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

Phase 1

Active, not recruiting

Conditions: Tuberculosis
HIV

Interventions: Drug: Bedaquiline

Registration Number: NCT02906007

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: P1108 was 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 was designed to evaluate the PK, safety, and tolerability of BDQ over 24 weeks.

Detailed Description: The purpose of this study was 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 was 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 were assigned to cohorts based on age. Cohort 1 included children six years of age or older but less than 18 years of age; Cohort 2 included children two years of age or older but less than six years of age; and Cohort 3 included children 0 months of age and older but less than two years of age. Cohort 1 was 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 included participants weighing greater than 7 kg. Cohort 3 included participants weighing at least 3 kg.

Study visits occured 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 took BDQ once a day for approximately two weeks. For the next 22 weeks, BDQ was taken three times a week. Dosing for Cohorts 2 and 3 was based on data from Cohort 1.

Study visits included physical examinations, blood and urine collection, an electrocardiogram (ECG), medical history reviews, and other assessments.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 54

Inclusion Criteria

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, potential 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 (pulmonary) RR-TB and/or any of the following forms of extrathoracic TB:
- 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 OR

Probable RR-TB (or clinically diagnosed RR-TB) with the inclusion of intrathoracic and/or extrathoracic TB as listed below:

A presumptive diagnosis of RR-TB based on well-documented clinical symptoms or signs of TB with chest radiological changes (in the case of intrathoracic TB), and/or any of the following extrathoracic disease manifestations:
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) Note: Laboratory tests may be repeated during the screening period, with the latest results used for eligibility determination.
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), until four weeks after discontinuation of 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: At entry, participant agrees to avoid pregnancy and to use at least two of the following contraception methods from entry through completion of study follow-up: condoms, diaphragm or cervical cap, intrauterine contraceptive device (IUCD), hormonal-based contraception.
For Cohort 3 participants less than six months of age: Gestational age at birth greater than or equal to 37 weeks as determined by the site investigator based on parent/guardian report and/or available medical records.

Exclusion Criteria

Has any documented or suspected clinically significant medical condition or any other condition (excluding HIV and TB) that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives.
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.
Participant is breastfeeding a child based on participant/parent/guardian report and/or available medical records.
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.
QTcF interval greater than 460 ms (i.e., ECG mean triplicate value greater than 460 ms) at screening. Note: The centralized ECG read should be used during screening for eligibility determination.
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 based on available medical records and centralized read of ECGs during screening.
Known personal or family history of long QT syndrome as determined by the site investigator based on participant/parent/guardian report and/or available medical records.
Within eight weeks prior to entry, participation in other clinical studies with investigational agents or devices, unless approved in advance by the Core Team.
Taking any prohibited medications specified in the protocol within three days prior to entry based on participant/parent/guardian report and/or available medical records.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 1 (>=6 to < 18 years)	Bedaquiline	Participants ≥30 kg: 400 mg once per day through the intensive PK sampling visit, then 200 mg three times per week on Monday, Wednesday, and Friday through the Week 24 visit Participants ≥15 to \<30 kg: 200 mg once per day through the intensive PK sampling visit, then 100 mg three times per week on Monday, Wednesday, and Friday through the Week 24
Cohort 2 (>=2 to < 6 years)	Bedaquiline	Participants \>7 to \<30 kg: 200 mg once per day through the intensive PK sampling visit, then 100 mg three times per week on Monday, Wednesday, and Friday through the Week 24 visit
Cohort 3 (>=0 to < 2 years)	Bedaquiline	Participants \>7 to \<30 kg: 200 mg once per day through the intensive PK sampling visit, then 100 mg three times per week on Monday, Wednesday, and Friday through the Week 24 visit Participants ≥ 3 to ≤ 7 kg: 100 mg once per day through the intensive PK sampling visit, then 50 mg three times per week on Monday, Wednesday, and Friday through the Week 24 visit

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Adverse Events of ≥ Grade 3 Severity	Measured from entry through Week 24	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1).
Percentage of Participants With Adverse Events of ≥ Grade 3 Assessed by the Core Team to be at Least Possibly Related to the Study Drug	Measured from entry through Week 24	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1.
Percentage of Participants Who Were Terminated From Study Treatment Due to a Drug-related Adverse Event	Measured from entry through Week 24	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1.
Percentage of Participants Who Died	Measured from entry through Week 24	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.0.
Percentage of Participants With Unstable Dysrhythmias Requiring Hospitalization and Treatment	Measured from entry through Week 24	At entry and follow-up, any participant who experienced unstable dysrhythmias that required hospitalization and treatment were considered as an adverse event. The core team reviewed and confirmed the sites assessment of event relatedness to study drug.
Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec	All participants had ECG performed at Screening and Entry visits and through week 24.	Evaluation of the Electrocardiogram (ECG) QTcF was performed per protocol. ECGs conducted at these visits should be performed in triplicate (if possible). Consultation with the protocol cardiologist was available and encouraged for any abnormal or equivocal ECG findings and/or questions related to cardiac toxicities and assessment. Participants were included if they had QTcF ≥ 500 msec at any study visit from entry to Week 24.
Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h or AUC0-168h) Bedaquiline	Intensive PK Week 1 or 2, Week 8, and Week 24, (if intensive then pre dose, and post dose at 2, 4, 6, 8 hours) and if not intensive then predose only.	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model The final population PK model was developed using a nonlinear mixed effects model (NNMEM, version 7.5). * Developed a population PK model as part of the final PK analysis * Data used in the population PK analysis included the intensive PK visit (Week 1 or Week 2), sparse PK samples from Weeks 4, 8, 12, 16, 20, 24, etc,as available at time of final analysis (when all participants have at least Week 24 PK samples) * Estimated individual AUC values at given time points for each participant using the developed model

