A Phase 2b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine (JNJ-64041575) Regimens in Hospitalized Adult Subjects Infected With Human Metapneumovirus
Overview
- Phase
- Phase 2
- Intervention
- Lumicitabine
- Conditions
- Metapneumovirus
- Sponsor
- Janssen Research & Development, LLC
- Locations
- 112
- Primary Endpoint
- Area Under the Concentration-Time Curve (AUC) of Human Metapneumovirus (hMPV) Viral Load
- Status
- Withdrawn
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to determine in hospitalized adult participants infected with human metapneumovirus (hMPV - a virus closely related to respiratory syncytial virus (RSV) and has been identified as an important cause of acute respiratory infections, affecting all age groups) the dose-response relationship of multiple regimens of lumicitabine on antiviral activity based on nasal hMPV shedding using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay.
Detailed Description
The study consists of 3 phases: screening phase, treatment phase (Day 1 to Day 5/6 \[depending on timing of loading dose\]), and follow-up phase of 28 days post randomization. Participants will have assessments at Days 7, 10, 14, and 28 to evaluate safety, efficacy, and pharmacokinetics (PK). The primary hypothesis of study is a positive dose-response relationship of active treatment on average hMPV viral load area under concentration versus time curve (AUC) over 7 days, meaning that either average AUC on pooled active treatments is lower than on placebo, or average AUC on high active dose is lower than average AUC on placebo using multiple contrast testing. Based on review of PK, efficacy and safety data, Independent Data Monitoring Committee (IDMC) may recommend modifications to study design that is changes in dose and treatment duration.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants hospitalized (or in Emergency room prior to hospitalization) at the time of randomization and unlikely to be discharged for the first 24 hours after randomization
- •Participants diagnosed with human metapneumovirus (hMPV) infection using a rapid polymerase chain reaction (PCR)-based molecular diagnostic assay, with or without coinfection with another respiratory pathogen (respiratory virus or bacteria)
- •Participants with an acute respiratory illness with signs and symptoms consistent with a viral infection (for example, fever, cough, nasal congestion, runny nose, sore throat, myalgia, lethargy, shortness of breath, or wheezing) with onset less than or equal to (\<=)5 days from the anticipated time of randomization
- •With the exception of the symptoms related to hMPV infection, participants must be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population, and/or the hMPV infection. This determination must be recorded in the participant's source documents and initialed by the investigator
- •A woman must have a negative urine pregnancy test (beta-human chorionic gonadotropin \[b-hCG\]) at screening
Exclusion Criteria
- •Participants who are not expected to survive for more than 48 hours
- •Participants who have had major thoracic or abdominal surgery in the 6 weeks prior to randomization
- •Participants who are considered by the investigator to be immunocompromised within the past 12 months, whether due to underlying medical condition (for example, malignancy or genetic disorder) or medical therapy (for example, medications other than corticosteroids for the treatment of chronic obstructive pulmonary disease (COPD) or asthma exacerbations, chemotherapy, radiation, stem cell or solid organ transplant)
- •Participants undergoing peritoneal dialysis, hemodialysis, or hemofiltration or with an estimated glomerular filtration rate (GFR, determined by Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation) of (\<) 60 milliliters per minute (mL/min) per 1.73 meter square (m\^2)
- •Participants with a known history of human immunodeficiency virus (HIV) or chronic viral hepatitis
Arms & Interventions
Regimen A (Low-Dose Lumicitabine)
Participants will receive a single 750 milligram (mg) loading dose (LD) (Dose 1) of lumicitabine and matching placebo followed by nine 250 mg tablets as maintenance doses (MDs) (Doses 2 to 10) of lumicitabine and matching placebo administered twice daily during Day 1 to Day 5/6 (depending on the timing of the LD).
Intervention: Lumicitabine
Regimen A (Low-Dose Lumicitabine)
Participants will receive a single 750 milligram (mg) loading dose (LD) (Dose 1) of lumicitabine and matching placebo followed by nine 250 mg tablets as maintenance doses (MDs) (Doses 2 to 10) of lumicitabine and matching placebo administered twice daily during Day 1 to Day 5/6 (depending on the timing of the LD).
Intervention: Placebo
Regimen B (High-Dose Lumicitabine)
Participants will receive a single 1000 mg LD (Dose 1) of lumicitabine followed by nine 500 mg tablets as MDs (Doses 2 to 10) of lumicitabine and matching placebo tablet, administered twice daily during Day 1 to Day 5/6 (depending on the timing of the LD).
Intervention: Lumicitabine
Regimen B (High-Dose Lumicitabine)
Participants will receive a single 1000 mg LD (Dose 1) of lumicitabine followed by nine 500 mg tablets as MDs (Doses 2 to 10) of lumicitabine and matching placebo tablet, administered twice daily during Day 1 to Day 5/6 (depending on the timing of the LD).
Intervention: Placebo
Regimen C (Placebo)
Participants will receive a placebo LD (Dose 1) followed by nine MDs (Doses 2 to 10) of matching placebo, administered twice daily during Day 1 to Day 5/6 (depending on the timing of the LD).
