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 With Pulmonary MDR-TB

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

Overview

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

• Drug Bedaquiline (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 bedaq
• Drug Background Regimen (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.

Primary outcome measures

• Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) [Time frame: Cohort 1 to 3 = up to 120 Weeks and Cohort 4 = up to 88 Weeks]
• Maximum Plasma Concentration (Cmax) [Time frame: Week 2 and 12]
• Time to Reach Maximum Plasma Concentration (Tmax) [Time frame: Week 2 and 12]
• Minimum Plasma Concentration (Cmin) [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) [Time frame: Week 2, 12 and 24]
• Elimination Half-life (t1/2) [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] [Time frame: Week 12 and 24]
• Volume of Distribution (Vd) [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) [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]

Secondary outcome measures (3)

• Percentage of Participants with Favorable Treatment outcome (Sustained Clinical Cure) [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 [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 [Time frame: Baseline (Day 1), up to Week 120 (for Cohorts 1 to 3), Week 88 (for Cohort 4)]

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 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

South Africa · 4 centers

• THINK: Tuberculosis & HIV Investigative Network — Durban
• Sizwe Tropical Diseases Hospital — Johannesburg
• Wits Health Consortium — Port Elizabeth
• Desmond Tutu TB Centre — Stellenboch

Philippines · 3 centers

• De La Salle Health Sciences Institute- DLSUMC — Dasmariñas
• Lung Center Of The Philippines — Quezon City
• Silang Specialists Medical Center — San Vincent Silang

Mozambique · 1 center

• Hospital Geral da Polana Caniço — Maputo

Russia · 1 center

• First Moscow State Medical University n.a. I.M. Sechenov — Moscow

Uganda · 1 center

• Makerere University Lung Institute — Kampala

Ukraine · 1 center

• State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine — Kiev

Identifiers

NCT: NCT02354014 · CR106371 · TMC207-TIDP59-C211 · 2014-003372-23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