A Study to Evaluate the Efficacy and Safety of Pimodivir in Combination With the Standard-of-Care Treatment in Adolescent, Adult, and Elderly Non-Hospitalized Participants With Influenza A Infection Who Are at Risk of Developing Complications

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

Detailed Description
-----------------
This double-blind (neither researchers nor participants know what treatment participant is receiving) study will evaluate efficacy/safety of pimodivir in combination with SOC treatment versus placebo in combination with SOC treatment in adolescent (13 to 17 years), adult (18 to 65 years), and elderly (greater than [>] 65 but less than or equal to [<=] 85 years) non-hospitalized participants with influenza A infection who are at risk of developing complications. The study will be conducted in 3 phases: screening phase, double-blind treatment period (5 days), a post treatment follow-up period (23 days). Study evaluations include efficacy, clinical and virological outcomes, pharmacokinetics (PK), PK/pharmacodynamics, biomarkers, safety and tolerability. The duration of participation in the study for each participant is 28 days.

Official Title
-----------------
A Phase 3 Randomized, Double-blind, Placebo-controlled, Multi-center Study to Evaluate the Efficacy and Safety of Pimodivir in Combination With the Standard-of-care Treatment in Adolescent, Adult, and Elderly Non-hospitalized Subjects With Influenza A Infection Who Are at Risk of Developing Complications

Conditions
-----------------
Influenza A

Intervention / Treatment
-----------------
* Drug: Pimodivir 600 mg
* Drug: Placebo
* Other: SOC Treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Present to the clinic with symptoms suggestive of a diagnosis of acute influenza and have at least 1 respiratory symptom and at least 1 systemic symptom, both scored as at least moderate if the symptom did not pre-exist before influenza onset, or scored worse than usual if the symptom pre-existed as determined by subject's ratings on Module 1 of the Flu-iiQ and the Pre-existing Symptom Questionnaire in the ePRO device. Symptoms must include the following by category: a) Respiratory symptoms: cough, sore throat, nasal congestion b) Systemic symptoms: headache, body aches or pain, feverishness, fatigue Tested positive for influenza A infection after the onset of symptoms, using a rapid influenza diagnostic test (RIDT) or, if available, a polymerase chain reaction (PCR)-based or other rapid molecular diagnostic assay Not be in need of hospitalized medical care at screening. Emergency room or hospital observation status for an anticipated duration of less than (<)24 hours is not considered hospitalization as long as a determination of the need for hospitalization has not been made Enrollment and initiation of study drug treatment less than or equal to (<=)72 hours after onset of influenza symptoms Participants 13 to 65 years of age, inclusive must also have at least 1 of the following: a) Cardiovascular or cerebrovascular disease (including congenital heart disease, chronic heart failure, coronary artery disease, or stroke; excluding isolated hypertension); b) Chronic lung disease (for example, asthma, chronic obstructive lung disease [COPD] or cystic fibrosis); c) Weakened immune system due to disease or medication (for example, participants with human immunodeficiency virus [HIV], cancer, or chronic liver or kidney disease [presence of kidney damage for >3 months, defined by structural or functional abnormalities of the kidney, with or without decreased GFR manifested by: pathological abnormalities; OR markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests], or participants taking chronic systemic steroids) Exclusion Criteria: Received more than (>)1 dose of influenza antiviral medication (for example, oseltamivir [OST] or zanamivir), or any dose of ribavirin within 2 weeks, prior to first study drug intake, or received intravenous (IV) peramivir >1 day prior to screening Unstable angina pectoris or myocardial infarction within 30 days prior to screening (inclusive) Presence of clinically significant heart arrhythmias, uncontrolled, unstable atrial arrhythmia, or sustained ventricular arrhythmia, or risk factors for Torsade de Pointes syndrome Known severe hepatic impairment (Child Pugh C cirrhosis) or chronic hepatitis C infection undergoing hepatitis C antiviral therapy Severely immunocompromised in the opinion of the investigator (for example, known cluster of differentiation 4 plus [CD4+] count <200 cells per cubic millimeter [cells/mm^3], absolute neutrophil count <750/mm^3, first course of chemotherapy completed within 2 weeks prior to screening, history of stem cell transplant within 1 year prior to screening, history of a lung transplant)

