continuous	58.1 years STANDARD_DEVIATION 16.06 • n=5 Participants	57.2 years STANDARD_DEVIATION 13.71 • n=7 Participants	57.8 years STANDARD_DEVIATION 15.21 • n=5 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	18 Participants n=7 Participants	45 Participants n=5 Participants
Sex: Female, Male Male	37 Participants n=5 Participants	17 Participants n=7 Participants	54 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	55 Participants n=5 Participants	32 Participants n=7 Participants	87 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized White	48 Participants n=5 Participants	19 Participants n=7 Participants	67 Participants n=5 Participants
Region of Enrollment BELGIUM	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment FRANCE	6 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment GERMANY	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment HONG KONG	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment MALAYSIA	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment NETHERLANDS	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment SINGAPORE	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment SPAIN	16 Participants n=5 Participants	7 Participants n=7 Participants	23 Participants n=5 Participants
Region of Enrollment SWEDEN	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Region of Enrollment TURKEY	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
Region of Enrollment UNITED STATES	18 Participants n=5 Participants	11 Participants n=7 Participants	29 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3

Population: Pharmacokinetic (PK) analysis set included all participants from whom sufficient concentration data were available to facilitate derivation of at least one PK parameter. Here, N (number of participants analyzed) signifies number of participants evaluable for this outcome measure (OM).

Cmax is the maximum observed plasma concentration. As per planned analysis, results are presented by age groups (65 to less than or equal to \[\<=\] 85 years and 18 to \<=64 years).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=15 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=20 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Maximum Observed Plasma Concentration (Cmax) of Pimodivir	5933 Nanogram per milliliter (ng/mL) Standard Deviation 4427	5378 Nanogram per milliliter (ng/mL) Standard Deviation 3888

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3

Population: PK analysis set included all participants from whom sufficient concentration data were available to facilitate derivation of at least one PK parameter. Here, N (number of participants analyzed) signifies number of participants evaluable for this OM.

Cmin is the minimum observed plasma concentration. As per planned analysis, results are presented by age groups (65 to \<= 85 years and 18 to \<=64 years).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=15 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=21 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Minimum Observed Plasma Concentration (Cmin) of Pimodivir	738 ng/mL Standard Deviation 892	507 ng/mL Standard Deviation 414

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3

AUC (0-12) is the area under the plasma concentration-time curve from time zero to 12 hours after dosing of pimodivir. As per planned analysis, results are presented by age groups (65 to \<= 85 years and 18 to \<=64 years).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=15 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=20 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Area Under the Plasma Concentration-time Curve From Time of Administration to 12 Hours After Dosing (AUC [0-12]) of Pimodivir	27386 nanogram hours per milliliter (ng*h/mL) Standard Deviation 25191	20101 nanogram hours per milliliter (ng*h/mL) Standard Deviation 11063

SECONDARY outcome

Timeframe: Up to 28 Days

Population: Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.

An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with treatment and therefore can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with use of a medicinal product, whether or not related to that medicinal product. TEAEs were defined as AEs that were reported or worsened on after start of study drug(s) dosing through safety follow-up visit. A serious adverse event (SAE) is any untoward medical occurrence that at any dose resulting in any of following outcomes: results in death, is life-threatening, 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.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=64 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=35 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious AEs (TESAEs) TEAEs	48 Participants	25 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious AEs (TESAEs) TESAEs	11 Participants	4 Participants

SECONDARY outcome

Timeframe: Up to 14 Days

Population: Full Analysis set (FAS) was defined as all randomly assigned participants who received at least 1 dose of study drug and who had a confirmed infection with influenza A.

Time to influenza A viral negativity was determined based on quantitative reverse transcription polymerase chain reaction (qRT-PCR). A participant was considered influenza A viral negative at the time point that the first negative nasal midturbinate (MT) swab was recorded (in days). Viral Load Limit of detection (LOD) = 2.18 log10 viral particles per milliliter (vp/mL). Results less than (\<) limit of quantification (LOQ) and greater than (\>) LOD (target detected) are imputed with 2.12 log10 vp/mL, results \<LOD (target not detected) are imputed with 0 log10 vp/mL.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=63 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Time to Influenza A Viral Negativity	9.53 Days Interval 8.55 to 12.68	9.74 Days Interval 6.67 to 12.99

SECONDARY outcome

Timeframe: Baseline, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14

Population: FAS was defined as all randomly assigned participants who received at least 1 dose of study drug and who have a confirmed infection with influenza A. Here, N (number of participants analyzed) signifies number of participants evaluable for this OM and 'n' signifies number of participants evaluable at specified time points.