Intervention: Placebo
Outcomes
Primary Outcomes
Area Under the Concentration-Time Curve (AUC) of Human Metapneumovirus (hMPV) Viral Load
Time Frame: Baseline up to Day 7
The AUC of hMPV ribonucleic acid (RNA) logarithm base 10 (log10) viral load (measured by quantitative real time reverse transcriptase polymerase chain reaction \[qRT-PCR\] in the mid-turbinate nasal swab specimens) is estimated by analyzing mean log10 viral load values over time using a restricted maximum likelihood based repeated measures approach.
Secondary Outcomes
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability(Up to 28 days)
- Number of Participants with an Abnormal Electrocardiogram (ECG) Reading as a Measure of Safety and Tolerability(Up to 28 days)
- Length of Hospital Stay from Study Treatment Initiation to Discharge(From study treatment initiation to discharge (Up to 28 days))
- Percentage of Enrolled Participants Who Require Hydration and/or Feeding by Intravenous (IV) Catheter or Nasogastric Tube(Up to 28 days)
- Number of Participants With Treatment-Emergent Complications(Up to 28 days)
- Time to Peak hMPV Viral Load(Up to 28 days)
- AUC of hMPV Viral Load in Participants Assigned to a Longer Dosing Duration From Baseline Until 1 day After the Last Dose of Study Drug(Baseline Until 1 day After the Last Dose of Study Drug (approximately up to 12 days))
- Number of Participants With Postbaseline Changes in the hMPV Polymerase Lgene and Other Regions of the hMPV Genome Compared With Baseline Sequences(Up to 28 days)
- Number of Participants with an Abnormal Vital Signs/Peripheral Capillary Oxygen Saturation (SpO2) Reading as a Measure of Safety and Tolerability(Up to 28 days)
- Number of Participants with Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability(Up to 28 days)
- Area Under the Plasma Concentration-Time Curve (AUC) of JNJ-63549109(Dose 1: 0.5 to 1 hour postdose, and 2 to 3 hours postdose; Dose 2: predose, and 3 to 6 hours postdose; Dose 3 and 10: predose)
- Length of Hospital Stay from Admission to Readiness for Discharge(From admission to readiness for discharge discharge (Up to 28 days))
- Percentage of Participants Requiring Admission to the Intensive Care Unit (ICU)(Up to 28 days)
- Duration of ICU Stay(Up to 28 days)
- Percentage of Participants Requiring Oxygen Supplementation/Noninvasive Mechanical Ventilation Support(Up to 28 days)
- Number of Participants with an Abnormal Physical Examination Findings (Height, Body Weight, Respiratory System, Nose, Ear, Throat, Facial and Neck Lymph Nodes, and Skin Examination) as a Measure of Safety and Tolerability(Up to 28 days)
- Length of Hospital Stay from Admission to Discharge(From admission to discharge (Up to 28 days))
- Duration of Oxygen Supplementation/Noninvasive Mechanical Ventilation Support(Up to 28 days)
- Percentage of Participants Requiring Invasive Mechanical Ventilation Support(Up to 28 days)
- Time to no Longer Requiring Supplemental Oxygen(Up to 28 days)
- Time for Peripheral Capillary Oxygen Saturation (SpO2) Return to Pre-hMPV Infection Status(Up to 28 days)
- Time for Body Temperature to Return to Pre-hMPV Infection Status(Up to 28 days)
- Change From Baseline in the National Early Warning Score (NEWS) Over Time(Baseline up to 28 days)
- Number of Participants With All-Cause Mortality(Up to 28 days)
- Time to hMPV Ribonucleic Acid (RNA) Being Undetectable(Up to 28 days)
- Percentage of Participants With Undetectable hMPV Viral Load at Each Timepoint(From Day 1 to Day 7 and on Day 10, Day 14, and Day 28)
- Maximum Observed Plasma Concentration (Cmax) of JNJ-63549109(Dose 1: 0.5 to 1 hour postdose, and 2 to 3 hours postdose; Dose 2: predose, and 3 to 6 hours postdose; Dose 3 and 10: predose)
- Concentration at 12 Hours Postdose (C12h) of JNJ-63549109(Days 1, 2, and 5/6: 12 hours postdose)
- Ordinal Scale(Day of last dose (Day 5 or Day 6))
- Length of Hospital Stay from Study Treatment Initiation to Readiness for Discharge(From study treatment initiation to readiness for discharge (Up to 28 days))
- hMPV Viral Load Over Time(Up to 28 days)
- Duration of Invasive Mechanical Ventilation Support(Up to 28 days)
- Time to Return to Pre-hMPV Infection Functional Status (Katz Activities of Daily Living [ADL] score)(Up to 28 Days)
- Peak hMPV Viral Load(Up to 28 days)
- Rate of Decline of hMPV Viral Load(Up to 28 days)
- Time to Clinical Stability(Up to 28 days)
- Number of Hours from Initiation of Study Treatment Until SpO2 is Greater Than or equal to (>=) 93 Percent (%) on Room air(Up to 28 days)
- Time for Respiratory Rate to Return to Pre-hMPV Infection Status(Up to 28 days)
- Number of Participants With Bacterial Superinfections Reported as AEs(Up to 28 days)
- AUC of hMPV Viral Load From Baseline up to Day 10(Baseline up to Day 10)
- AUC of hMPV Viral Load from Baseline up to Day 14(Baseline up to Day 14)