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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Bedaquiline (TMC207) oral tablet adult formulation (containing 100 mg bedaquiline (TMC207) per tablet) administered as 400 milligram (mg), once daily, for the first 2 weeks, followed by bedaquiline 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 bedaquiline . Bedaquiline tablet administered orally as 200 mg, once daily, for the first 2 weeks, followed by bedaquiline 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 bedaquiline 8 mg/kg qd for the first 2 weeks, followed by bedaquiline 4 mg/kg times weekly (TIW) with intakes at least 2 days (48 hours) apart for 22 weeks will be administered. In cohort 4, bedaquiline (TMC207) qd for the first 2 weeks, followed by bedaquiline TIW with intakes at least 2 days (48 hours) apart for 22 weeks.
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.
Unnamed facility
Maputo, Mozambique
Unnamed facility
Dasmariñas, Philippines
Unnamed facility
Quezon City, Philippines
Unnamed facility
San Vincent Silang, Philippines
Unnamed facility
Moscow, Russia
Unnamed facility
Durban, South Africa
Unnamed facility
Johannesburg, South Africa
Unnamed facility
Port Elizabeth, South Africa
Unnamed facility
Stellenboch, South Africa
Unnamed facility
Kampala, Uganda
...and 1 more locations
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.
Time frame: Cohort 1 to 3 = up to 120 Weeks and Cohort 4 = up to 88 Weeks
Maximum Plasma Concentration (Cmax)
The Cmax is the maximum plasma concentration.
Time frame: Week 2 and 12
Time to Reach Maximum Plasma Concentration (Tmax)
The Tmax is time to reach the maximum plasma concentration.
Time frame: Week 2 and 12
Minimum Plasma Concentration (Cmin)
The Cmin is the minimum plasma concentration.
Time frame: 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.
Time frame: 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.
Time frame: 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
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.
Time frame: 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.
Time frame: 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 (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.
Time frame: 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
Percentage of Participants with Favorable Treatment outcome (Sustained Clinical Cure)
Sustained Clinical Cure is defined as the percentage of participants with favorable treatment outcome at Week 24 and at study end.
Time frame: 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
Culture conversion is defined as 2 consecutive negative cultures in the 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.
Time frame: 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
AFB smear conversion is defined as 2 consecutive negative AFB smear at least 25 days apart.
Time frame: Baseline (Day 1), up to Week 120 (for Cohorts 1 to 3), Week 88 (for Cohort 4)
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