Influenza viral load over time (Log 10 viral particles per milliliter \[vp/mL\]) was measured by qRT-PCR. Viral Load LOD = 2.18 log10 vp/mL. Results \< LOQ and \> LOD (target detected) are imputed with 2.12 log10 vp/mL and results \<LOD (target not detected) are imputed with 0 log10 vp/mL.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=58 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=30 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Influenza Viral Load Over Time Day 12	1.06 Log 10 vp/mL Standard Deviation 1.499	—
Influenza Viral Load Over Time Day 13	1.06 Log 10 vp/mL Standard Deviation 1.499	—
Influenza Viral Load Over Time Day 14	1.05 Log 10 vp/mL Standard Deviation 1.636	0.20 Log 10 vp/mL Standard Deviation 0.646
Influenza Viral Load Over Time Baseline	5.45 Log 10 vp/mL Standard Deviation 1.737	5.90 Log 10 vp/mL Standard Deviation 1.513
Influenza Viral Load Over Time Day 1	6.40 Log 10 vp/mL Standard Deviation 0.757	4.43 Log 10 vp/mL Standard Deviation NA Here, NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Influenza Viral Load Over Time Day 2	4.75 Log 10 vp/mL Standard Deviation 1.290	4.63 Log 10 vp/mL Standard Deviation 1.757
Influenza Viral Load Over Time Day 3	3.83 Log 10 vp/mL Standard Deviation 1.310	3.98 Log 10 vp/mL Standard Deviation 1.924
Influenza Viral Load Over Time Day 4	3.00 Log 10 vp/mL Standard Deviation 1.486	3.14 Log 10 vp/mL Standard Deviation 1.806
Influenza Viral Load Over Time Day 5	2.57 Log 10 vp/mL Standard Deviation 1.716	2.60 Log 10 vp/mL Standard Deviation 1.803
Influenza Viral Load Over Time Day 6	2.07 Log 10 vp/mL Standard Deviation 1.454	2.18 Log 10 vp/mL Standard Deviation 2.457
Influenza Viral Load Over Time Day 7	1.95 Log 10 vp/mL Standard Deviation 1.478	2.38 Log 10 vp/mL Standard Deviation 2.212
Influenza Viral Load Over Time Day 8	1.82 Log 10 vp/mL Standard Deviation 1.709	1.43 Log 10 vp/mL Standard Deviation 1.648
Influenza Viral Load Over Time Day 9	1.51 Log 10 vp/mL Standard Deviation 1.034	0.00 Log 10 vp/mL Standard Deviation NA Here, NA indicates that data was not available as standard deviation could not be calculated for a single participant.
Influenza Viral Load Over Time Day 10	1.39 Log 10 vp/mL Standard Deviation 1.676	0.99 Log 10 vp/mL Standard Deviation 1.295
Influenza Viral Load Over Time Day 11	0.42 Log 10 vp/mL Standard Deviation 1.017	0.00 Log 10 vp/mL Standard Deviation NA Here, NA indicates that data was not available as standard deviation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Up to Day 7

Population: FAS was defined as all randomly assigned participants who received at least 1 dose of study drug and who have a confirmed infection with influenza A.

Rate of decline in viral load (Log10 viral particles per milliliter per day \[log10 vp/mL/day\]) during treatment was measured by qRT-PCR. Viral Load Limit of quantification (LOQ) = 2.18 log10 vp/mL, LOD = 2.05 log10 vp/mL. Results \< LOQ and greater than \> LOD (target detected) are imputed with 2.12 log10 vp/mL. Results \<LOD (target not detected) are imputed with 0 log10 vp/mL.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=63 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Rate of Decline in Viral Load	-0.35 Log10 vp/mL/day Interval -0.39 to -0.3	-0.42 Log10 vp/mL/day Interval -0.49 to -0.35

SECONDARY outcome

Timeframe: Baseline up to Day 8

Population: FAS was defined as all randomly assigned participants who received at least 1 dose of study drug and who have a confirmed infection with influenza A.

