Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine Regimens in Adult Participants Hospitalized With Respiratory Syncytial Virus

Study Overview
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Brief Summary
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The purpose of this study is to characterize the Pharmacokinetic and to confirm the popPK model derived from healthy volunteers in hospitalized adults who are infected with respiratory syncytial virus (RSV) and to determine in adults who are hospitalized with respiratory syncytial virus (RSV) infection 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) assay.

Detailed Description
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The study will be conducted in 3 phases: a screening phase, a treatment phase from Day 1 to Day 5/6 (depending on the timing of the loading dose), and a follow-up phase for a total of 28 days post randomization. Participants will have assessments completed at Day 7, Day 10, Day 14, and Day 28. Depending on discharge date, assessments will be completed either while hospitalized or during outpatient visits. The duration of the participant's participation will be approximately 28 days. The study will be performed in 2 parts. Participants will be randomly assigned to one of 2 treatment groups in part 1, and to one of 3 treatment groups in part 2. Treatment groups will be evaluated for PK and safety after a target of approximately 24 participants have been enrolled in part 1 and before initiating part 2 (approximately 90 participants in part 2). An Independent Data Monitoring Committee (IDMC) will be established to monitor the safety of participants and will review data in an unblinded manner on a regular basis to ensure the continuing safety of the participants enrolled in this study and to evaluate whether efficacy objectives are met. The committee will meet periodically to review interim data. Based on the recommendations of the IDMC following interim analyses/reviews, an increase in duration may be implemented.

Official Title
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A Phase 2b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine Regimens in Adult Subjects Hospitalized 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: 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 Diagnosed with respiratory syncytial virus (RSV) infection based on polymerase chain reaction (PCR)-based assay with or without co infection with another respiratory pathogen (eg, influenza, human metapneumovirus, or bacteria) With the exception of the RSV disease, medically stable on the basis of medical history, physical examination, 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 RSV infection. This determination must be recorded in the participant's source documents and initialed by the investigator A woman must have a negative urine beta human chorionic gonadotropin at screening A woman must agree not to donate eggs (ova, oocytes) during the study and for at least 44 days after receiving the last dose of study drug Contraceptive use by women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies A woman must be of non-childbearing potential defined as either: a) Postmenopausal: a postmenopausal state is defined as more than (>) 45 years and no menses for 12 consecutive months without an alternative medical cause, OR Permanently sterile: permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures (without reversal operation), and bilateral oophorectomy. b) Of childbearing potential and, if heterosexually active, also included: practicing a highly effective method of contraception (failure rate of less than (<) 1percent (%) per year when used consistently and correctly) Participants must have a body weight of at least 50.0 kilogram, 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 immuno-compromised within the past 12 months, whether due to underlying medical condition (example, malignancy or genetic disorder) or medical therapy (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 with a known history of human immunodeficiency virus (HIV) or chronic viral hepatitis 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 1 or more of the following laboratory abnormalities at screening as defined by the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table: Hemoglobin <9.5 gram per deciliter (g/dL), Platelet count <75,000 per millimeter cube (/mm^³), White blood cell count <1,000/mm^³, Absolute neutrophil count <1,000/mm^³

Ages Eligible for Study
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Minimum Age: 18 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: Regimen A (Placebo)<br>Participants of part 1 and part 2 will receive a single loading dose (LD) (Dose 1) followed by 9 maintenance doses (MDs) (Doses 2 to 10) of matching placebo, administered twice daily. | Drug: Placebo<br>* Oral administration of matching placebo.<br>|
| Experimental: Regimen B (low-dose lumicitabine)<br>Participants of part 1 and part 2 will receive a single 750 mg LD (Dose 1) followed by nine 250 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily. | Drug: lumicitabine<br>* Oral administration of lumicitabine as tablet.<br>* Other names: ALS-8176/JNJ-64041575;|
| Experimental: Regimen C (High-dose lumicitabine)<br>Participants of part 2 will receive a single 1000 mg LD (Dose 1) followed by nine 500 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily. | Drug: lumicitabine<br>* Oral administration of lumicitabine as tablet.<br>* Other names: ALS-8176/JNJ-64041575;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of JNJ-63549109 at Day 1 | Cmax is the maximum observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine. | Day 1 | 
