A Study to Evaluate the Efficacy and Safety of Pimodivir in Combination With the Standard-of-Care Treatment in Adolescent, Adult, and Elderly Hospitalized Participants With Influenza A Infection

Phase 3

Terminated

Conditions: Influenza A

Interventions: Drug: Pimodivir 600 mg
Drug: Placebo
Other: SOC Treatment

Registration Number: NCT03376321

Lead Sponsor: Janssen Research & Development, LLC

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

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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 334

Inclusion Criteria

Tested positive for influenza A infection after the onset of symptoms using a polymerase chain reaction (PCR)-based or other rapid molecular diagnostic assay
Requires hospitalization to treat influenza infection and/or to treat complications of influenza infection (for example, radiological signs of lower respiratory tract disease, septic shock, central nervous system [CNS] involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney disease, severe dehydration, myocarditis, pericarditis, ischemic heart disease, exacerbation of underlying chronic pulmonary disease, including asthma, chronic obstructive pulmonary disease [COPD], decompensation of previously controlled diabetes mellitus), including participants admitted to the Intensive Care Unit (ICU)
Enrollment and initiation of study drug treatment less than or equal to (<=)96 hours after onset of influenza symptoms
Being on invasive mechanical ventilation or having a peripheral capillary oxygen saturation (SpO2) less than (<)94 percent (%) on room air during screening. Participants with known pre-influenza SpO2 <94% must have an SpO2 decline greater than or equal to (>=)3% from pre-influenza SpO2 during screening
Having a screening/baseline National Early Warning Score 2 (NEWS2) of >=4

Exclusion Criteria

Received more than 3 doses of influenza antiviral medication (for example, oseltamivir [OST] or zanamivir), or any dose of ribavarin (RBV) within 2 weeks, prior to first study drug intake. Received intravenous (IV) peramivir more than one 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, any history of a lung transplant)
Known allergies, hypersensitivity, or intolerance to pimodivir or its excipients

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Hospital Recovery Scale on Day 6	Day 6	The hospital recovery scale assesses a participant's clinical status. The scale provides 6 mutually exclusive conditions ordered from best to worst: 1) not hospitalized; 2) non-ICU hospitalization, not requiring supplemental oxygen; 3) non-ICU hospitalization, requiring supplemental oxygen; 4) admitted to the ICU, not requiring invasive mechanical ventilation; 5) requiring invasive mechanical ventilation; and 6) death.

Secondary Outcome Measures

Name	Time	Method
Viral Load Over Time	Baseline, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14 and 19	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.
Number of Participants With Adverse Events as a Measure of Safety and Tolerability	Up to Day 33	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.
Number of Participants With Clinically Significant Changes in Laboratory Tests	Up to Day 33	Number of participants with clinically significant changes in laboratory tests were reported. Blood samples for hematology, serum chemistry, and urinalysis were collected at predefined time points for clinical laboratory testing.
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)	Up to Day 33	Number of participants with clinically significant changes in Electrocardiogram (ECG) was reported.
Time to Hospital Discharge	Up to Day 33	The time to hospital discharge was defined as the time from start of study drug to hospital discharge.
Number of Participants With Adjudicated Influenza Complications	Up to Day 33	Influenza complications include pulmonary complications (such as respiratory failure, primary viral pneumonia, secondary bacterial pneumonia \[including pneumonia attributable to unusual pathogens\], exacerbations of chronic underlying pulmonary diseases such as chronic obstructive pulmonary disease \[COPD\] and asthma) and extrapulmonary complications (such as cardiovascular and cerebrovascular diseases \[for example, myocardial infarction, congestive heart failure, arrhythmia, stroke\], muscular disorders \[for example, myositis, rhabdomyolysis\], central nervous system \[CNS\] involvement, acute exacerbation of chronic kidney disease, decompensation of previously controlled diabetes mellitus, other infections \[for example, sinusitis and otitis\]).
Number of Participants With Emergence of Viral Resistance to Pimodivir	Up to Day 33	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).
Plasma Concentration of Pimodivir	Day 1: 1 hour30minutes to 6 hours postdose, Day 3: Predose, Day 5: Predose and 1 hour30minutes to 6 hours postdose, Day 6: 12 hours postdose	Plasma concentration of Pimodivir was reported.
Number of Participants With Clinically Significant Changes in Vital Signs	Up to Day 33	Number of participants with clinically significant changes in vital signs (temperature, pulse rate, respiratory rate and blood pressure) was reported.

Trial Locations

Locations (266): University of Alabama at Birmingham
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Birmingham, Alabama, United States
Nea Baptist Clinic
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Jonesboro, Arkansas, United States
UCSF Fresno
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Fresno, California, United States
Miller Children's at Long Beach Medical Center
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Long Beach, California, United States
Stanford University School of Medicine
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Stanford, California, United States
Destin Pulmonary Critical Care, PLLS.
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Santa Rosa Beach, Florida, United States
Northside Hospital
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Atlanta, Georgia, United States
Augusta University
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Augusta, Georgia, United States
Anne Arundel Medical Center
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Annapolis, Maryland, United States
University Of Maryland Medical Center
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Baltimore, Maryland, United States
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University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States