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

• ClinicalTrials.gov Identifier: NCT02354014
• Recruitment Status: Recruiting
• First Posted: February 3, 2015
• Last Update Posted: June 12, 2019
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Multidrug-Resistant Tuberculosis	Drug: Bedaquiline (TMC207); Drug: Background Regimen (BR)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 3, 2016
• Estimated Primary Completion Date: March 11, 2021
• Estimated Study Completion Date: July 13, 2025

Arms and Interventions

Arm

Intervention/treatment

Experimental: TMC207/Background Regimen (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 6 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: Dose will depend upon review of safety and pharmacokinetic data from Cohort 1, 2, 3 by internal safety monitoring group (ISMG). 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); 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 6 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 the dose will depend upon the review of safety and pharmacokinetic data from Cohort 1 and 2 by internal safety monitoring group.; Other Name: Bedaquiline; 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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: 120 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.
2. Maximum Plasma Concentration (Cmax) [ Time Frame: Week 2 and 12 ]
   The Cmax is the maximum plasma concentration.
3. Time to Reach Maximum Plasma Concentration (Tmax) [ Time Frame: Week 2 and 12 ]
   The Tmax is time to reach the maximum plasma concentration.
4. Minimum Plasma Concentration (Cmin) [ Time Frame: Week 2, 12 and 24 ]
   The Cmin is the minimum plasma concentration.
5. 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 ]
   AUCtime-h is the area under the plasma concentration-time curve from the time of dose administration up to X hours.
6. Elimination Half-life (t1/2) [ Time Frame: Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120 ]
   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.
7. Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 168 Hours [AUC168h] [ Time Frame: Week 12 and 24 ]
   AUC168h is the area under the plasma concentration-time curve from the time of dose administration up to 168 Hours.
8. Volume of Distribution (Vd) [ Time Frame: Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120 ]
   Volume of distribution is calculated as Dose divided by Lambda(z) multiplied by AUC(inifinity). The AUC (infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
9. Apparent Clearance (CL) [ Time Frame: Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120 ]
   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 Outcome Measures :

1. Percentage of Participants with Favorable Treatment outcome (Sustained Positive Clinical Cure) [ Time Frame: Week 24, Week 120 (end of study) ]
   Sustained Positive Clinical Cure is defined as the percentage of participants with favorable treatment outcome at Week 24 and at study end.
2. Time to First Confirmed Sputum Culture Conversion, to acid-fast bacilli (AFB) smear conversion, or Other Microbiology Specimen Sample [ Time Frame: Baseline (Day 1) up to Week 120 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: up to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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
• Participants must be starting the initial MDR-TB treatment at baseline or have started an MDR-TB treatment within 8 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 complicated or severe extrapulmonary manifestations of TB, including TB meningitis. Participants with adenopathy or adenitis are allowed to enter the study
• 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

Contacts and Locations

Contacts

• Contact: Use link at the bottom of the page to see if you qualify for an enrolling site (see list). If you still have questions: JNJ.CT@sylogent.com

Locations

Philippines

De La Salle Health Sciences Institute- DLSUMC; Recruiting

Dasmarinas, Philippines, 4114

Lung Center Of The Philippines; Completed

Quezon City, Philippines, 1100

Russian Federation

First Moscow State Medical University n.a. I.M. Sechenov; Recruiting

Moscow, Russian Federation, 119991

South Africa

THINK: Tuberculosis & HIV Investigative Network; Recruiting

Durban, South Africa, 4001

Uganda

Makerere University Lung Institute; Not yet recruiting

Kampala, Uganda

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

More Information

Additional Information:

To learn how to participate in this trial please click here. 

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02354014 History of Changes
• Other Study ID Numbers: CR106371; TMC207-TIDP59-C211 ( Other Identifier: Janssen Research & Development, LLC. ); 2014-003372-23 ( EudraCT Number )
• First Posted: February 3, 2015
• Last Update Posted: June 12, 2019
• Last Verified: June 2019

• Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Janssen Research & Development, LLC:

Multidrug-Resistant Tuberculosis; Bedaquiline; TMC207

Additional relevant MeSH terms:

Tuberculosis; Tuberculosis, Multidrug-Resistant; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bedaquiline; Diarylquinolines; Anti-Bacterial Agents; Antitubercular Agents; Anti-Infective Agents