Tuberculosis, Multidrug-Resistant
Conditions
Keywords
Multidrug-Resistant Tuberculosis, Bedaquiline, TMC207
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.
Interventions
DRUGBedaquiline (TMC207)
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.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Months to 18 Years
Healthy volunteers
No
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 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
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) | 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. |
| Maximum Plasma Concentration (Cmax) | Week 2 and 12 | The Cmax is the maximum plasma concentration. |
| Time to Reach Maximum Plasma Concentration (Tmax) | Week 2 and 12 | The Tmax is time to reach the maximum plasma concentration. |
| Minimum Plasma Concentration (Cmin) | Week 2, 12 and 24 | The Cmin is the minimum plasma concentration. |
| Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to X Hours (AUCtime-h) | 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. |
| Elimination Half-life (t1/2) | 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. |
| Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 168 Hours [AUC168h] | Week 12 and 24 | AUC168h is the area under the plasma concentration-time curve from the time of dose administration up to 168 Hours. |
| Volume of Distribution (Vd) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Sustained Clinical Cure is defined as the percentage of participants with favorable treatment outcome at Week 24 and at study end. |
| 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) | 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 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) | AFB smear conversion is defined as 2 consecutive negative AFB smear at least 25 days apart. |
Countries
Mozambique, Philippines, Russia, South Africa, Uganda, Ukraine
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Outcome results
None listed