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.
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 occurred 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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
54
Participants received bedaquiline (BDQ) once per day through intensive PK sampling visit, then 3 times per week on Monday, Wednesday and Friday through the week 24 visit.
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
Port-au-Prince, Haiti
Sizwe CRS
Johannesburg, Gauteng, South Africa
PHRU Matlosana CRS
Klerksdorp, North West, South Africa
Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS
Cape Town, Western Cape, South Africa
Percentage of Participants With Adverse Events of ≥ Grade 3 Severity
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).
Time frame: Measured from entry through Week 24
Percentage of Participants With Adverse Events of ≥ Grade 3 Assessed by the Core Team to be at Least Possibly Related to the Study Drug
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.
Time frame: Measured from entry through Week 24
Percentage of Participants Who Were Terminated From Study Treatment Due to a Drug-related Adverse Event
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.
Time frame: Measured from entry through Week 24
Percentage of Participants Who Died
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.
Time frame: Measured from entry through Week 24
Percentage of Participants With Unstable Dysrhythmias Requiring Hospitalization and Treatment
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.
Time frame: Measured from entry through Week 24
Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec
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.
Time frame: All participants had ECG performed at Screening and Entry visits and through week 24.
Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h or AUC0-168h) Bedaquiline
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
Time frame: 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.
Percentage of Participants With Adverse Events ≥ Grade 3 Severity
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). A higher grade indicates worse outcome.
Time frame: Measured from entry through study completion, up to 120 weeks
Percentage of Participants With Adverse Events ≥ Grade 3 Severity Assessed by the Core Team to be at Least Possibly Related to the Study Drug.
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). A higher grade indicates worse outcome.
Time frame: Measured from entry through study completion, up to 120 weeks
Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec
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 40.
Time frame: Measured from entry through study week 40
Percentage of Participants With Unstable Dysrhythmias Requiring Hospitalization and Treatment
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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). A higher grade indicates worse outcomes.
Time frame: Measured from entry through study completion, up to 120 weeks
Percentage of Participants Who Died
At entry and follow-up, death of all causes
Time frame: Measured from entry through study completion, up to 120 weeks
Percentage of Participants With TB Treatment Outcomes at End of Rifampin Resistant (RR) Treatment Among Those Not Living With HIV
TB treatment outcomes were evaluated by team-identified independent endpoint reviewers through end of RR treatment and end of study. TB Treatment outcomes in children were defined as bacteriologic cure, probable cure, death, treatment failure, TB recurrence, and loss to follow-up as per protocol.
Time frame: Measured from entry through end of RR treatment, up to 81 weeks
Percentage of Participants With TB Treatment Outcomes at End of Rifampin Resistant (RR) Treatment Among Those Living With HIV
TB treatment outcomes were evaluated by team-identified independent endpoint reviewers through end of RR treatment and end of study. TB Treatment outcomes in children were defined as bacteriologic cure, probable cure, death, treatment failure, TB recurrence, and loss to follow-up as per protocol.
Time frame: Measured from entry through end of RR treatment, up to 81 weeks
Percentage of Participants With TB Treatment Outcomes at End of Study Among Those Not Living With HIV
TB treatment outcomes were evaluated by team-identified independent endpoint reviewers through end of study. TB Treatment outcomes in children were defined as bacteriologic cure, probable cure, death, treatment failure, TB recurrence, and loss to follow-up as per protocol.
Time frame: Measured from entry through study completion, up to 120 weeks
Percentage of Participants With TB Treatment Outcomes at End of Study Among Those Living With HIV
TB treatment outcomes were evaluated by team-identified independent endpoint reviewers through end of study. TB Treatment outcomes in children were defined as bacteriologic cure, probable cure, death, treatment failure, TB recurrence, and loss to follow-up as per protocol.
Time frame: Measured from entry through study completion, up to 120 weeks
Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h or AUC0-168h) Bedaquiline Mono-desmethyl Metabolite (M2)
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
Time frame: 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.
Geometric Mean of Maximal Concentration (Cmax) Bedaquiline
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
Time frame: 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.
Geometric Mean of Maximal Concentration (Cmax) Bedaquiline Mono-desmethyl Metabolite (M2)
PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Time frame: 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.
Geometric Mean of Trough Concentration (Ctrough) Bedaquiline
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.
Time frame: Intensive PK (Week 1 or 2) 24h post dose and Weeks 8 and 24 48-72h post dose
Geometric Mean of Trough Concentration (Ctrough) Bedaquiline Mono-desmethyl Metabolite (M2)
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.
Time frame: Intensive PK (Week 1 or 2) 24h post dose and Weeks 8 and 24 48-72h post dose
Median of Time of Maximal Concentration (Tmax) Bedaquiline
PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Time frame: Intensive PK (Week 1 or 2) pre-dose and 2, 4, 6, 8 hours post dose
Median of Time of Maximal Concentration (Tmax) Bedaquiline Mono-desmethyl Metabolite (M2)
PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Time frame: Intensive PK (Week 1 or 2) pre dose and 2, 4, 6, 8 hours post dose
Geometric Mean of Oral Clearance (CL/F) Bedaquiline
Individual clearance (CL) relative to bioavailability (F) determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model
Time frame: Week 24
Geometric Mean of Theoretical Steady State AUC (AUC0-168h)
Calculated PK parameter determined from weekly continuation phase dose divided by oral clearance at week 24
Time frame: Week 24
Median Quantitative Post-treatment Bedaquiline Concentrations
PK assessments were performed to determine plasma concentrations of BDQ at selected time points. All concentrations reported to be below the limit of quantification were imputed to zero in these calculations
Time frame: Weeks 8, 16, 24, 36, 48, 72, and 96 after BDQ discontinuation
Percentage of Participants With Post-treatment Bedaquiline Concentrations Below Limit of Quantifications (BLQ)
PK assessments were performed to determine plasma concentrations of BDQ at selected time points. "
Time frame: Weeks 8, 16, 24, 36, 48, 72, and 96 after BDQ discontinuation