Influenza A
Conditions
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.
Interventions
DRUGPimodivir 600 mg
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).
DRUGPlacebo
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).
OTHERSOC Treatment
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).
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
13 Years to 85 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to Day 28 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Viral Load Over Time | Baseline, Day 3, 6, 10, 14 | 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 Emergence of Viral Resistance to Pimodivir | Up to Day 28 | 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 3, 6, 7 | Plasma concentration of Pimodivir was reported. |
| Number of Participants Hospitalized After Treatment Initiation | Up to Day 28 | The number of participants hospitalized after treatment initiation were reported. |
| Number of Participants With Clinically Significant Changes in Laboratory Tests | Up to Day 28 | 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. |
| Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) | Up to Day 28 | Number of participants with clinically significant changes in Electrocardiogram (ECG) were reported. |
| Number of Participants With Clinically Significant Changes in Vital Signs | Up to Day 28 | Number of participants with clinically significant changes in vital signs (temperature, pulse rate, respiratory rate and blood pressure) were reported. |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Up to Day 28 | 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. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czechia, Estonia, France, Germany, Hungary, India, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Peru, Poland, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pimodivir + SOC Participants received 600 milligrams (mg) pimodivir twice daily (bid) on Day 1 through Day 5 along with standard of care (SOC) treatment. | 273 |
| Placebo + SOC Participants received matching placebo bid on Day 1 through Day 5 along with SOC treatment. | 271 |
| Total | 544 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 5 | 4 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Randomized, not treated | 3 | 6 |
| Overall Study | Withdrawal by Subject | 7 | 7 |
Baseline characteristics
| Characteristic | Pimodivir + SOC | Total | Placebo + SOC |
|---|---|---|---|
| Age, Continuous | 51.1 years STANDARD_DEVIATION 16.6 | 50.7 years STANDARD_DEVIATION 16.97 | 50.3 years STANDARD_DEVIATION 17.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 83 Participants | 172 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 185 Participants | 363 Participants | 178 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 27 Participants | 61 Participants | 34 Participants |
| Race (NIH/OMB) Black or African American | 33 Participants | 61 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) White | 206 Participants | 407 Participants | 201 Participants |
| Region of Enrollment ARGENTINA | 13 Participants | 25 Participants | 12 Participants |
| Region of Enrollment AUSTRALIA | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment BELGIUM | 3 Participants | 4 Participants | 1 Participants |
| Region of Enrollment BRAZIL | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment BULGARIA | 8 Participants | 10 Participants | 2 Participants |
| Region of Enrollment CANADA | 1 Participants | 4 Participants | 3 Participants |
| Region of Enrollment ESTONIA | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment FRANCE | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment GERMANY | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment HUNGARY | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment INDIA | 5 Participants | 8 Participants | 3 Participants |
| Region of Enrollment ITALY | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment LATVIA | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment LITHUANIA | 6 Participants | 11 Participants | 5 Participants |
| Region of Enrollment MALAYSIA | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment MEXICO | 3 Participants | 7 Participants | 4 Participants |
| Region of Enrollment POLAND | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment SOUTH AFRICA | 25 Participants | 58 Participants | 33 Participants |
| Region of Enrollment SOUTH KOREA | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment SPAIN | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment SWEDEN | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment TAIWAN | 2 Participants | 6 Participants | 4 Participants |
| Region of Enrollment THAILAND | 8 Participants | 13 Participants | 5 Participants |
| Region of Enrollment TURKEY | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment UKRAINE | 6 Participants | 10 Participants | 4 Participants |
| Region of Enrollment UNITED KINGDOM | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment UNITED STATES | 178 Participants | 355 Participants | 177 Participants |
| Sex: Female, Male Female | 152 Participants | 293 Participants | 141 Participants |
| Sex: Female, Male Male | 121 Participants | 251 Participants | 130 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 273 | 1 / 271 |
| other Total, other adverse events | 122 / 273 | 99 / 271 |
| serious Total, serious adverse events | 3 / 273 | 4 / 271 |
Outcome results
Primary
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.
Time frame: Up to Day 28
Population: The Intent-To-Treat infected (ITT-i) Set included all randomized participants who received at least 1 dose of study drug and who had confirmed infection with influenza A and analyzed by planned treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pimodivir + SOC | 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) | 92.62 hours |
| Placebo + SOC | 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) | 105.13 hours |
p-value: 0.0216Gehan-Wilcoxon test
Secondary
Number of Participants Hospitalized After Treatment Initiation
The number of participants hospitalized after treatment initiation were reported.
