Clinical trial NCT02354014: 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Multidrug-Resistant Tuberculosis
Keywords: Multidrug-Resistant Tuberculosis
Bedaquiline
TMC207
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2015-02-03
Enrollment: 60
Sex: ALL
Minimum age (years): 0
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
timeFrame: 120 weeks
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Week 2 and 12
measure: Time to Reach Maximum Plasma Concentration (Tmax)
timeFrame: Week 2 and 12
measure: Minimum Plasma Concentration (Cmin)
timeFrame: Week 2, 12 and 24
measure: Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to X Hours (AUCtime-h)
timeFrame: Week 2, 12 and 24
measure: Elimination Half-life (t1/2)
timeFrame: Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120
measure: Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 168 Hours [AUC168h]
timeFrame: Week 12 and 24
measure: Volume of Distribution (Vd)
timeFrame: Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120
measure: Apparent Clearance (CL)
timeFrame: Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120
Secondary outcomes:
measure: Percentage of Participants with Favorable Treatment outcome (Sustained Positive Clinical Cure)
timeFrame: Week 24, Week 120 (end of study)
measure: Time to First Confirmed Sputum Culture Conversion, to acid-fast bacilli (AFB) smear conversion, or Other Microbiology Specimen Sample
timeFrame: Baseline (Day 1) up to Week 120
Other outcomes:
Locations:
city: Maputo
country: Mozambique
facility: Hospital Geral da Polana Caniço
city: Dasmarinas
country: Philippines
facility: De La Salle Health Sciences Institute- DLSUMC
city: Quezon City
country: Philippines
facility: Lung Center Of The Philippines
city: Moscow
country: Russian Federation
facility: First Moscow State Medical University n.a. I.M. Sechenov
city: Durban
country: South Africa
facility: THINK: Tuberculosis & HIV Investigative Network
city: Johannesburg
country: South Africa
facility: Sizwe Tropical Diseases Hospital
city: Port Elizabeth
country: South Africa
facility: Wits Health Consortium
city: Stellenboch
country: South Africa
facility: Desmond Tutu TB Centre
city: Kampala
country: Uganda
facility: Makerere University Lung Institute
city: Kiev
country: Ukraine
facility: State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: