A Phase 2, Open-label, Multicenter, Single-arm Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Anti-mycobacterial Activity of TMC207 in Combination With a Background Regimen (BR) of Multidrug Resistant Tuberculosis (MDR-TB) Medications for the Treatment of Children and Adolescents 0 Months to <18 Years of Age Who Have Confirmed or Probable Pulmonary MDR-TB
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 20
- 主要终点
- Maximum Plasma Concentration (Cmax)
研究概览
简要总结
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (explores what the body does to the drug), and anti-mycobacterial activity of bedaquiline (TMC207) in children and adolescents (0 months to less than [<] 18 years of age) diagnosed with confirmed or probable pulmonary multidrug resistant tuberculosis (MDR-TB), in combination With a Background Regimen (BR) of MDR-TB Medications.
详细描述
This is an open-label (all people know the identity of the intervention), multicenter (when more than one hospital or medical school team work on a medical research study) and Phase 2 study. The study will consist of a screening phase, a 24-week open-label treatment phase during which all participants will receive bedaquiline (TMC207) in combination with a BR of MDR-TB medications, and a 96-week follow-up phase. Upon completion of the 24-week treatment with bedaquiline, all participants will continue to receive their BR under the care of the investigator. The total study duration will be 120 weeks for each participant. There will be 4 age based cohorts in this study. Cohort 1: greater than or equal to (>=) 12 to less than (<) 18 years of age; Cohort 2: >=5 to <12 years of age; Cohort 3: >=2 to <5 years of age; Cohort 4: 0 months to <2 years of age. Participants in Cohorts 1 and 2 will be enrolled concurrently followed by sequential enrollment of Cohorts 3 and 4. An internal safety monitoring group will review safety and pharmacokinetic data from each cohort to determine subsequent cohort enrollment and dose. Participants' safety will be monitored throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 0 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be a boy or girl, aged from birth (0 months) to less than (<) 18 years at screening. Participants in Cohort 4 who are <6 months of age at screening, gestational age at birth had to be greater than or equal to (>=) 37 weeks
- •Participant must weigh >3 kilogram (kg) at baseline and be within the 5th and 95th percentiles (inclusive) for the participant's age, based on the World Health Organization (WHO) child growth standards; Body Mass Index (BMI) for age. In Cohorts 3 and 4, weight for height/length may be used instead of BMI for age according to the local standard of care. Per WHO guidance, for participants aged < 2 years in Cohort 4, length will be used to calculate the BMI instead of height
- •For Cohorts 1 and 2 only: Heterosexually active girls may participate if they are of non-childbearing potential, or if they are using effective birth control methods and are willing to continue practicing birth control methods throughout Multidrug Resistant Tuberculosis (MDR-TB) treatment and for 6 months after stopping TMC207 treatment, or if they are non-heterosexually active or willing to practice sexual abstinence throughout MDR-TB treatment
- •For Cohorts 1 and 2 only: Boys who engage in sexual activity that could lead to pregnancy of the female partner must use at minimum a male condom throughout MDR-TB treatment and for 3 months after stopping TMC207 treatment
- •Participant must have confirmed or probable (clinically diagnosed or presumed) pulmonary and/or non-severe extrapulmonary MDR-TB, including pre-extensively drug-resistant TB (pre- extensively drug resistant [XDR]-TB) or XDR-TB infection, based on the case definitions of pediatric pulmonary and non-severe extrapulmonary TB as described in the International (WHO) guidelines and in accordance with the local standard of care
- •Participants must be starting the initial MDR-TB treatment at Day 1 or have started an MDR-TB treatment within 12 weeks of Day 1 and are willing to modify it if necessary to an acceptable MDR-TB regimen for use with TMC207
- •Participant must be willing to permanently discontinue RMP from at least 7 days before the baseline visit
- •Participant or legally acceptable representative must consent/assent to human Immunodeficiency virus (HIV) testing of the participant. The mother must also consent to testing of her own HIV status, if the potential participant is a child aged <2 years, or if the participant is >= 2 years old and being breastfed or was breastfed within the last 8 weeks before screening, unless the mother had HIV test performed within 1 month prior to screening and documentation of HIV status can be provided. When documented HIV-positive status is available prior to screening for participants in Cohort 4 or their mother, HIV testing for the participant and mother is not required
排除标准
- •Participant has a clinically significant active medical condition or the presence of any concomitant severe illness or rapidly deteriorating health condition, including immune deficiency (except HIV infection), which in the opinion of the investigator would prevent appropriate participation in the study, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the subject a poor candidate for a clinical study
- •Participant is a girl who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 6 months after stopping TMC207 treatment
- •Participant has known or presumed forms of extrapulmonary TB, other than: Lymphadenopathy (peripheral nodes or isolated mediastinal mass without significant airway compression); Pleural effusion or pleural fibrotic lesions
- •Participant has a significant cardiac arrhythmia that requires medication or risk factors for Torsade de Pointes, example heart failure, hypokalemia, known personal or family history of Long QT Syndrome, and untreated hypothyroidism
研究组 & 干预措施
Bedaquiline (TMC207)/Background Regimen (BR)
There will be 4 age-based cohorts. Participants will be enrolled concurrently in Cohorts 1 and 2 followed by sequential enrollment of Cohorts 3, 4. Cohort 1: >= 12 to < 18 years: bedaquiline (TMC207) tablet orally as 400 mg, once daily(qd),for first 2 weeks, followed by bedaquiline (TMC207), 200 mg 3 times per week (tiw) for 22 weeks; Cohort 2: >=5 to <12 years: bedaquiline (TMC207) tablet given orally as 200 mg, qd, for first 2 weeks, followed by bedaquiline (TMC207) 100 mg, tiw for 22 weeks. Cohort 3: >=2 to <5 years: bedaquiline (TMC207) 8 milligram per kilogram (mg/kg) qd for the first 2 weeks, followed by bedaquiline (TMC207) 4 mg/kg tiw for 22 weeks. Cohort 4: 0 months to <2 years: bedaquiline (TMC207) doses will be selected as per weight band and age group. Bedaquiline (TMC207) will be given in combination with Background Regimen for Multidrug Resistant Tuberculosis (MDR-TB) according to WHO/national tuberculosis program (NTP) guidelines/current standard of care.