Time frame: Up to Day 28
Population: The Intent-To-Treat infected (ITT-i) Set included all randomized participants who received at least 1 dose of study drug and who had confirmed infection with influenza A and analyzed by planned treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pimodivir + SOC | Number of Participants Hospitalized After Treatment Initiation | 4 Participants |
| Placebo + SOC | Number of Participants Hospitalized After Treatment Initiation | 4 Participants |
Secondary
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.
Time frame: Up to Day 28
Population: The Safety Set (or all participants treated) included all participants who received at least one dose of study drug and were analyzed by treatment arm as treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pimodivir + SOC | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 123 Participants |
| Placebo + SOC | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 101 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)
Number of participants with clinically significant changes in Electrocardiogram (ECG) were reported.
Time frame: Up to Day 28
Population: The safety set (or all participants treated) includes all participants who received at least one dose of study drug and were analyzed by treatment arm as treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pimodivir + SOC | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) | 0 Participants |
| Placebo + SOC | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) | 0 Participants |
Secondary
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.
Time frame: Up to Day 28
Population: The Safety Set (or all participants treated) included all participants who received at least one dose of study drug and were analyzed by treatment arm as treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pimodivir + SOC | Number of Participants With Clinically Significant Changes in Laboratory Tests | 0 Participants |
| Placebo + SOC | Number of Participants With Clinically Significant Changes in Laboratory Tests | 0 Participants |
Secondary
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.
Time frame: Up to Day 28
Population: The safety set (or all participants treated) includes all participants who received at least one dose of study drug and were analyzed by treatment arm as treated.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pimodivir + SOC | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
| Placebo + SOC | Number of Participants With Clinically Significant Changes in Vital Signs | 0 Participants |
Secondary
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).
Time frame: Up to Day 28
Population: Population included participants from ITT-i set with both baseline and post-baseline sequencing data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pimodivir + SOC | Number of Participants With Emergence of Viral Resistance to Pimodivir | 4 Participants |
| Placebo + SOC | Number of Participants With Emergence of Viral Resistance to Pimodivir | 0 Participants |
Secondary
Plasma Concentration of Pimodivir
Plasma concentration of Pimodivir was reported.
Time frame: Day 3, 6, 7
Population: The Safety Set (or all participants treated) included all participants who received at least one dose of study drug and were analyzed by treatment arm as treated. Here, N (number of participants analyzed) signifies participants evaluable for this outcome measure and n (number analyzed) signifies number of participants analyzed for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pimodivir + SOC | Plasma Concentration of Pimodivir | Day 3 | 1233.0 nanograms per milliliter (ng/mL) | Standard Deviation 1912.6 |
| Pimodivir + SOC | Plasma Concentration of Pimodivir | Day 6 | 933.8 nanograms per milliliter (ng/mL) | Standard Deviation 2131.4 |
| Pimodivir + SOC | Plasma Concentration of Pimodivir | Day 7 | 276.7 nanograms per milliliter (ng/mL) | Standard Deviation 308.6 |
Secondary
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.
Time frame: Baseline, Day 3, 6, 10, 14
Population: The Intent-To-Treat infected (ITT-i) Set included all randomized participants who received at least 1 dose of study drug and who had confirmed infection with influenza A and analyzed by planned treatment. Here N (number of participants analyzed) are participants evaluable for this outcome measure and n (number analyzed) signifies number of participants analyzed for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pimodivir + SOC | Viral Load Over Time | Day 3 | 3.558 log 10 viral particles per milliliter | Standard Deviation 1.1918 |
| Pimodivir + SOC | Viral Load Over Time | Day 10 | 2.234 log 10 viral particles per milliliter | Standard Deviation 0.4586 |
| Pimodivir + SOC | Viral Load Over Time | Day 6 | 2.644 log 10 viral particles per milliliter | Standard Deviation 0.9159 |
| Pimodivir + SOC | Viral Load Over Time | Day 14 | 2.153 log 10 viral particles per milliliter | Standard Deviation 0.3904 |
| Pimodivir + SOC | Viral Load Over Time | Baseline | 5.891 log 10 viral particles per milliliter | Standard Deviation 1.5745 |
| Placebo + SOC | Viral Load Over Time | Day 14 | 2.162 log 10 viral particles per milliliter | Standard Deviation 0.4355 |
| Placebo + SOC | Viral Load Over Time | Baseline | 5.914 log 10 viral particles per milliliter | Standard Deviation 1.4947 |
| Placebo + SOC | Viral Load Over Time | Day 3 | 4.244 log 10 viral particles per milliliter | Standard Deviation 1.3535 |
| Placebo + SOC | Viral Load Over Time | Day 6 | 2.833 log 10 viral particles per milliliter | Standard Deviation 1.0432 |
| Placebo + SOC | Viral Load Over Time | Day 10 | 2.289 log 10 viral particles per milliliter | Standard Deviation 0.6279 |