Viral load AUC was determined by qRT-PCR assay of nasal swabs. Viral Load LOQ = 2.18 log10 vp/mL, LOD = 2.05 log10 vp/mL. Results \<LOQ and \>LOD (target detected) are imputed with 2.12 log10 vp/mL. Results \<LOD (target not detected) are imputed with 0 log10 vp/mL.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=63 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Area Under the Plasma Concentration-time Curve (AUC) of Viral Load	22.8 Days*vp/mL Interval 20.4 to 25.1	22.1 Days*vp/mL Interval 19.0 to 25.2

SECONDARY outcome

Timeframe: Up to 28 Days

Population: FAS was defined as all randomly assigned participants who received at least 1 dose of study drug and who have a confirmed infection with influenza A.

Percentage of participants with following Influenza Complications: bacterial pneumonia (culture confirmed where possible), bacterial superinfections, respiratory failure, pulmonary disease (example, asthma, chronic obstructive pulmonary disease \[COPD\]), cardiovascular and cerebrovascular disease (example, myocardial infarction, congestive heart failure \[CHF\], arrhythmia, stroke) and all complications were reported.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=63 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Percentage of Participants With Influenza Complications Cardiovascular and Cerebrovascular disease	1.6 Percentage of participants	0 Percentage of participants
Percentage of Participants With Influenza Complications All complications	7.9 Percentage of participants	15.6 Percentage of participants
Percentage of Participants With Influenza Complications Bacterial pneumonia	0 Percentage of participants	0 Percentage of participants
Percentage of Participants With Influenza Complications Bacterial superinfections	1.6 Percentage of participants	3.1 Percentage of participants
Percentage of Participants With Influenza Complications Respiratory failure	1.6 Percentage of participants	0 Percentage of participants
Percentage of Participants With Influenza Complications Pulmonary disease	3.2 Percentage of participants	6.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33

FLU-PRO assesses 32 influenza symptoms in each of the following body areas (domains): Nose, Throat, Eyes, Chest/Respiratory, Gastrointestinal and Body/Systemic . Participants rate each symptom on a 5-point ordinal scale, with higher scores indicating a more frequent sign or symptom. For 27 of the items, the scale is as follows: 0 ("Not at all"), 1 ("A little bit"), 2 ("Somewhat"), 3 ("Quite a bit"), and 4 ("Very much"). For 5 items, severity is assessed in terms of numerical frequency, that is (i.e), vomiting or diarrhea (0 times, 1 time, 2 times, 3 times, or 4 or more times); with frequency of sneezing, coughing, and coughed up mucus or phlegm evaluated on a scale from 0 ("Never") to 4 ("Always").The FLU-PRO total score is computed as a mean score across all 32 items comprising the instrument. Total scores can range from 0 (symptom free) to 4 (very severe symptoms).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=38 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 2	-0.48 Units on a scale Standard Deviation 0.644	-0.33 Units on a scale Standard Deviation 0.798
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 10	-0.91 Units on a scale Standard Deviation 0.723	-0.81 Units on a scale Standard Deviation 0.743
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 25	-0.94 Units on a scale Standard Deviation 0.659	-0.85 Units on a scale Standard Deviation 0.661
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 28	-0.60 Units on a scale Standard Deviation 0.505	-0.82 Units on a scale Standard Deviation 0.675
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 32	-0.61 Units on a scale Standard Deviation 0.420	—
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 1	-0.08 Units on a scale Standard Deviation 0.247	-0.11 Units on a scale Standard Deviation 0.349
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 3	-0.60 Units on a scale Standard Deviation 0.624	-0.52 Units on a scale Standard Deviation 0.641
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 4	-0.71 Units on a scale Standard Deviation 0.702	-0.56 Units on a scale Standard Deviation 0.625
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 5	-0.76 Units on a scale Standard Deviation 0.689	-0.67 Units on a scale Standard Deviation 0.643
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 6	-0.85 Units on a scale Standard Deviation 0.692	-0.75 Units on a scale Standard Deviation 0.659
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 7	-0.87 Units on a scale Standard Deviation 0.738	-0.69 Units on a scale Standard Deviation 0.623
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 8	-0.89 Units on a scale Standard Deviation 0.729	-0.80 Units on a scale Standard Deviation 0.764
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 9	-0.93 Units on a scale Standard Deviation 0.764	-0.84 Units on a scale Standard Deviation 0.732
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 11	-0.87 Units on a scale Standard Deviation 0.756	-0.76 Units on a scale Standard Deviation 0.534
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 12	-0.87 Units on a scale Standard Deviation 0.725	-0.89 Units on a scale Standard Deviation 0.695
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 13	-0.93 Units on a scale Standard Deviation 0.702	-0.94 Units on a scale Standard Deviation 0.650
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 14	-0.85 Units on a scale Standard Deviation 0.613	-0.92 Units on a scale Standard Deviation 0.670
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 15	-0.88 Units on a scale Standard Deviation 0.630	-0.90 Units on a scale Standard Deviation 0.724
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 16	-0.84 Units on a scale Standard Deviation 0.588	-0.90 Units on a scale Standard Deviation 0.762
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 17	-0.98 Units on a scale Standard Deviation 0.690	-0.97 Units on a scale Standard Deviation 0.774
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 18	-1.06 Units on a scale Standard Deviation 0.753	-1.00 Units on a scale Standard Deviation 0.868
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 19	-1.06 Units on a scale Standard Deviation 0.749	-1.05 Units on a scale Standard Deviation 0.880
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 20	-1.03 Units on a scale Standard Deviation 0.710	-1.03 Units on a scale Standard Deviation 0.847
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 21	-1.00 Units on a scale Standard Deviation 0.701	-0.98 Units on a scale Standard Deviation 0.849
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 22	-1.02 Units on a scale Standard Deviation 0.789	-0.92 Units on a scale Standard Deviation 0.690
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 23	-1.11 Units on a scale Standard Deviation 0.858	-0.96 Units on a scale Standard Deviation 0.731
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 24	-0.87 Units on a scale Standard Deviation 0.534	-0.91 Units on a scale Standard Deviation 0.580
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 26	-0.86 Units on a scale Standard Deviation 0.755	-0.87 Units on a scale Standard Deviation 0.742
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 27	-1.02 Units on a scale Standard Deviation 0.745	-0.74 Units on a scale Standard Deviation 0.734
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 29	-1.13 Units on a scale Standard Deviation 0.354	-1.63 Units on a scale Standard Deviation 0.398
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 30	-0.61 Units on a scale Standard Deviation 0.552	—
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 31	-0.75 Units on a scale Standard Deviation NA Here, NA indicates that data was not available as standard deviation could not be calculated for a single participant.	—
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score Day 33	-0.94 Units on a scale Standard Deviation NA Here, NA indicates that data was not available as standard deviation could not be calculated for a single participant.	—

