Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis, Living With or Without HIV

Study Overview
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Brief Summary
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P1108 is a Phase I/II, open-label, single-arm, exposure-controlled dose finding study of BDQ in infants, children, and adolescents living with and without HIV, with clinically diagnosed or bacteriologically confirmed rifampin-resistant tuberculosis (RR-TB). The study is designed to evaluate the PK, safety, and tolerability of BDQ over 24 weeks.

Detailed Description
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The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of bedaquiline (BDQ) in combination with an individualized RR-TB therapy in infants, children, and adolescents with RR-TB disease, living with or without HIV. This study will be conducted among infants, children, and adolescents less than 18 years of age treated for clinically diagnosed or bacteriologically confirmed intra-thoracic (pulmonary) RR-TB and/or selected forms of extrathoracic RR-TB. Participants will be assigned to cohorts based on age. Cohort 1 will include children six years of age or older but less than 18 years of age; Cohort 2 will include children two years of age or older but less than six years of age; and Cohort 3 will include children 0 months of age and older but less than two years of age. Cohort 1 will be divided into two weight bands, one for participants weighing 15 kg or more but less than 30 kg and one for participants weighing 30 kg or more. Cohort 2 will include participants weighing greater than 7 kg. Cohort 3 will include participants weighing at least 3 kg. Study visits will occur at enrollment (Day 0) and at Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 60, 72, and 96. Participants who exited the study before implementation of protocol Version 2.0 also had a study visit at Week 120. Participants in each cohort will take BDQ once a day for approximately two weeks. For the next 22 weeks, BDQ will be taken three times a week. Dosing for Cohorts 2 and 3 is based on data from Cohort 1. Study visits may include physical examinations, blood and urine collection, an electrocardiogram (ECG), medical history reviews, and other assessments.

Official Title
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A Phase I/II, Open-Label, Single Arm Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Bedaquiline (BDQ) Given in Combination With an Individualized Rifampin-Resistant Tuberculosis (RR-TB) Therapy in Infants, Children, and Adolescents With RR-TB Disease, Living With or Without HIV

Conditions
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Tuberculosis, HIV

Intervention / Treatment
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* Drug: Bedaquiline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Less than 18 years old. Parent/legal guardian willing and able to provide written informed consent for study participation; in addition, when applicable per local Institutional Review Board (IRB)/Ethics Committee (EC) policies and procedures, participant is willing and able to provide written assent for study participation. Age at enrollment: Cohort 1: 6 years of age or older but younger than 18 years of age Cohort 2: 2 years of age or older but younger than 6 years of age Cohort 3: 0 months of age or older but younger than 2 years of age Weight at enrollment: Cohort 1: At least 15 kg Cohort 2: Greater than 7 kg Cohort 3: At least 3 kg HIV status determined by testing requirements in the protocol. Either bacteriologically confirmed intrathoracic RR-TB or probable RR-TB and/or extrathoracic TB as listed below: Peripheral TB lymphadenitis Pleural effusion or fibrotic pleural lesions Stage 1 TBM or clinically stable Stage 2A TBM Osteoarticular TB, including spinal TB Other non-disseminated forms of TB disease More information on this criterion can be found in the protocol. Participant is on an RR-TB regimen as per local standard of care for at least seven days and not more than 12 weeks prior to entry, and tolerating the regimen well at entry, as determined by the site investigator based on available medical records. Note: Participants may have received up to seven doses of non-study BDQ during the seven days prior to study enrollment. The date and dose amount of non-study BDQ doses must be available in medical records For potential participants living with HIV: At least 14 days prior to entry, initiated an acceptable ART regimen defined as zidovudine/lamivudine/abacavir; NVP and two NRTIs; LPV/r and two NRTIs; an integrase class drug including dolutegravir or raltegravir with two NRTIs; or another regimen approved in advance by the Core Team. At entry, the participant has the following laboratory test results according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (refer to the protocol for guidance on severity grading): Absolute neutrophil count (normal or grade 1) Creatinine (normal or grade 1) Aspartate Amino Transferase (AST) (normal or grade 1) Alanine Amino Transferase (ALT) (normal or grade 1) Total bilirubin (normal or grade 1) If male and engaging in sexual activity that could lead to pregnancy of the female partner: At entry, participant agrees to use a barrier method of contraception (i.e., male condom) throughout the first 28 weeks on study (i.e., until four weeks after discontinuation of bedaquiline [BDQ]). If female and of reproductive potential, defined as having reached menarche and not having undergone a documented sterilization procedure (hysterectomy, bilateral oophorectomy, or salpingotomy): Negative pregnancy test at screening within five days prior to entry. If female, of reproductive potential (defined in the protocol), and engaging in sexual activity that could lead to pregnancy: Agrees to avoid pregnancy and to use at least two of the following contraception methods throughout the entire period of study participation: condoms, diaphragm or cervical cap, intrauterine contraceptive device (IUCD), hormonal-based contraception. It is required that the method would have had to be initiated at the time of study entry. Among Cohort 3 participants, no documentation that estimated gestational age at birth was less than 37 weeks. Note: Infants born to HIV-infected women will be eligible for enrollment in Cohort 3 regardless of feeding mode and receipt of antiretroviral drugs (ARVs) for prevention of perinatal transmissions. Exclusion Criteria: A clinically significant active medical condition or concomitant severe (Grade 3 or higher) illness or rapidly deteriorating health condition (excluding TB), including immune deficiency (excluding HIV infection), which, in the opinion of the site investigator, would be worsened by participation in the study or would prevent appropriate participation in the trial, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the participant a poor candidate for a clinical trial. Known or presumed severe extrapulmonary manifestations of TB, including Stages 2B and 3 TBM as determined by the site investigator based on participant/parent/guardian report and/or available medical records. Pregnant or lactating. A significant cardiac arrhythmia that requires medication or a history of heart disease (heart failure, coronary artery disease) that increases the risk for Torsade de Pointes as determined by the site investigator based on participant/parent/guardian report and available medical records. Mean QTcF interval of greater than 460 ms (mean value of QT interval, corrected using Fredericia correction, on electrocardiogram [ECG] performed in triplicate). Clinically relevant ECG changes including but not limited to pathological Q-waves (defined as greater than 40 ms or depth greater than 0.4-0.5 mV); evidence of ventricular pre-excitation; evidence of complete or incomplete left bundle branch block or right bundle branch block; evidence of second or third degree heart block; intraventricular conduction delay with QRS duration greater than 120 ms; age-related bradycardia as defined by sinus rate less than lower limit as indicated in the protocol. Known personal or family history of long QT syndrome. Having participated in other clinical studies with investigational agents or devices, within eight weeks prior to enrollment. Currently taking any of the disallowed medications specified in the protocol. If taking any disallowed medications, a washout period of three days or more prior to entry is required.

