A Study of Rilematovir in Infants and Children and Subsequently in Neonates Hospitalized With Acute Respiratory Tract Infection Due to Respiratory Syncytial Virus (RSV)

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy of rilematovir compared to placebo treatment with respect to the clinical outcome on the RSV Recovery Scale (RRS).

Detailed Description
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Respiratory syncytial virus (RSV), a negative-stranded ribonucleic acid (RNA) virus belonging to the Pneumoviridae family, is considered the most important cause of acute lower respiratory tract infection (LRTI) in infants and young children. In most patients, RSV results in upper respiratory tract infection (URTI) eliciting common cold-like symptoms, which might last up to 2 weeks, and are usually self-limiting. RSV-related LRTI is a major cause of hospital admissions and death in young children worldwide. Rilematovir is an investigational, small molecule, RSV fusion inhibitor. This study aims to evaluate the efficacy and safety of rilematovir in hospitalized infants and children (greater than or equal to [>=] 28 days to less than or equal to [<=] 5 years) and, subsequent to completion of the neonatal substudy, in hospitalized neonates (born at term, less than [<] 28 days of age) with RSV infection. The study will include a Screening Period, a Treatment Period, and a Follow-up Period. The total study duration for each participant will be approximately 36 days (Screening included). The efficacy assessments include evaluation under the RRS and the safety assessments include evaluations of physical examinations, vital signs, electrocardiograms, clinical laboratory tests, and adverse events.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Rilematovir in Infants and Children (≥28 Days to ≤5 Years of Age) and Subsequently in Neonates (<28 Days of Age), Hospitalized With Acute Respiratory Tract Infection Due to Respiratory Syncytial Virus (RSV)

Conditions
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Respiratory Tract Infections

Intervention / Treatment
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* Drug: Rilematovir
* Drug: Rilematovir X mg/kg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: The participant weighs within greater than or equal to (>=) 2.4 kilograms (kg) and less than or equal to (<=) 24.6 kg Each participant's parent(s) (preferably both if available or as per local requirements) or their legally acceptable representative(s) has/have signed an informed consent form (ICF) indicating that (s)he understands the purpose of, and procedures required for, the study; is willing for their child to participate in the study; with regards to the concomitant medication, the lifestyle consideration and study procedures and assessments to be performed by the parent(s)/caregiver(s) as well as those by the investigator/study site personnel The participant has an acute respiratory illness with at least 1 of the signs/symptoms within 24 hours prior to start of screening and at screening, as evaluated by the investigator in Upper respiratory tract infection: nasal congestion or rhinorrhea; and Lower respiratory tract infection: increased respiratory effort (as evidenced by subcostal, intercostal or tracheosternal retractions, grunting, head bobbing, nasal flaring, or tachypnea), wheezing, cough, cyanosis, or apnea; and systemic/general: feeding difficulties (defined as <75 percent [%] intake of normal food amounts); dehydration; fever; disturbed sleep, or disturbed activity level (irritable/restless/agitated/less responsive). Cough or wheezing cannot be the only LRTI sign/symptom present, that is, at least one other LRTI sign/symptom needs to be present for eligibility The time of onset of RSV signs/symptoms to the anticipated time of randomization must be less than or equal to (<=) 3 days. Onset of signs/symptoms is defined as the time of the day (or part of the day if time of the day cannot be specified) the parent(s)/caregiver(s) became aware of the first sign and/or symptom consistent with respiratory or systemic/general manifestation of signs/symptoms of RSV infection. The time of sign/symptom onset has to be assessed as accurately as possible Participants are otherwise healthy or have (a) risk factor(s) for severe RSV disease Exclusion criteria: The participant has had either confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (test positive) during the four weeks prior to randomization, or close contact with a person with COVID-19 (test confirmed or suspected SARS CoV-2 infection) within 14 days prior to randomization Confirmed QT interval corrected for heart rate according to Fridericia's formula (QTcF) interval greater than (>) 450 milliseconds (msec) per the machine read parameter result at screening. Presence of an abnormal QTcF interval should be confirmed by repeat electrocardiogram (ECG) recording during screening Known personal or family history of Long QT Syndrome or sudden cardiac death Presence of repetitive ventricular premature contractions (>10/minutes [min]), second- or third-degree heart block, or complete or incomplete left bundle branch block, or complete right bundle branch block per the machine read ECG result at screening. Presence of any of the above abnormalities should be confirmed by repeat ECG recording during screening

