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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 49
- 主要终点
- Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours After Dosing (AUC[0-24h]) of JNJ-63549109 at Day 1
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Regimen A (Placebo)
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.
干预措施: Placebo (Drug)
Regimen B (low-dose lumicitabine)
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.
干预措施: lumicitabine (Drug)
Regimen C (High-dose lumicitabine)
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.
干预措施: lumicitabine (Drug)
结局指标
主要结局
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours After Dosing (AUC[0-24h]) of JNJ-63549109 at Day 1
时间窗: 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.
Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours After Dosing (AUC[0-24h]) of JNJ-63549109 at Day 5
时间窗: 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.
Trough Observed Plasma Concentration (Ctrough) of JNJ-63549109 at Day 1
时间窗: Day 1
Ctrough is the trough observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine.
Trough Observed Plasma Concentration (Ctrough) of JNJ-63549109 at Day 5
时间窗: Day 5
Ctrough is the trough observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine.
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])
时间窗: Day 1 (Baseline) to 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.
Maximum Observed Plasma Concentration (Cmax) of JNJ-63549109 at Day 1
时间窗: Day 1
Cmax is the maximum observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine.
Maximum Observed Plasma Concentration (Cmax) of JNJ-63549109 at Day 5
时间窗: Day 5
Cmax is the maximum observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolized product of lumicitabine.
次要结局
- Number of Participants Who Required Invasive Mechanical Ventilation Support(Up to 28 Days)
- Number of Participants With Adverse Events (AEs)(Up to 28 Days)
- Number of Participants With Vital Sign Abnormalities(Up to 28 Days)
- Number of Participants With QT Interval Abnormalities(Up to 28 Days)
- Number of Participants With Clinical Laboratory Abnormalities(Up to 28 Days)
- Time of Hospital Stay From Study Treatment Initiation to Discharge(From study treatment initiation to discharge (Up to 28 Days))
- Time of Hospital Stay From Admission to Discharge(From admission to discharge (Up to 28 Days))
- Time of Hospital Stay From Study Treatment Initiation to Readiness for Discharge(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(Up to 28 Days)
- Number of Participants Who Required to be Admitted to the Intensive Care Unit (ICU) Since Initiation of Treatment(Up to 28 Days)
- Duration of Intensive Care Unit Stay(Up to 28 Days)
- Number of Participants Who Required Supplemental Oxygen(Up to 28 Days)
- Time to End of Oxygen Supplementation(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(Up to 28 Days)
- Time to Return to Pre-respiratory Syncytial Virus (Pre-RSV) Disease Level for Respiratory Rate(Up to 28 Days)
- Time to Return to Pre-RSV Disease Level for Oxygen Saturation(Up to 28 Days)
- Time to Return to Pre-RSV Disease Level for Body Temperature(Up to 28 Days)
- Number of Participants Who Required Noninvasive Mechanical Ventilation Support(Up to 28 Days)
- Time to End of Noninvasive Mechanical Ventilation Support(Up to 28 Days)
- Time to Clinical Stability(Up to 28 Days)
- RSV RNA Viral Load Over Time(Days 2, 3, 4, 5, 6, 7, 10, 14, and 28)
- Peak Viral Load(Up to 28 Days)
- Time to Peak Viral Load(Up to 28 Days)
- Time to End of Invasive Mechanical Ventilation Support(Up to 28 Days)
- Time to Return to Pre-RSV Functional Status as Assessed by KATZ Activities of Daily Living (ADL) Score(Up to 28 Days)
- Number of Participants Who Required Hydration or Feeding by Intravenous (IV) Catheter or Nasogastric Tube(Up to 28 Days)
- Number of Participants in Each Ordinal Scale Category(Day 5/6 (Day of last study treatment))
- Number of Participants With All-Cause Mortality(Up to 28 Days)
- Rate of Decline of Viral Load(Up to 28 Days)
- Time to RSV RNA Viral Load Being Undetectable(Up to 28 Days)
- Number of Participants With Undetectable Viral Load(Up to 28 Days)
- RSV RNA Viral Load AUC up to Day 14(Up to Day 14)
- RSV RNA Viral Load AUC in Participants Assigned to a Longer Dosing Duration(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(Baseline up to 28 Days)