Ages Eligible for Study
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Minimum Age: 0 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bedaquiline (BDQ)<br>Participants will receive bedaquiline (BDQ) once a day for 2 weeks. For the next 22 weeks, participants will take BDQ 3 times a week on Monday, Wednesday, and Friday. | Drug: Bedaquiline<br>* 100 mg oral tablets. In Cohorts 2 and 3 only under protocol Version 2.0, 20 mg oral dispersible tablet may alternatively be used. Doses will vary based on the participant's age and weight.<br>* Other names: BDQ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of participant termination from treatment due to a drug-related adverse event | Frequency of participant termination from treatment due to a drug-related adverse event | Measured through Week 24 | 
| Frequency of adverse events of ≥ Grade 3 severity |  | Measured through Week 24 | 
| Frequency of adverse events of ≥ Grade 3 severity assessed by the Core Team to be at least possibly related to the study medication |  | Measured through Week 24 | 
| Frequency of participants with absolute QTcF ≥ 500 msec |  | Measured through Week 24 | 
| Frequency of unstable dysrhythmias requiring hospitalization and treatment |  | Measured through Week 24 | 
| Incidence of death |  | Measured through Week 24 | 
| Area Under the Curve (AUC0-24h or AUC0-168h) |  | Week 1 or 2, Week 8, and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events ≥ Grade 3 severity |  | Measured through Week 96 or 72 weeks post BDQ discontinuation | 
| Frequency of adverse events ≥ Grade 3 severity assessed by the Core Team to be at least possibly related to the study drug. |  | Measured through Week 96 or 72 weeks post BDQ discontinuation | 
| Frequency of participants with absolute QTcF greater than or equal to 500 msec |  | Measured through Week 96 or 72 weeks post BDQ discontinuation | 
| Frequency of unstable dysrhythmias requiring hospitalization and treatment |  | Measured through Week 96 or 72 weeks post BDQ discontinuation | 
| Incidence of death |  | Measured through Week 96 or 72 weeks post BDQ discontinuation | 
| Pharmacokinetic parameter maximal concentration |  | Time frame: Week 1 or 2, Week 8, and Week 24 | 
| Pharmacokinetic parameter trough concentration (concentration at the end of an dosing interval) |  | Week 1 or 2, Week 8, and Week 24 | 
| Pharmacokinetic parameter time of maximal concentration |  | Week 1 or 2 | 
| Pharmacokinetic parameter oral clearance |  | Week 24 | 
| Pharmacokinetic parameter theoretical steady state AUC |  | Week 24 | 
| Quantitative post-treatment bedaquiline concentrations |  | Weeks 32-96 | 
| Post-treatment bedaquiline concentrations below limit of quantifications |  | Weeks 32-96 |