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rilematovir<br>Participants will receive rilematovir orally based on body weight and age group. | Drug: Rilematovir<br>* Participants of age group greater than or equal to (>=) 28 days to less than (<) 3 months (age group 1) or >= 3 months to < 6 months (age group 2) or >= 6 months to less than or equal to (<=) 5 years (age group 3) will receive rilematovir orally twice a day (BID) from Days 1 to Day 7 or Day 8.<br>* Other names: JNJ-53718678;Drug: Rilematovir X mg/kg<br>* Participants of age group birth at term (after at least 37 weeks of gestation) to < 28 days (age group 4) will receive rilematovir orally BID from Days 1 to Day 7 or Day 8. The dose is dependent on outcome of the substudy in neonates and following independent data monitoring (IDMC) review and recommendation.<br>* Other names: JNJ-53718678;|
| Experimental: Placebo<br>Participants will receive matching placebo of rilematovir based on body weight and age group. | Drug: Placebo<br>* Participant of age group 1, 2, 3 and 4 will receive matching placebo of rilematovir BID from Days 1 to Day 7 or Day 8 as per assigned age group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants by Respiratory Syncytial Virus (RSV) Recovery Scale (RRS) Category | RRS was an ordinal scale to assess a participant's clinical status. The RRS provided 7 mutually exclusive categories ordered from best (1) to worst (7) where 1 =home without signs/symptoms, 2 =home with sign/symptoms, 3 =ward without supplemental oxygen (O2) or feeding/hydration, 4 =ward with supplemental or feeding/hydration, 5 =intensive care unit (ICU) without mechanical ventilation (included both invasive and non-invasive mechanical ventilation), 6 =required mechanical ventilation and 7=worst (death). Higher category indicates worse condition. With or without signs/symptoms was defined as the key RSV signs/symptoms (breathing problems, retractions, tachypnea, cough, wheezing/breathing sounds, and tachycardia) resolved (absent or mild) or not resolved assessed by parent/caregiver. | Baseline to Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Clinically Resolved From RSV Disease Based on the Clinician Reported Outcome (ClinRO) Sign/Symptoms at Day 8 | Clinically resolved was defined as participant required no oxygen supplementation, no supplemental feeding/hydration, no need for ICU and had Key RSV signs/symptoms resolved to absent or mild as per ClinRO signs/symptoms. Clinically resolved Key RSV signs/symptoms were assessed based on clinician's observations as resolved if participant had no retractions, tachypnea, tachycardia, breathing problems (nasal flaring, head bobbing, grunting); cough (resolved if little or no coughing or occasional strong cough or sometimes productive) and wheezing (resolved if no wheezing or terminal expiratory wheezing or only with stethoscope). | Day 8 | 
| Time From First Study Dose to Resolution of Key RSV Signs/Symptoms Based on Observer Reported Outcome (ObsRO) After Free of Supplementation (Oxygen/Feeding/Hydration) for at Least 24 Hours | Time (in hours) from first dose of study intervention to first resolution of key RSV signs/symptoms was evaluated based on ObsRO assessment after free of supplementation (O2/feeding/hydration) for at least 24 hours. Clinically resolved was defined as participant required no oxygen supplementation, no supplemental feeding/hydration, no need for ICU and had key RSV signs/symptoms resolved to absent or mild as per ObsRO signs/symptoms. Resolution of key signs/symptoms assessment was based on observations of child's parent/caregiver as resolved if no retractions, tachypnea, tachycardia, breathing problems (gasping for air nostrils, flaring when breathing, head bobbed back and forth when breathing), no breathing sound; cough (no coughing, little coughing without problems). Kaplan-Meier method was used for estimation. | Up to Day 21 | 
| Number of Participants With Post-baseline RSV-related Complications | RSV related complications included respiratory complications (respiratory failure, apnoeic attacks, bronchiolitis, bronchial obstruction, pneumonia and asthmatic crisis), infectious complications (otitis media, bacterial respiratory tract infections and sepsis), cardiovascular complications (arrhythmia, cardiogenic shock, hemodynamic instability, congestive cardiac failure), acid-base or electrolyte complications (metabolic acidosis, metabolic alkalosis, hyponatremia, hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypoglycemia and hyperglycemia). Participants were counted only once, regardless of the number of complications they actually experienced. | Up to Day 35 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product and did not necessarily have a causal relationship with the treatment. A TEAE was defined as an AE with an onset after the initiation study drug (Day 1) up to end of study (Day 35). AEs included both serious and non-serious AEs. | Day 1 up to Day 35 | 