SECONDARY outcome

Timeframe: Up to 28 Days

Time to improvement of vital signs was defined as the time from first study treatment to when at least 4 of 5 symptoms (temperature, blood oxygen saturation, heart rate, systolic blood pressure, and respiration rate) had recovered, including normalization of temperature and blood oxygen saturation. Resolution criteria for vital signs: for Temperature: oral temperature less than or equal to (\<=) 36.5 degree Celsius (C) for elderly and \<=37.2 C for adults; for oxygen saturation: greater than or equal to (\>=) 92 percent (%) on room air without supplemental oxygen; for respiratory rate: \<= 24 per minutes; for heart rate: \<= 100 per minutes and for systolic blood pressure: \>= 90 millimeters of mercury (mmHg).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=60 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=28 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Time to Improvement of Vital Signs	169.92 Hours Interval 46.63 to Here 'NA' indicates that the upper limit of 95% confidence interval (CI) was not estimable due to less number of events.	69.90 Hours Interval 35.83 to Here 'NA' indicates that the upper limit of 95% CI was not estimable due to less number of events.

SECONDARY outcome

Timeframe: Up to 28 Days

The time to improvement of respiratory status was defined as the time from first study treatment until the first assessment of a successive series of 3 recording where normalization of blood oxygen saturation and respiration rate occurred at respiration rate \<=24 per minutes).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=60 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=28 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Time to Improvement of Respiratory Status	33.53 Hours Interval 21.33 to 241.92	40.57 Hours Interval 22.75 to Here 'NA' indicates that the upper limit of 95% CI was not estimable due to less number of events.