干预措施: Background Regimen (BR) (Drug)
Bedaquiline (TMC207)/Background Regimen (BR)
There will be 4 age-based cohorts. Participants will be enrolled concurrently in Cohorts 1 and 2 followed by sequential enrollment of Cohorts 3, 4. Cohort 1: >= 12 to < 18 years: bedaquiline (TMC207) tablet orally as 400 mg, once daily(qd),for first 2 weeks, followed by bedaquiline (TMC207), 200 mg 3 times per week (tiw) for 22 weeks; Cohort 2: >=5 to <12 years: bedaquiline (TMC207) tablet given orally as 200 mg, qd, for first 2 weeks, followed by bedaquiline (TMC207) 100 mg, tiw for 22 weeks. Cohort 3: >=2 to <5 years: bedaquiline (TMC207) 8 milligram per kilogram (mg/kg) qd for the first 2 weeks, followed by bedaquiline (TMC207) 4 mg/kg tiw for 22 weeks. Cohort 4: 0 months to <2 years: bedaquiline (TMC207) doses will be selected as per weight band and age group. Bedaquiline (TMC207) will be given in combination with Background Regimen for Multidrug Resistant Tuberculosis (MDR-TB) according to WHO/national tuberculosis program (NTP) guidelines/current standard of care.
干预措施: Bedaquiline (TMC207) (Drug)
结局指标
主要结局
Maximum Plasma Concentration (Cmax)
时间窗: Week 2 and 12
The Cmax is the maximum plasma concentration.
Minimum Plasma Concentration (Cmin)
时间窗: Week 2, 12 and 24
The Cmin is the minimum plasma concentration.
Time to Reach Maximum Plasma Concentration (Tmax)
时间窗: Week 2 and 12
The Tmax is time to reach the maximum plasma concentration.
Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to X Hours (AUCtime-h)
时间窗: Week 2, 12 and 24
AUCtime-h is the area under the plasma concentration-time curve from the time of dose administration up to X hours.
Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 168 Hours [AUC168h]
时间窗: Week 12 and 24
AUC168h is the area under the plasma concentration-time curve from the time of dose administration up to 168 Hours.
Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
时间窗: Cohort 1 to 3 = up to 120 Weeks and Cohort 4 = up to 88 Weeks
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Elimination Half-life (t1/2)
时间窗: For Cohorts 1 to 3: Day 1, Weeks 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120; For Cohort 4: Day 1, Weeks 2,12, 24, 32, 48, 88
Elimination half-life (t \[1/2\]) is associated with the terminal slope (lambda \[z\]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z). Lambda(z) is first-order rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.
Volume of Distribution (Vd)
时间窗: For Cohorts 1 to 3: Day 1, Weeks 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120; For Cohort 4: Day 1, Weeks 2,12, 24, 32, 48, 88
Volume of distribution is calculated as Dose divided by Lambda(z) multiplied by AUC(infinity). The AUC (infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
Apparent Clearance (CL)
时间窗: For Cohorts 1 to 3: Day 1, Weeks 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120; For Cohort 4: Day 1, Weeks 2,12, 24, 32, 48, 88
Apparent clearance is calculated as Dose/AUC (infinity). The AUC (infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
次要结局
- Percentage of Participants with Favorable Treatment outcome (Sustained Clinical Cure)(Week 24, Week 120 (for Cohorts 1 to 3) and Week 88 (for Cohort 4))
- Time to First Confirmed Mycobacteria Growth Indicator Tube (MGIT) Culture Conversion of Clinical Specimen Sample(Baseline (Day 1), up to Week 120 (for Cohorts 1 to 3), Week 88 (for Cohort 4))
- Time to Acid-Fast Bacilli (AFB) Smear Conversion of Clinical Specimen Sample(Baseline (Day 1), up to Week 120 (for Cohorts 1 to 3), Week 88 (for Cohort 4))