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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

Primary Purpose

Multidrug-Resistant Tuberculosis

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Bedaquiline (TMC207)
Background Regimen (BR)
Sponsored by
Janssen Research & Development, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multidrug-Resistant Tuberculosis focused on measuring Multidrug-Resistant Tuberculosis, Bedaquiline, TMC207

Eligibility Criteria

0 Months - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hospital Geral da Polana CaniçoRecruiting
  • De La Salle Health Sciences Institute- DLSUMCRecruiting
  • Lung Center Of The Philippines
  • First Moscow State Medical University n.a. I.M. Sechenov
  • THINK: Tuberculosis & HIV Investigative NetworkRecruiting
  • Wits Health ConsortiumRecruiting
  • Makerere University Lung InstituteRecruiting
  • State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

TMC207/Background Regimen (BR)

Arm Description

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 8 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: TMC207 dose will be selected based on the results from the previous cohorts 1, 2 and 3. 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.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
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)
The Cmax is the maximum plasma concentration.
Time to Reach Maximum Plasma Concentration (Tmax)
The Tmax is time to reach the maximum plasma concentration.
Minimum Plasma Concentration (Cmin)
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)
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)
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]
AUC168h is the area under the plasma concentration-time curve from the time of dose administration up to 168 Hours.
Volume of Distribution (Vd)
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)
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

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

Full Information

First Posted
January 29, 2015
Last Updated
October 10, 2023
Sponsor
Janssen Research & Development, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02354014
Brief Title
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

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 2016 (Actual)
Primary Completion Date
February 2025 (Anticipated)
Study Completion Date
February 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Janssen Research & Development, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multidrug-Resistant Tuberculosis
Keywords
Multidrug-Resistant Tuberculosis, Bedaquiline, TMC207

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
TMC207/Background Regimen (BR)
Arm Type
Experimental
Arm Description
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 8 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: TMC207 dose will be selected based on the results from the previous cohorts 1, 2 and 3. 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.
Intervention Type
Drug
Intervention Name(s)
Bedaquiline (TMC207)
Other Intervention Name(s)
Bedaquiline
Intervention Description
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 8 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, TMC207 dose will be selected based on the results from the previous cohorts 1, 2 and 3.
Intervention Type
Drug
Intervention Name(s)
Background Regimen (BR)
Intervention Description
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 Measure Information:
Title
Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs)
Description
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.
Time Frame
120 weeks
Title
Maximum Plasma Concentration (Cmax)
Description
The Cmax is the maximum plasma concentration.
Time Frame
Week 2 and 12
Title
Time to Reach Maximum Plasma Concentration (Tmax)
Description
The Tmax is time to reach the maximum plasma concentration.
Time Frame
Week 2 and 12
Title
Minimum Plasma Concentration (Cmin)
Description
The Cmin is the minimum plasma concentration.
Time Frame
Week 2, 12 and 24
Title
Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to X Hours (AUCtime-h)
Description
AUCtime-h is the area under the plasma concentration-time curve from the time of dose administration up to X hours.
Time Frame
Week 2, 12 and 24
Title
Elimination Half-life (t1/2)
Description
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.
Time Frame
Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120
Title
Area Under the Plasma Concentration-time Curve From the Time of Dose Administration up to 168 Hours [AUC168h]
Description
AUC168h is the area under the plasma concentration-time curve from the time of dose administration up to 168 Hours.
Time Frame
Week 12 and 24
Title
Volume of Distribution (Vd)
Description
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.
Time Frame
Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120
Title
Apparent Clearance (CL)
Description
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.
Time Frame
Day 1, week 2, 4,6,8,12,16,20,24,28,32,40,48,60,72,84,96,108,120
Secondary Outcome Measure Information:
Title
Percentage of Participants with Favorable Treatment outcome (Sustained Positive Clinical Cure)
Description
Sustained Positive Clinical Cure is defined as the percentage of participants with favorable treatment outcome at Week 24 and at study end.
Time Frame
Week 24, Week 120 (end of study)
Title
Time to First Confirmed Sputum Culture Conversion, to acid-fast bacilli (AFB) smear conversion, or Other Microbiology Specimen Sample
Description
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.
Time Frame
Baseline (Day 1) up to Week 120

10. Eligibility

Sex
All
Minimum Age & Unit of Time
0 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Study Contact
Email
Participate-In-This-Study@its.jnj.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Research & Development, LLC Clinical Trial
Organizational Affiliation
Janssen Research & Development, LLC
Official's Role
Study Director
Facility Information:
Facility Name
Hospital Geral da Polana Caniço
City
Maputo
ZIP/Postal Code
00000
Country
Mozambique
Individual Site Status
Recruiting
Facility Name
De La Salle Health Sciences Institute- DLSUMC
City
Dasmarinas
ZIP/Postal Code
4114
Country
Philippines
Individual Site Status
Recruiting
Facility Name
Lung Center Of The Philippines
City
Quezon City
ZIP/Postal Code
1100
Country
Philippines
Individual Site Status
Completed
Facility Name
First Moscow State Medical University n.a. I.M. Sechenov
City
Moscow
ZIP/Postal Code
119991
Country
Russian Federation
Individual Site Status
Completed
Facility Name
THINK: Tuberculosis & HIV Investigative Network
City
Durban
ZIP/Postal Code
4001
Country
South Africa
Individual Site Status
Recruiting
Facility Name
Wits Health Consortium
City
Port Elizabeth
ZIP/Postal Code
6200
Country
South Africa
Individual Site Status
Recruiting
Facility Name
Makerere University Lung Institute
City
Kampala
Country
Uganda
Individual Site Status
Recruiting
Facility Name
State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine
City
Kiev
ZIP/Postal Code
3038
Country
Ukraine
Individual Site Status
Completed

12. IPD Sharing Statement

Learn more about this trial

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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