A Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine (JNJ-64041575) Regimens in Hospitalized Infants and Children Aged 28 Days to 36 Months Infected With Respiratory Syncytial Virus

Study Overview
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Brief Summary
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The purpose of this study is to determine in hospitalized infants and children who are infected with respiratory syncytial virus (RSV) the dose-response relationship of multiple regimens of lumicitabine on antiviral activity based on nasal RSV shedding using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR).

Detailed Description
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RSV is a leading cause of lower respiratory tract disease in infants. Most infants and children who get RSV recover fully after 1-2 weeks, but RSV infection can sometimes worsen and may lead to hospitalization and admission into an intensive care unit. The main purpose of this study is to learn how well the study drug (lumicitabine, also known as JNJ-64041575 or ALS-008176) works, how the human body handles the study drug, which dose of the study drug is effective for treatment of RSV infection in infants/children and how safe it is compared to a placebo (placebo looks just like lumicitabine [given in same way] but has no effect against RSV). Approximately up to 180 participants aged between 28 days to 36 months and hospitalized with RSV infection will take part in this world-wide study.

Official Title
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A Phase 2, 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 Infants and Children Aged 28 Days to 36 Months Infected With Respiratory Syncytial Virus

Conditions
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Respiratory Syncytial Viruses

Intervention / Treatment
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* Drug: Lumicitabine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants hospitalized (or in emergency room [ER]) at the time of randomization and unlikely to be discharged for the first 24 hours after randomization Participants diagnosed with respiratory syncytial virus (RSV) infection using a polymerase chain reaction (PCR)-based molecular diagnostic assay, with or without co-infection with another respiratory pathogen (respiratory virus or bacteria) Participants who have 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. Onset of symptoms is defined as the first time (within 1 hour) the parent(s)/caregiver(s) becomes aware of respiratory or systemic symptoms of RSV infection With the exception of the symptoms related to the RSV infection or defined comorbid condition for severe RSV disease (prematurity at birth [participant's gestational age was less than {<}37 weeks; for infants <1 year old at randomization], bronchopulmonary dysplasia, congenital heart disease, other congenital diseases, Down syndrome, neuromuscular impairment, or cystic fibrosis), participant must be medically stable on the basis of physical examination, medical history, vital signs/peripheral capillary oxygen saturation (SpO2), and electrocardiogram (ECG) performed at screening. If there are abnormalities, they must be consistent with the underlying condition in the study population and/or the RSV infection. This determination must be recorded in the participant's source documents and initialed by the investigator. Participants with comorbidities will be allowed to be enrolled once the Independent Data Monitoring Committee (IDMC) has reviewed the pharmacokinetic (PK) and safety data of the highest dose that will be used in this study and once the IDMC has recommended opening recruitment to this group. Sites will be notified when the restriction is lifted The participant's estimated glomerular filtration rate (eGFR) is not below the lower limit of normal for the participant's age 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 have a known or suspected immunodeficiency (except immunoglobulin A [IgA] deficiency), such as a known human immunodeficiency virus infection Participants being treated with extracorporeal membrane oxygenation Participant receiving chronic oxygen therapy at home prior to admission Participants who have a poorly functioning gastrointestinal tract (that is, unable to absorb drugs or nutrition via enteral route)