Ages Eligible for Study
-----------------
Minimum Age: 13 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm 1 (pimodivir + SOC treatment)<br>Participants will receive pimodivir 600 milligram (mg), orally, twice daily, for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of pimodivir on Day 1 [evening], dosing will continue until the morning of Day 6) along with Standard-of-Care (SOC) treatment. The SOC treatment is determined by the investigator based on local practice, and may include influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of the SOC should be made before randomization. The influenza antiviral should be started no later than Day 2 morning (up to noon). An influenza antiviral as part of the SOC cannot be changed (for example, switching one influenza antiviral for another) during the treatment period, with the exception that an influenza antiviral may be discontinued in the case of a suspected adverse event (AE). | Drug: Pimodivir 600 mg<br>* Participants will receive pimodivir 600 mg, orally, twice daily, for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of pimodivir on Day 1 [evening], dosing will continue until the morning of Day 6).<br>* Other names: JNJ-63623872;Other: SOC Treatment<br>* Participants may receive SOC treatment as a part of background therapy. The SOC treatment is determined by the investigator based on local practice, and may include influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of the SOC should be made before randomization. The influenza antiviral should be started no later than Day 2 morning (up to noon).<br>|
| Placebo Comparator: Treatment Arm 2 (placebo + SOC treatment)<br>Participants will receive placebo matching to pimodivir orally, twice daily, for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of placebo on Day 1 [evening], dosing will continue until the morning of Day 6) along with SOC treatment. The SOC treatment is determined by the investigator based on local practice, and may include influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of the SOC should be made before randomization. The influenza antiviral should be started no later than Day 2 morning (up to noon). An influenza antiviral as part of the SOC cannot be changed (for example, switching one influenza antiviral for another) during the treatment period, with the exception that an influenza antiviral may be discontinued in the case of a suspected AE. | Drug: Placebo<br>* Participants will receive placebo matching to pimodivir, orally twice daily for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of placebo on Day 1 [evening], dosing will continue until the morning of Day 6).<br>Other: SOC Treatment<br>* Participants may receive SOC treatment as a part of background therapy. The SOC treatment is determined by the investigator based on local practice, and may include influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of the SOC should be made before randomization. The influenza antiviral should be started no later than Day 2 morning (up to noon).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Resolution of 7 Primary Influenza-related Symptoms as Assessed by the Patient-Reported Outcome (PRO) Measure Flu-Intensity and Impact Questionnaire (Flu-iiQ) | The Flu-iiQ is a PRO that measures influenza symptom intensity (none, mild, moderate, or severe) on a 4 point Likert response rating scale ranging from 0 to 3, where 0 represents the absence of symptom and 3 represents the severe symptom. The resolution of influenza-related symptoms is defined as the beginning of the 24-hour period that 7 influenza symptoms (cough, sore throat, headache, nasal congestion, feeling feverish, body aches and pains, fatigue) are at most mild or at least back to previous level of symptom severity in case the participant reported the symptom as pre-existing. | Up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Hospitalized After Treatment Initiation | The number of participants hospitalized after treatment initiation were reported. | Up to Day 28 | 
| Viral Load Over Time | Viral load over time was measured by quantitative real time polymerase chain reaction (qRT-PCR) and viral culture in the mid-turbinate (MT) nasal swabs and endotracheal samples. | Baseline, Day 3, 6, 10, 14 | 
| Number of Participants With Emergence of Viral Resistance to Pimodivir | Emergence of viral resistance to pimodivir was detected by genotyping and/or phenotyping. Nasal MT swabs and endotracheal samples were used for sequence analysis of the polymerase basic protein (PB)2 region of the influenza polymerase gene, and of neuraminidase (NA) genes for participants using an NA inhibitor (NAI) as part of their Standard of Care (SOC). | Up to Day 28 | 
| Plasma Concentration of Pimodivir | Plasma concentration of Pimodivir was reported. | Day 3, 6, 7 | 
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | Up to Day 28 | 
| Number of Participants With Clinically Significant Changes in Laboratory Tests | Number of participants with clinically significant changes in laboratory tests were reported. Blood samples for hematology, serum chemistry, and urinalysis was collected at predefined time points for clinical laboratory testing. | Up to Day 28 | 
| Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) | Number of participants with clinically significant changes in Electrocardiogram (ECG) were reported. | Up to Day 28 | 
| Number of Participants With Clinically Significant Changes in Vital Signs | Number of participants with clinically significant changes in vital signs (temperature, pulse rate, respiratory rate and blood pressure) were reported. | Up to Day 28 |