| Number of Participants With Abnormalities in Clinical Laboratory Values | Number of participants with abnormally low (AL) and abnormally high (AH) values of bicarbonate, direct bilirubin, urea nitrogen, basophils, eosinophils, erythrocyte (Ery). mean corpuscular hemoglobin (HGB) concentration (conc), Ery. mean corpuscular hemoglobin, erythrocytes, leukocytes, lymphocytes, monocytes, neutrophils and reticulocytes were reported based on the investigator's discretion. | Up to Day 35 | 
| Number of Participants With Abnormalities in Electrocardiograms (ECGs) | Number of participants with abnormally low and abnormally high values of ECG parameters (PR interval and RR interval) as assessed based on the investigator's discretion were reported. | Up to Day 35 | 
| Number of Participants With Abnormalities in Vital Signs | Number of participants with abnormally low and abnormally high values of vital signs from baseline were assessed based on investigator's discretion. Vital signs included systolic blood pressure (SBP) (millimeter of mercury [mmHg]), diastolic blood pressure (DBP) (mmHg), pulse rate (beats per minute), respiratory rate (breaths per minute), temperature (degree Celsius) and oxygen saturation (in percentage). | Up to Day 35 | 
| Percentage of Participants Requiring Intensive Care Unit (ICU) Stay After First Dose of Rilematovir | Percentage of participants requiring ICU stay was analyzed and reported. | Up to Day 35 | 
| Duration of ICU Stay | Duration (in hours) of ICU stay was defined as total number of hours a participant experienced an ICU stay from first dose of rilematovir until study termination, calculated as the sum of all separate records of ICU stay. | Up to Day 35 | 
| Percentage of Participants Requiring Re-hospitalization for Respiratory/Other Reasons | Percentage of participants requiring re-hospitalization (participants re-hospitalized [ward or ICU] after been discharged from hospital) for respiratory/other reasons were reported. | Up to Day 35 | 
| Percentage of Participants Requiring Oxygen Supplementation After First Dose of Rilematovir | Percentage of participants requiring any type of oxygen supplementation (invasive mechanical ventilation, non-invasive mechanical ventilation and non-invasive non-mechanical ventilation) were reported. | Up to Day 35 | 
| Duration of Oxygen Supplementation | Duration (in hours) of oxygen supplementation was defined as total number of hours a participant used supplemental oxygen from either prior to first dose and/or after first dose of drug until study termination, calculated as the sum of all separate records of supplementation. | Up to Day 35 | 
| Percentage of Participants Requiring Hydration and/or Feeding by Intravenous (IV) Administration or Nasogastric Tube After First Dose of Rilematovir | Percentage of participants requiring any type of hydration and/or feeding by intravenous (IV) administration or nasogastric tube or percutaneous endoscopic gastrostomy was reported. | Up to Day 35 | 
| Duration of Supplemental Feeding/Hydration | Duration (in hours) of supplemental feeding/hydration was defined as total number of hours a participant was administered feeding/hydration supplementation from either prior to first dose and/or after first dose of drug until study termination, calculated as the sum all separate records of supplementation use per participant. | Up to Day 35 | 
| Number of Participants With Medical Encounters and Treatments | Medical resource utilization was assessed by medical care encounters and treatments. Medical encounters and treatments included physician or emergency room visits, tests and procedures, and medications, surgeries and other selected procedures, inpatient and outpatient. | Up to Day 35 | 
| RSV Viral Load at Baseline, Days 2, 3, 5, 8, 14 and 21 | Antiviral activity was determined based on measurements of RSV viral load which was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in the mid-turbinate (MT) nasal swab specimens. | Baseline, Days 2, 3, 5, 8, 14 and 21 | 
| Change From Baseline in RSV Viral Load at Days 2, 3, 5, 8, 14 and 21 | Antiviral activity was determined based on measurements of RSV viral load which was measured by qRT-PCR in the MT nasal swab specimens. | Baseline, Days 2, 3, 5, 8, 14 and 21 | 
| Percentage of Participants With Undetectable RSV Viral Load | Percentage of participants with undetectable RSV viral load was analyzed. | Baseline, Days 2, 3, 5, 8, 14 and 21 | 
| Plasma Concentrations of Rilematovir | Plasma concentrations of rilematovir were assessed. Participant wise data were reported for this outcome measure. | 1 hour Post-dose (Day 1) and pre-dose (Day 2) | 
| Percentage of Participants With Acceptability and Palatability of the Rilematovir Formulation as Assessed by Parent(s)/Caregiver(s) | Acceptability and palatability were assessed by clinician electronic clinical outcome assessment (eCOA) questionnaire which consisted of 7 questions, 1- child took medicine easily, 2- disgusted expressions after tasting medicine, 3- cried after tasting medicine, 4- would not open mouth or turned head away to avoid medicine, 5- spit out or coughed out medicine, 6- gagged, 7- vomited (within 2 minutes of swallowing medicine). | Day 8 |