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 36 Months

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: Regimen A (Low-Dose Lumicitabine)<br>Participants will receive a single 40 milligram per kilogram (mg/kg) loading dose (LD) (Dose 1) followed by nine 20 mg/kg maintenance doses (MDs) (Doses 2 to 10) of lumicitabine twice daily up to Day 5/6. | Drug: Lumicitabine<br>* Participants will receive oral administration of lumicitabine.<br>* Other names: JNJ-64041575;|
| Experimental: Regimen B (High-Dose Lumicitabine)<br>Participants will receive a single 60 mg/kg LD (Dose 1) followed by nine 40 mg/kg MDs (Doses 2 to 10) of lumicitabine twice daily up to Day 5/6. | Drug: Lumicitabine<br>* Participants will receive oral administration of lumicitabine.<br>* Other names: JNJ-64041575;|
| Placebo Comparator: Regimen C (Placebo)<br>Participants will receive either a single 40 mg/kg placebo LD (Dose 1) followed by nine 20 mg/kg maintenance dose (MDs) (Doses 2 to 10) of placebo twice daily or single 60 mg/kg placebo LD (Dose 1) followed by nine 40 mg/kg placebo MDs (Doses 2 to 10), twice daily up to Day 5/6. | Drug: Placebo<br>* Participants will receive oral administration of matching placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) of Respiratory Syncytial Virus (RSV) Viral Load | AUC of RSV viral load was measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay of the mid-turbinate nasal swab. | Day 1 to 7: Predose, 0.25 and 2 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Emergent Adverse Event | 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 the treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. All AEs reported during treatment or follow-up were considered emergent and were included in the analysis. | Up to 28 days | 
| Number of Participants With Clinically Significant Physical Examinations Abnormalities | The number of participants with clinically significant physical examination (respiratory system, nose, ear, throat, facial and neck lymph nodes, and skin examination) abnormalities that emerged after treatment initiation was reported. | Up to 28 days | 
| Number of Participants With Emergent Clinical Relevant Vital Signs Abnormalities | The number of participants with emergent clinically relevant vital signs (temperature, pulse rate, respiratory rate, diastolic blood pressure, systolic blood pressure, oxygen saturation) abnormalities that emerged after treatment initiation reported. An abnormality was considered emergent in a particular phase if it is worse than baseline. If baseline is missing, the abnormality is always considered as emergent. A shift from 'abnormally low' at baseline to 'abnormally high' post baseline (or vice versa) was also emergent. | Up to 28 days | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | The number of participants with ECG (QT, and QTc intervals) abnormalities reported. | Up to 28 days | 
| Number of Participants With Worst Emergent Laboratory Abnormalities (Division of Microbiology and Infectious Diseases [DMID] Toxicity Grades) | Number of participants with Laboratory (hematology, serum chemistry, and urinalysis) abnormalities reported based on DMID toxicity grading scale. DMID toxicity grades ranges from 1 to 4. Grade 0 is normal and not meeting the criteria of Grade 1-4. Hb: Grade 1: for 22-35 days old- 9.5-10.5 gram per deciliter (g/dL); for 36-60 days old- 8.5-9.4 g/dL; for 61-90 days old- 9.0-9.9 g/dL; Hb: Grade 2: for 22-35 days old- 8.0-9.4 g/dL, for 36-60 days old- 7.0-8.4 g/dL; for 61-90 days old- 7.0-8.9 g/dL. ALT: Grade 1- 1.1 - <2.0*Upper limit of normal (ULN); Creatinine: Grade 2- 1.8-2.4 milligram per deciliter (mg/dL); Hyperkalemia: Grade 1- 3.0-3-5 milliequivalents per Liter (mEq/L); ANC: Grade 1: for 7-60 days old- 1200-1800/ millimeter cube(mm^3); for 61-90 days old- 750-1200/mm^3; ANC: Grade 3: for 7-60 days old- 500-899/mm^3, for 61-90 days old- 250-399/mm^3; ANC: Grade 4- for 7-60 days old <500/mm^3, for 61-90 days old- <250/mm^3; Platelets: Grade 3: 25000 - 49999/mm^3. | Up to 28 days | 
| Maximum Observed Plasma Concentration (Cmax) of JNJ-63549109 (Metabolite of Lumicitabine) | Cmax is the maximum observed plasma concentration of JNJ-63549109 (Metabolite of Lumicitabine). | Day 1 and Day 5 | 
| Area Under Plasma Concentration-time Curve (AUC) of JNJ-63549109 (Metabolite of Lumicitabine) | AUC is the area under the plasma concentration-time curve of JNJ-63549109 (Metabolite of Lumicitabine). | Day 1 and Day 5 | 
| Trough Observed Analyte Concentration (C[Trough]) of JNJ-63549109 (Metabolite of Lumicitabine) | C(trough) is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen of JNJ-63549109 (Metabolite of Lumicitabine). | Day 1 and Day 5 | 
| Predicted Concentration of JNJ-63549109 (Metabolite of Lumicitabine) at 12 Hours Postdose (C12h) | C12h is the predicted concentration of JNJ-63549109 at 12 hours Postdose. C12h is a model-based prediction. It was determined using a population pharmacokinetic (PK) model and based on the individual model predicted concentration-time profiles. | 12 hours postdose | 
| Length of Hospital Stay | Length of hospital stay is defined as the time from hospitalization to actual hospital discharge. | Up to 28 days | 
| Number of Participants Admitted to the Intensive Care Unit (ICU) | Number of participants who were admitted to the ICU was reported. | Up to 28 days | 
| Duration of ICU Stay | In the event that a participant required ICU, the duration for how long the participant remained in the ICU was reported. | Up to 28 days | 
| Number of Participants Who Required Supplemental Oxygen | The number of participants who required supplemental oxygen above pre-RSV infection status was reported. | Up to 28 days | 