SECONDARY outcome

Timeframe: Day 8

The ordinal scale was used to assess participant's clinical outcome. It consists of 6 categories or clinical states that are exhaustive, mutually exclusive, and ordered, where 1- Death, 2- Admitted to intensive care unit (ICU) or mechanically ventilated/ extracorporeal membrane oxygenation (ECMO), 3- Non-ICU plus supplemental oxygen, 4- Non-ICU plus no supplemental oxygen, 5- Not hospitalized, but unable to continue activity, 6- Not hospitalized (NH) and continues activities.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=62 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=31 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Percentage of Participants With Clinical Outcome Based on Ordinal Scale Day 8: NH and Continues Activities	40.3 Percentage of Participants	29.0 Percentage of Participants
Percentage of Participants With Clinical Outcome Based on Ordinal Scale Day 8: NH, but Unable to Continue Activity	27.4 Percentage of Participants	45.2 Percentage of Participants
Percentage of Participants With Clinical Outcome Based on Ordinal Scale Day 8: Non-ICU+No Supplemental Oxygen	14.5 Percentage of Participants	6.5 Percentage of Participants
Percentage of Participants With Clinical Outcome Based on Ordinal Scale Day 8: Non-ICU+Supplemental Oxygen	8.1 Percentage of Participants	3.2 Percentage of Participants
Percentage of Participants With Clinical Outcome Based on Ordinal Scale Day 8: Death	1.6 Percentage of Participants	0 Percentage of Participants
Percentage of Participants With Clinical Outcome Based on Ordinal Scale Day 8: Missing	8.1 Percentage of Participants	16.1 Percentage of Participants

SECONDARY outcome

Timeframe: Up to 28 Days

Population: FAS was defined as all randomly assigned participants who received at least 1 dose of study drug and who have a confirmed infection with influenza A.

Number of participants with emergence (from baseline) of drug resistance mutations detected by genotype or phenotype were reported.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=63 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Number of Participants With the Emergence of Drug Resistance Mutations With Oseltamivir (OST) and Pimodivir Emergence of Pimodivir Mutation	0 Participants	0 Participants
Number of Participants With the Emergence of Drug Resistance Mutations With Oseltamivir (OST) and Pimodivir Emergence of OST Mutation	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Up to Day 33

Time to return to premorbid functional status (time to return usual activities) was defined as time in hours from the first dose of investigational product till the first one of 2 successive cases where the response is 'Yes' on FLU-PRO additional question 7 (Have you returned to your usual activities today?).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=60 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Time to Return to Premorbid Functional Status	142.85 Hours Interval 83.27 to 220.15	154.83 Hours Interval 74.97 to 386.52

SECONDARY outcome

Timeframe: Up to 28 Days

Population: FAS was defined as all randomly assigned participants who received at least 1 dose of study drug and who have a confirmed infection with influenza A.

Time to hospital discharge was calculated from the date of first study drug intake during hospitalization up to date of discharge.

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=63 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Time to Hospital Discharge	4.00 Days Interval 3.0 to 5.0	4.00 Days Interval 3.0 to 4.0

SECONDARY outcome

Timeframe: Up to Day 33

Time to return to usual health was 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 FLU-PRO additional question 9 (Have you returned to your health today?).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=60 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Time to Return to Usual Health	217.05 Hours Interval 122.03 to 291.42	338.83 Hours Interval 107.4 to Here 'NA' indicates that the upper limit of 95% CI was not estimable due to less number of events.

SECONDARY outcome

Timeframe: Up to Day 33

Time to significant reduction in influenza symptom severity (mild/none) is time from first dose of investigational drug until first of 2 successive recordings in which total score for each of 2 recordings is lower or equal to 1 and all domain scores is lower or equal to 1. FLU-PRO assesses 32 influenza symptoms in body areas (domains): Nose, throat, eyes, chest, gastrointestinal, body. Participants rate each symptom on 5-point scale, with higher scores indicates more frequent symptom. For 27 of items, scale is as follows: 0 (Not at all), 1 (A little bit), 2 (Somewhat), 3 (Quite a bit), 4 (Very much). For 5 items, severity is assessed in terms of numerical frequency, i.e, vomiting/diarrhea (0 times, 1 time, 2 times, 3 times, or 4 or more times); with frequency of sneezing, coughing and coughed up mucus or phlegm evaluated on scale from 0=Never to 4=Always. FLU-PRO total score is computed as mean score across all 32 items and ranges from 0 (symptom free) to 4 (very severe symptoms).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=60 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=32 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Time to Significant Reduction in FLU-PRO Influenza Symptom Severity	118.45 Hours Interval 82.33 to 171.93	218.72 Hours Interval 94.7 to 275.58

