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
- Conditions
- Influenza A Virus
- Interventions
- Registration Number
- NCT02532283
- Lead Sponsor
- Janssen Research & Development, LLC
- Brief Summary
The purpose of this study is to evaluate the Pharmacokinetic parameters of JNJ-63623872 in combination with oseltamivir in elderly participants (aged 65 to \<= 85 years) compared to adults (aged 18 to \<= 64 years) with influenza A infection.
- Detailed Description
This is a randomized (study medication assigned to participants by chance), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), placebo-controlled, multicenter (when more than one hospital or medical school team work on a medical research study) study to evaluate the effect of JNJ-63623872 in combination with oseltamivir in participants with influenza A infection. The study consists of 3 Phases: Screening visit (1 Day), participants who meet all eligibility criteria will be randomized in a 2:1 ratio to receive study drug in double-blind treatment Phase (7 Days) and follow up Phase (21 Days). The duration of participation in the study for each participant is approximately 28 Days. Primarily Pharmacokinetic parameters of JNJ-63623872 will be measured. Participants' safety will be monitored throughout the study.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 102
- Participant requires hospitalization to treat influenza infection and/or to treat complications of influenza infection
- Participant tested positive for influenza A infection within 1 day of signing of the informed consent form (ICF)/assent form using a polymerase chain reaction (PCR)-based rapid molecular diagnostic assay
- Participants must be capable of swallowing study medication tablets and capsules
- Each participant (or their legally acceptable representative) must sign an ICF indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study
- Participant must be willing and able to adhere to the prohibitions and restrictions specified in the protocol
- Participant received more than 3 doses of the influenza antiviral medication oseltamivir, zanamivir, or peramivir since the start of the influenza symptoms, or ribavirin within 6 months prior to Screening
- Participant is unwilling to undergo regular nasal Mid-turbinate (MT) swabs or has any physical abnormality which limits the ability to collect regular nasal specimens
- Participant is immunocompromised, whether due to underlying medical condition (example, malignancy) or medical therapy (example, medications, chemotherapy, radiation, post-transplant)
- Participant is undergoing peritoneal dialysis, hemodialysis, or hemofiltration
- Participant has an estimated glomerular filtration rate (eGFR) less than or equal to (<=)30 milliliter (mL)/minute (min)/1.73 meter^2 (m^2) according to the Modification of Diet in Renal Disease (MDRD) equation, assessed at Screening or based on the most recent clinically relevant creatinine value if available
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo plus Oseltamivir Placebo Participants will be administered placebo tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. JNJ-63623872 plus Oseltamivir JNJ-63623872 Participants will be administered JNJ-63623872 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. Placebo plus Oseltamivir Oseltamivir Participants will be administered placebo tablets and oseltamivir 75 mg capsules orally twice daily for 7 days. JNJ-63623872 plus Oseltamivir Oseltamivir Participants will be administered JNJ-63623872 600 milligram (mg) tablets and oseltamivir 75 mg capsules orally twice daily for 7 days.
- Primary Outcome Measures
Name Time Method Maximum Observed Plasma Concentration (Cmax) of Pimodivir Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3 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).
Minimum Observed Plasma Concentration (Cmin) of Pimodivir Pre-dose, 1, 2, 4, 6, 8, 10 and 12 hours post-dose on Day 3 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).
Area Under the Plasma Concentration-time Curve From Time of Administration to 12 Hours After Dosing (AUC [0-12]) of Pimodivir 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).
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Influenza Complications Up to 28 Days 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.
Change From Baseline in Influenza Patient-Reported Outcome Questionnaire (FLU-PRO) Total Score 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).
Time to Improvement of Respiratory Status 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).
Time to Return to Premorbid Functional Status 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?).
Time to Influenza A Viral Negativity Up to 14 Days 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.
Time to Improvement of Vital Signs 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).
Percentage of Participants With Clinical Outcome Based on Ordinal Scale 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.
Time to Significant Reduction in FLU-PRO Influenza Symptom Severity 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).
Percentage of Participants With Significant Reduction in FLU-PRO All Influenza Symptoms (Mild or None for All Symptoms) 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).
Number of Participants With the Emergence of Drug Resistance Mutations With Oseltamivir (OST) and Pimodivir Up to 28 Days Number of participants with emergence (from baseline) of drug resistance mutations detected by genotype or phenotype were reported.
Time to Hospital Discharge Up to 28 Days Time to hospital discharge was calculated from the date of first study drug intake during hospitalization up to date of discharge.
Time to Return to Usual Health 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?).
Influenza Viral Load Over Time Baseline, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 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.
Rate of Decline in Viral Load Up to Day 7 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.
Area Under the Plasma Concentration-time Curve (AUC) of Viral Load Baseline up to Day 8 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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious AEs (TESAEs) Up to 28 Days 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.