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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

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ClinicalTrials.gov Identifier: NCT02354014
Recruitment Status : Recruiting
First Posted : February 3, 2015
Last Update Posted : December 10, 2018
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

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 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

Resource links provided by the National Library of Medicine


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.




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.



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02354014


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
India
B. J. Medical College & Civil Hospital Withdrawn
Ahmedabad, India, 380 016
National Institute for Research in Tuberculosis (NIRT) Withdrawn
Chennai, India, 600 031
National Institute of Tuberculosis and Respiratory Diseases (NITRD) Withdrawn
New Delhi, India, 110 030
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
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Additional Information:
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    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: December 2018

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