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Adverse Events ≥ Grade 3 Severity	Measured through Week 96 or 72 weeks post BDQ discontinuation	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1).
Percentage of Participants With 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	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1).
Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec	Measured through Week 96 or 72 weeks post BDQ discontinuation	Evaluation of the Electrocardiogram (ECG) QTcF was performed per protocol. ECGs conducted at these visits should be performed in triplicate (if possible). Consultation with the protocol cardiologist was available and encouraged for any abnormal or equivocal ECG findings and/or questions related to cardiac toxicities and assessment. Participants were included if they had QTcF ≥ 500 msec at any study visit from entry to Week 24.
Percentage of Participants With Unstable Dysrhythmias Requiring Hospitalization and Treatment	Measured through Week 96 or 72 weeks post BDQ discontinuation	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1).
Percentage of Participants Who Died	Measured through Week 96 or 72 weeks post BDQ discontinuation	At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1).
Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h or AUC0-168h) Bedaquiline Mono-desmethyl Metabolite (M2)	Intensive PK Week 1 or 2, Week 8, and Week 24, (if intensive then pre dose, and post dose at 2, 4, 6, 8 hours) and if not intensive then predose only.	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model The final population PK model was developed using a nonlinear mixed effects model (NNMEM, version 7.5). * Developed a population PK model as part of the final PK analysis * Data used in the population PK analysis included the intensive PK visit (Week 1 or Week 2), sparse PK samples from Weeks 4, 8, 12, 16, 20, 24, etc,as available at time of final analysis (when all participants have at least Week 24 PK samples) * Estimated individual AUC values at given time points for each participant using the developed model
Geometric Mean of Maximal Concentration (Cmax) Bedaquiline	Intensive PK Week 1 or 2, Week 8, and Week 24, (if intensive then pre dose, and post dose at 2, 4, 6, 8 hours) and if not intensive then pre dose only.	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model The final population PK model was developed using a nonlinear mixed effects model (NNMEM, version 7.5). * Developed a population PK model as part of the final PK analysis * Data used in the population PK analysis included the intensive PK visit (Week 1 or Week 2), sparse PK samples from Weeks 4, 8, 12, 16, 20, 24, etc,as available at time of final analysis (when all participants have at least Week 24 PK samples) * Estimated individual AUC values at given time points for each participant using the developed model
Geometric Mean of Maximal Concentration (Cmax) Bedaquiline Mono-desmethyl Metabolite (M2)	Intensive PK Week 1 or 2, Week 8, and Week 24, (if intensive then pre dose, and post dose at 2, 4, 6, 8 hours) and if not intensive then pre dose only.	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Geometric Mean of Trough Concentration (Ctrough) Bedaquiline	Intensive PK (Week 1 or 2) 24h post dose and Weeks 8 and 24 48-72h post dose	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model. Lowest concentration at end of the dosing interval which is approximately 24h after dose at Intensive PK (Week 1 or 2) and 48-72h at Weeks 8 and 24.
Geometric Mean of Trough Concentration (Ctrough) Bedaquiline Mono-desmethyl Metabolite (M2)	Intensive PK (Week 1 or 2) 24h post dose and Weeks 8 and 24 48-72h post dose	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model. Lowest concentration at end of the dosing interval which is approximately 24h after dose at Intensive PK (Week 1 or 2) and 48-72h at Weeks 8 and 24.
Median of Time of Maximal Concentration (Tmax) Bedaquiline	Intensive PK (Week 1 or 2) pre-dose and 2, 4, 6, 8 hours post dose	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Median of Time of Maximal Concentration (Tmax) Bedaquiline Mono-desmethyl Metabolite (M2)	Intensive PK (Week 1 or 2) pre dose and 2, 4, 6, 8 hours post dose	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Geometric Mean of Oral Clearance (CL/F) Bedaquiline	Week 24	Individual clearance (CL) relative to bioavailability (F) determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Geometric Mean of Theoretical Steady State AUC (AUC0-168h)	Week 24	Calculated PK parameter determined from weekly continuation phase dose divided by oral clearance at week 24
Quantitative Post-treatment Bedaquiline Concentrations	Weeks 32-96	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Post-treatment Bedaquiline Concentrations Below Limit of Quantifications	Weeks 32-96	PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

Trial Locations

Locations (4): Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS
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Cape Town, Western Cape Province, South Africa
Sizwe CRS
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Johannesburg, Gauteng, South Africa
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
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Port-au-Prince, Haiti
PHRU Matlosana CRS
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Klerksdorp, North West Province, South Africa