| Maximum Observed Plasma Concentration (Cmax) of JNJ-63549109 at Day 5 | Cmax is the maximum observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine. | Day 5 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours After Dosing (AUC[0-24h]) of JNJ-63549109 at Day 1 | AUC(0-24) is the area under the plasma concentration-time curve from time 0 to 24 hours after dosing of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine. | Day 1 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours After Dosing (AUC[0-24h]) of JNJ-63549109 at Day 5 | AUC(0-24) is the area under the plasma concentration-time curve from time 0 to 24 hours after dosing of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine. | Day 5 | 
| Trough Observed Plasma Concentration (Ctrough) of JNJ-63549109 at Day 1 | Ctrough is the trough observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine. | Day 1 | 
| Trough Observed Plasma Concentration (Ctrough) of JNJ-63549109 at Day 5 | Ctrough is the trough observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine. | Day 5 | 
| Least Square Mean Difference (Low and High Dose Lumicitabine Versus Placebo) of Respiratory Syncytial Virus (RSV) Ribonucleic Acid (RNA) Viral Load Area Under the Concentration-time Curve From Day 1 to 7 (AUC[1-7]) | RSV RNA viral load in log10 copies/milliliter/day (log10 copies/mL/day) was measured in mid-turbinate nasal swabs and in endotracheal samples (obtained from intubated participants or via suction through tracheostomy or other sampling methods) using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Due to early termination of study, the analysis was not conducted as planned. Instead, using the same specification as for the primary analysis, a comparison was made on the AUC(1-7) days of pooled active treatment groups versus pooled placebo. The comparison was done as planned using a mixed model for repeated measures, using all available viral load data of baseline up to and including Day 7. The model computes the AUC at group level based on all available data, taking missing data into account under the missing at random assumption. The table reports the planned difference versus (pooled) placebo. No adjustment for multiplicity was applied. | Day 1 (Baseline) to 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | An 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. | Up to 28 Days | 
| Number of Participants With Vital Sign Abnormalities | Number of participants with vital sign (systolic and diastolic blood pressure [BP], pulse rate, respiratory rate, temperature and oxygen saturation) abnormalities were reported. For systolic BP: abnormally low refers to less than or equal to (<=) 90 millimeter of mercury (mmHg); for diastolic BP: abnormally low refers to <= 50 mmHg; for pulse rate abnormally low refers to less than (<) 45 beats per minutes (bpm) and abnormally high refers to greater than or equal to (>=) 120 bpm; for temperature in degree Celsius abnormally high refers to greater than (>) 37.8 (tympanic), >38.0 (forehead), >38.0 (oral), >37.2 (rectal), >38.0 (axillary); for oxygen saturation in percentage (%) abnormally low refers to < 95. Grade 1 = mild; grade 2 = moderate; grade 3 = severe. | Up to 28 Days | 
| Number of Participants With QT Interval Abnormalities | Number of participants with QT interval abnormalities (prolonged) were reported. | Up to 28 Days | 
| Number of Participants With Clinical Laboratory Abnormalities | Number of participants with clinical laboratory (serum chemistry and hematology) abnormalities were reported. Abbreviations; Erythrocyte MCHC = Erythrocyte Mean Corpuscular Hemoglobin Concentration; Erythrocyte MCH = Erythrocyte Mean Corpuscular Hemoglobin; Ery. = Erythrocyte | Up to 28 Days | 
| Time of Hospital Stay From Study Treatment Initiation to Discharge | It is the time from treatment initiation to hospital discharge in hours. | From study treatment initiation to discharge (Up to 28 Days) | 
| Time of Hospital Stay From Admission to Discharge | It is the time from hospital admission to hospital discharge in hours. | From admission to discharge (Up to 28 Days) | 
| Time of Hospital Stay From Study Treatment Initiation to Readiness for Discharge | It is the time from study treatment initiation to readiness for discharge in hours, with readiness for discharge defined by the investigator. | From study treatment initiation to readiness for discharge on Day 2 or up to Day 6 if hospitalization is prolonged | 
| Time of Hospital Stay From Admission to Readiness for Discharge | It is the time from hospital admission to readiness for discharge in hours, with readiness for discharge defined by the investigator. | Up to 28 Days | 
| Number of Participants Who Required to be Admitted to the Intensive Care Unit (ICU) Since Initiation of Treatment | Number of participants who required to be admitted to the ICU since initiation of treatment were reported. | Up to 28 Days | 
| Duration of Intensive Care Unit Stay | In the event that a participant required ICU since initiation of treatment, the duration for how long the participant remained in the ICU was measured. | Up to 28 Days | 
| Number of Participants Who Required Supplemental Oxygen | Number of participants who required supplemental oxygen were reported. | Up to 28 Days | 
| Time to End of Oxygen Supplementation | It is the time from first dose of study drug to the last end date and time of any oxygen supplementation in hours. | Up to 28 Days | 
| Time (Number of Hours) 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 the Onset of Respiratory Symptoms | Time (number of hours) 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 to Return to Pre-respiratory Syncytial Virus (Pre-RSV) Disease Level for Respiratory Rate | It is the time from first dose of study drug until the time to return to pre-RSV disease level for respiratory rate. The return to pre-RSV disease level occurred when the observed value of the parameter was indicated by the investigator as normal, and no later observed values were indicated by the investigator as abnormal. | Up to 28 Days | 
| Time to Return to Pre-RSV Disease Level for Oxygen Saturation | It is the time from first dose of study drug until the time to return to pre-RSV disease level for oxygen saturation. The return to pre-RSV disease level occurred when the observed value of the parameter was indicated by the investigator as normal, and no later observed values were indicated by the investigator as abnormal. | Up to 28 Days | 
