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

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.

• Pimodivir 600 mg (Drug): Participants will receive pimodivir 600 mg orally twice daily for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of pimodivir on Day 1 \[evening\], dosing will continue until the morning of Day 6). Participants who meet treatment extension criteria may receive an additional 5 day course of the same treatment as received at study start (on Days 6 through 10).
• Placebo (Drug): Participants will receive placebo matching to pimodivir, orally twice daily for 5 days (on Days 1 through 5; for participants who will receive only 1 dose of placebo on Day 1 \[evening\], dosing will continue until the morning of Day 6). Participants who meet treatment extension criteria may receive an additional 5 day course of the same treatment as received at study start (on Days 6 through 10).
• SOC Treatment (Other): Participants may receive SOC treatment as a part of background therapy. The SOC treatment is determined by the investigator based on local practice, and may include influenza antivirals and/or supportive care only. The choice to use influenza antivirals as part of the SOC should be started no later than the day when participants initially receive pimodivir. An influenza antiviral as part of the SOC cannot be changed (for example, switching one influenza antiviral for another) during either the treatment period or extension phase, with the exception that an influenza antiviral may be discontinued in the case of a suspected AE.

Primary outcomes

• 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 outcomes

• 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 \[for example, sinusitis and otitis\]).
• 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 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 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.
• 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.

Sex: All, ages: 13 Years to 85 Years

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

Participant flow

Outcome results

• Number of Participants With Hospital Recovery Scale on Day 6 (Primary), Count of participants, Participants: Pimodivir + SOC 73; Placebo + SOC 69
• Time to Hospital Discharge (Secondary), Median, hours: Pimodivir + SOC 113 (94.20 to 118.50); Placebo + SOC 108 (92.70 to 116.30)
• Number of Participants With Adjudicated Influenza Complications (Secondary), Count of participants, Participants: Pimodivir + SOC 28; Placebo + SOC 29
• Viral Load Over Time (Secondary), Mean, Log 10 viral particles per milliliter: Pimodivir + SOC 5.657 +/- 1.4693; Placebo + SOC 5.655 +/- 1.4117
• Number of Participants With Adverse Events as a Measure of Safety and Tolerability (Secondary), Count of participants, Participants: Pimodivir + SOC 85; Placebo + SOC 84
• Number of Participants With Emergence of Viral Resistance to Pimodivir (Secondary), Count of participants, Participants: Pimodivir + SOC 0; Placebo + SOC 3
• Plasma Concentration of Pimodivir (Secondary), Mean, Nanogram per milliliter (ng/mL): Pimodivir + SOC 1696.3 +/- 2298.4
• Number of Participants With Clinically Significant Changes in Laboratory Tests (Secondary), Count of participants, Participants: Pimodivir + SOC 0; Placebo + SOC 0
• Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) (Secondary), Count of participants, Participants: Pimodivir + SOC 0; Placebo + SOC 0
• Number of Participants With Clinically Significant Changes in Vital Signs (Secondary), Count of participants, Participants: Pimodivir + SOC 0; Placebo + SOC 0

Adverse events

Time frame: Up to Day 33

Serious adverse events by term

Other adverse events by term

112 more terms not shown.

Limitations and caveats: As the study was terminated early after a pre-planned interim analysis which showed futility, the Sponsor decided not to perform the complete analysis planned per protocol. Hence, data was collected and analyzed for safety and selected efficacy parameters only.

169 more sites not listed.

• Results publication: Leopold L, Vingerhoets J, Deleu S, Nalpas C, Weber K, van Dromme I, Lowson D, Michiels B, van Duijnhoven W. Efficacy and Safety of Pimodivir Combined With Standard of Care in Hospitalized and Nonhospitalized High-Risk Adolescents and Adults With Influenza A Infection. J Infect Dis. 2025 Feb 4;231(1):e132-e143. doi: 10.1093/infdis/jiae408. PMID 39172627
• Results publication: Young B, Tan TT, Leo YS. The place for remdesivir in COVID-19 treatment. Lancet Infect Dis. 2021 Jan;21(1):20-21. doi: 10.1016/S1473-3099(20)30911-7. Epub 2020 Nov 26. No abstract available. PMID 33248473

• Study Protocol (PDF, 2019-06-11)
• Statistical Analysis Plan (PDF, 2020-07-01)

• Janssen Research & Development, LLC Clinical Trial, Study director, Janssen Research & Development, LLC

NIH grants: 2017