Pharmacokinetic Study to Evaluate Anti-mycobacterial Activity of TMC207 in Combination With Background Regimen (BR) of Multidrug Resistant Tuberculosis (MDR-TB) Medications for Treatment of Children/Adolescents Pulmonary MDR-TB

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Multidrug-Resistant Tuberculosis

Intervention / Treatment
-----------------
* Drug: Bedaquiline (TMC207)
* Drug: Background Regimen (BR)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 must be greater than or equal to (>=) 37 weeks gestation at baseline Participant must weigh >3 kilogram (kg) at entry 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 may be used instead of BMI for age according to the local standard of care 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 baseline or have started an MDR-TB treatment within 12 weeks of baseline 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 Exclusion Criteria: 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 tested positive for Human Immunodeficiency Virus (HIV) for the first time at screening. In addition, participants aged <2 years and participants who are being breastfed or were breastfed within the last 8 weeks before screening will be excluded if the mother has tested positive for HIV 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 a history of risk factors for Torsade de Pointes, example heart failure, hypokalemia, known personal or family history of Long QT Syndrome, and untreated hypothyroidism

Ages Eligible for Study
-----------------
Minimum Age: 0 Months
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC207/Background Regimen (BR)<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 TMC207, 200 mg 3 times per week (tiw) for 22 weeks; Cohort 2: >=5 to <12 years: TMC207 tablet given orally as 200 mg, qd, for first 2 weeks, followed by TMC207, 100 mg, tiw for 22 weeks. Cohort 3: >=2 to <5 years: TMC207 8 milligram per kilogram (mg/kg) qd for the first 2 weeks, followed by TMC207 4 mg/kg tiw for 22 weeks. Cohort 4: 0 months to <2 years: TMC207 dose will be selected based on the results from the previous cohorts 1, 2 and 3. 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. | Drug: Bedaquiline (TMC207)<br>* TMC207 oral tablet adult formulation (containing 100 mg TMC207 per tablet) administered as 400 milligram (mg), once daily, for the first 2 weeks, followed by bedaquiline (TMC207) 200 mg 3 times per week with intakes at least 2 days (48 hours) apart for 22 weeks in cohort 1. Cohort 2, 3 and 4 will receive an age appropriate oral tablet formulation containing 20mg TMC207. Bedaquiline (TMC207) tablet administered orally as 200 mg, once daily, for the first 2 weeks, followed by bedaquiline (TMC207) 100 mg 3 times per week with intakes at least 2 days (48 hours) apart for 22 weeks in cohort 2. In Cohort 3, dose of TMC207 8 mg/kg qd for the first 2 weeks, followed by TMC207 4 mg/kg tiw with intakes at least 2 days (48 hours) apart for 22 weeks will be administered. In cohort 4, TMC207 dose will be selected based on the results from the previous cohorts 1, 2 and 3.<br>* Other names: Bedaquiline;Drug: Background Regimen (BR)<br>* Background Regimen (BR) of Multidrug Resistant Tuberculosis (MDR-TB) medications will be dosed according to World Health Organization (WHO) guidelines, National Tuberculosis Program (NTP) guidelines and current standard of care at the site.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | 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. | 120 weeks | 
| Maximum Plasma Concentration (Cmax) | The Cmax is the maximum plasma concentration. | Week 2 and 12 | 
| Time to Reach Maximum Plasma Concentration (Tmax) | The Tmax is time to reach the maximum plasma concentration. | Week 2 and 12 | 
| Minimum Plasma Concentration (Cmin) | The Cmin is the minimum plasma concentration. | Week 2, 12 and 24 | 
| Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to X Hours (AUCtime-h) | AUCtime-h is the area under the plasma concentration-time curve from the time of dose administration up to X hours. | Week 2, 12 and 24 | 
| Elimination Half-life (t1/2) | 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. | Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120 | 
| Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 168 Hours [AUC168h] | AUC168h is the area under the plasma concentration-time curve from the time of dose administration up to 168 Hours. | Week 12 and 24 | 
| Volume of Distribution (Vd) | 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. | Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120 | 
| Apparent Clearance (CL) | 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. | Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Favorable Treatment outcome (Sustained Positive Clinical Cure) | Sustained Positive Clinical Cure is defined as the percentage of participants with favorable treatment outcome at Week 24 and at study end. | Week 24, Week 120 (end of study) | 
| Time to First Confirmed Sputum Culture Conversion, to acid-fast bacilli (AFB) smear conversion, or Other Microbiology Specimen Sample | Culture conversion is defined as 2 consecutive negative cultures in the Mycobacteria Growth Indicator Tube (MGIT) system at least 25 days apart with the last culture within the analysis window, unless a repeat microbiology sample (eg, lymph node biopsy) cannot be obtained. AFB smear conversion is defined as 2 consecutive negative AFB smear at least 25 days apart. | Baseline (Day 1) up to Week 120 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multidrug-Resistant Tuberculosis, Bedaquiline, TMC207