| Time to Return to Pre-RSV Disease Level for Body Temperature | It is the time from first dose of study drug until the time to return to pre-RSV disease level for body temperature. The return to pre-RSV disease level occurred when the observed value of the parameter was indicated by the investigator as normal, and no later observed values were indicated by the investigator as abnormal. | Up to 28 Days | 
| Number of Participants Who Required Noninvasive Mechanical Ventilation Support | Number of participants who required noninvasive mechanical ventilation support (that is supplemental oxygen [excluding mechanical ventilation]) were reported. | Up to 28 Days | 
| Time to End of Noninvasive Mechanical Ventilation Support | It is the time from first dose of study drug to the last end date and time of noninvasive mechanical ventilation support in hours. | Up to 28 Days | 
| Number of Participants Who Required Invasive Mechanical Ventilation Support | Number of participants who required invasive mechanical ventilation support were reported. | Up to 28 Days | 
| Time to End of Invasive Mechanical Ventilation Support | It is the time from first dose of study drug to the last end date and time of invasive mechanical ventilation support in hours. | Up to 28 Days | 
| Time to Return to Pre-RSV Functional Status as Assessed by KATZ Activities of Daily Living (ADL) Score | It is the time from first dose of study drug until the time to return to pre-RSV functional status. Functional status is the total points on the KATZ index of independence in activities of daily living (KATZ ADL score). Katz activities of daily living assessed questions related to bathing, dressing, toileting, transferring, continence and feeding components. Total score was calculated by adding the scores for all 6 activities which ranges from 0 high (participant independent) to 6 low (participant very dependent). If one or more component was missing, then the KATZ ADL score was not calculated. The return to pre-RSV functional status occurs at the timepoint where for the first time the KATZ ADL score is equal or higher than the pre-RSV KATZ ADL score and after which no scores lower than the pre-RSV KATZ ADL score occur anymore. | Up to 28 Days | 
| Number of Participants Who Required Hydration or Feeding by Intravenous (IV) Catheter or Nasogastric Tube | Number of participants who required hydration or feeding by IV catheter or nasogastric tube were reported. | Up to 28 Days | 
| Time to Clinical Stability | Time to clinical stability is defined as the time from first dose of study drug until the time at which the following criteria were all met: normalization of blood oxygen level (return to baseline; by pulse oximetry) without requirement of supplemental oxygen beyond baseline level, normalization of oral feeding, normalization of respiratory rate and normalization of heart rate. | Up to 28 Days | 
| Number of Participants in Each Ordinal Scale Category | Number of participants in each ordinal scale category were reported. Ordinal scale consists of 6 categories or clinical states that are exhaustive, mutually exclusive, and ordered: category 1) death; category 2) admitted to ICU; category 3) non-ICU hospitalization requiring supplemental oxygen; category 4) non-ICU hospitalization not requiring supplemental oxygen; category 5) not hospitalized, unable to resume normal activities; category 6) not hospitalized, resumption of normal activities. | Day 5/6 (Day of last study treatment) | 
| Number of Participants With All-Cause Mortality | All-cause mortality included all deaths of participants due to any cause. | Up to 28 Days | 
| RSV RNA Viral Load Over Time | Antiviral activity RSV RNA viral load was measured in mid-turbinate nasal swabs (obtained from non-intubated participants) or in mid-turbinate nasal swabs and endotracheal samples (obtained from intubated participants or via suction through tracheostomy or other sampling methods) using qRT-PCR performed at the central laboratory. | Days 2, 3, 4, 5, 6, 7, 10, 14, and 28 | 
| Peak Viral Load | Peak Viral load is the highest value of log10 viral load at or after the baseline measurement. Peak viral load over time was measured by qRT-PCR. | Up to 28 Days | 
| Time to Peak Viral Load | Time to peak viral load is the time from initiation of study treatment until the first time point with the peak viral load. | Up to 28 Days | 
| Rate of Decline of Viral Load | Rate of decline of viral load over the first 24 hours calculated as a log decline/24 hours defined as: 24-hour log viral load after first dose of study drug minus (-) log viral load at baseline divided by (/) date/time of 24-hour viral load sample - date/time of baseline viral load. | Up to 28 Days | 
| Time to RSV RNA Viral Load Being Undetectable | It is the time in hours from initiation of study treatment until the first post baseline time point at which the virus is undetectable in an assessment and after which time no detectable virus assessment follows as measured by qRT-PCR. | Up to 28 Days | 
| Number of Participants With Undetectable Viral Load | Number of participants with undetectable viral load up to 28 days were reported. | Up to 28 Days | 
| RSV RNA Viral Load AUC up to Day 14 | RSV RNA viral load was measured in midturbinate nasal swabs and in endotracheal samples (obtained from intubated participants or via suction through tracheostomy or other sampling. | Up to Day 14 | 
| RSV RNA Viral Load AUC in Participants Assigned to a Longer Dosing Duration | RSV RNA viral load was measured in midturbinate nasal swabs and in endotracheal samples (obtained from intubated participants or via suction through tracheostomy or other sampling. | Up to 1 Day after the last dose of study drug | 
| Number of Participants With Postbaseline Changes in the RSV Polymerase L Gene and Other Regions of the RSV Genome Compared With Baseline Sequences | Number of participants with 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 |