| Number of Participants Who Required Non-invasive Mechanical Ventilation Support | The number of participants who required non-invasive mechanical ventilation support (that is, continuous positive airway pressure) above pre-RSV infection status was reported. | Up to 28 days | 
| Number of Participants Who Required Invasive Mechanical Ventilation Support | The number of participants who required invasive mechanical ventilation support (for example, endotracheal-mechanical ventilation or mechanical ventilation via tracheostomy) above pre-RSV infection status was reported. | Up to 28 days | 
| Duration of Supplemental Oxygen | Duration of supplemental oxygen above pre-RSV infection status was assessed. | Up to 28 days | 
| Duration of Non-invasive Mechanical Ventilation Support | Duration of non-invasive mechanical ventilation support (that is, continuous positive airway pressure) to deliver oxygen above pre-RSV infection status was measured. | Up to 28 days | 
| Duration of Invasive Mechanical Ventilation Support | Duration of invasive mechanical ventilation support (for example, endotracheal-mechanical ventilation or mechanical ventilation via tracheostomy) to deliver oxygen above pre-RSV infection status was measured. | Up to 28 days | 
| Time to no Longer Requiring Supplemental Oxygen | Time to no longer requiring supplemental oxygen above pre-RSV infection status was reported. | Up to 28 days | 
| Time to Clinical Stability | Time to clinical stability was defined as the time at which the following criteria are all met: normalization of blood oxygen level (return to baseline, by pulse oximetry) without the requirement of supplemental oxygen beyond baseline level, normalization of oral feeding, normalization of respiratory rate, and normalization of heart rate. | Up to 28 days | 
| Time From Initiation of Study Treatment Until Peripheral Capillary Oxygen Saturation (SpO2) Greater Than or Equal to (>=)93 Percent (%) on Room Air Among Participants Who Were Not on Supplemental Oxygen Prior to Onset of Respiratory Symptoms | Time from initiation of study treatment until SpO2 >=93% on room air among participants who were not on supplemental oxygen prior to the onset of respiratory symptoms was reported. | Up to 28 days | 
| Time for Respiratory Rate to Return to Pre-RSV Infection Status | Time for the respiratory rate to return to pre-RSV infection status was measured. | Up to 28 days | 
| Time for SpO2 to Return to Pre-RSV Infection Status | Time for SpO2 to return to pre-RSV infection status was measured. | Up to 28 days | 
| Time for Body Temperature to Return To Pre-RSV Infection Status | Time for body temperature to return to pre-RSV infection status was measured. | Up to 28 days | 
| Number of Participants With Acute Otitis Media | Number of participants with acute otitis media was reported. | Up to 28 days | 
| Duration of Signs and Symptoms of RSV Infection | Duration of signs and symptoms of RSV infection was assessed. | Up to 28 days | 
| Severity of Signs and Symptoms of RSV Infection Assessed by the Pediatric RSV Electronic Severity and Outcome Rating System (PRESORS) | The severity of signs and symptoms of RSV infection were assessed by the PRESORS. PRESORS Score consisted of 5-items, each score ranges from 0 to 3 and the total score was analyzed by summing up the individual score ranging from 0 (minimum; best) to 15 (maximum; worse). | Up to 28 days | 
| RSV Viral Load Over Time | RSV viral load over time was measured by qRT-PCR in the mid-turbinate nasal swab specimens. | On Day 2, 3, 4, 5, 6, 7, 10, 14 and 28 | 
| Peak Viral Load | Peak viral load was measured by qRT-PCR in the mid-turbinate nasal swab specimens. | Up to 28 days | 
| Time To Peak Viral Load | Time to peak viral load was reported. | Up to 28 days | 
| Percentage of Participants With Decline of Viral Load | Percentage of participants with decline in viral load during treatment as measured by qRT-PCR was reported. | Up to 28 days | 
| Time to RSV Ribonucleic Acid (RNA) Being Undetectable | Time to RSV RNA being undetectable (the time from initiation of study treatment until the time at which it is observed that the virus is undetectable in an assessment and after which time no virus positive assessment follows) was assessed as measured by qRT-PCR. | Up to 28 days | 
| Percentage of Participants With Undetectable RSV Viral Load | Percentage of participants with the undetectable viral load was reported. | Up to 28 days | 
| AUC of RSV RNA Viral Load From Baseline up to Day 10 | AUC of RSV RNA viral load was measured in mid-turbinate nasal swabs and in the endotracheal sample. | Baseline up to Day 10 | 
| AUC of RSV RNA Viral Load From Baseline up to Day 14 | AUC of RSV RNA viral load was measured in midturbinate nasal swabs and in endotracheal samples. | Baseline up to Day 14 | 
| AUC of RSV Viral Load From Baseline Until 1 Day After the Last Dose of Study Drug | AUC of RSV viral load was measured in midturbinate nasal swabs and in endotracheal samples. | Baseline Until 1 Day after the last dose of study drug (up to 10 days) | 
| Number of Participants With Emergent Postbaseline Changes in the RSV Polymerase L-gene and Other Regions of the RSV Genome Compared With Baseline Sequences | Number of participants with emergent postbaseline changes in the RSV polymerase L-gene and other regions of the RSV genome compared with baseline sequences were reported. | Baseline up to 28 days | 
| Acceptability and Palatability of Lumicitabine Formulation as Assessed by Clinician Electronic Clinical Outcome Assessment (eCOA) | Acceptability and Palatability of lumicitabine formulation was assessed by clinician eCOA questionnaire ranging from score 0 (minimum; best) to 8 (maximum; worse). | Up to Day 6 |