SECONDARY outcome

Timeframe: Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33

Percentage of participants with significant reduction in influenza symptom severity was defined as time from first dose of investigational product until first of 2 successive recordings in which FLU-PRO total score for each of 2 recordings \<= to 1 and all FLU-PRO domain scores is \<=1. FLU-PRO assesses 32 influenza symptoms in body areas (domains): Nose, throat, eyes, chest, gastrointestinal, body. Participants rate each symptom on a 5-point ordinal scale, with higher scores indicates more frequent symptom. For 27 of items, scale is as follows: 0 (Not at all), 1 (A little bit), 2 (Somewhat), 3 (Quite a bit), 4 (Very much). For 5 items, severity is assessed as numerical frequency i.e, vomiting or diarrhea (0-4 or more times); with frequency of sneezing, coughing, coughed up mucus or phlegm evaluated on a scale from 0 (Never)-4 (Always). FLU-PRO total score is computed as a mean score across all 32 items comprising instrument and ranges from 0 (symptom free) to 4 (very severe symptoms).

Outcome measures

Outcome measures
Measure	Elderly Adults (65 to Less Than or Equal to [<=] 85 Years) n=55 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.	Non-elderly Adults (18 to <=64 Years) n=30 Participants Participants received pimodivir 600 mg tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 2	37.3 Percentage of participants	34.6 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 1	9.4 Percentage of participants	18.2 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 3	36.4 Percentage of participants	26.7 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 4	42.0 Percentage of participants	38.5 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 5	54.0 Percentage of participants	37.5 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 6	59.2 Percentage of participants	40.0 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 7	55.1 Percentage of participants	34.8 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 8	62.7 Percentage of participants	32.0 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 9	76.0 Percentage of participants	38.5 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 10	76.5 Percentage of participants	53.8 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 11	70.2 Percentage of participants	59.1 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 12	77.1 Percentage of participants	72.0 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 13	76.1 Percentage of participants	69.2 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 14	77.1 Percentage of participants	65.4 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 15	63.9 Percentage of participants	57.9 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 16	71.4 Percentage of participants	66.7 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 17	74.3 Percentage of participants	63.2 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 18	70.0 Percentage of participants	57.9 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 19	77.4 Percentage of participants	58.8 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 20	81.8 Percentage of participants	63.2 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 21	79.4 Percentage of participants	60.0 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 22	86.2 Percentage of participants	61.1 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 23	78.1 Percentage of participants	70.6 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 24	86.2 Percentage of participants	66.7 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 25	92.3 Percentage of participants	69.2 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 26	81.5 Percentage of participants	57.1 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 27	83.3 Percentage of participants	50.0 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 28	77.8 Percentage of participants	44.4 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 29	80.0 Percentage of participants	66.7 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 30	100.0 Percentage of participants	0 Percentage of participants
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 31	100.0 Percentage of participants	—
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 32	100.0 Percentage of participants	—
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) Day 33	100 Percentage of participants	—

Adverse Events

Pimodivir 600 mg Plus Oseltamivir 75 mg

Serious events: 11 serious events

Other events: 45 other events

Deaths: 1 deaths

Placebo Plus Oseltamivir 75 mg

Serious events: 4 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Director

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER

Measure	Pimodivir 600 mg Plus Oseltamivir 75 mg n=64 participants at risk Participants received pimodivir 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the estimated-glomerular filtration rate (eGFR) value.	Placebo Plus Oseltamivir 75 mg n=35 participants at risk Participants received matching placebo tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Dose of oseltamivir was adjusted from 75 mg to 30 mg and vice versa during the course of treatment based on the eGFR value.
Blood and lymphatic system disorders Neutropenia	0.00% 0/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	2.9% 1/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Cardiac disorders Cardiac arrest	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Immune system disorders Hypersensitivity	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Infections and infestations Bacterial infection	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Infections and infestations Infective pulmonary exacerbation of cystic fibrosis	0.00% 0/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	2.9% 1/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Infections and infestations Oral candidiasis	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Nervous system disorders Cerebrovascular accident	0.00% 0/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	2.9% 1/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Renal and urinary disorders Bladder outlet obstruction	0.00% 0/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	2.9% 1/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Renal and urinary disorders Renal failure	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Respiratory, thoracic and mediastinal disorders Bronchial hyperreactivity	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Skin and subcutaneous tissue disorders Dermatitis exfoliative	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Vascular disorders Aortic dissection	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Vascular disorders Circulatory collapse	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Vascular disorders Hypotension	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.
Vascular disorders Orthostatic hypotension	1.6% 1/64 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.	0.00% 0/35 • Up to 28 days Safety analysis set included all participants who received at least one dose of study drug(s) and were analyzed by drug received.