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

NCT02906007 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: P110811884IMPAACT P1108
• Study Type: interventional
• Target: 54
• Locations: 2 countries
• Sites: 4

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.

Conditions

Tuberculosis; HIV

Outcome Measures

Primary Outcomes (7)

• 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).

  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.

  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.

  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.

  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.

  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.

  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

  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.

Secondary Outcomes (16)

• Percentage of Participants With Adverse Events ≥ Grade 3 Severity

  Measured through Week 96 or 72 weeks post BDQ discontinuation

• 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

• Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec

  Measured through Week 96 or 72 weeks post BDQ discontinuation

• Percentage of Participants With Unstable Dysrhythmias Requiring Hospitalization and Treatment

  Measured through Week 96 or 72 weeks post BDQ discontinuation

• Percentage of Participants Who Died

  Measured through Week 96 or 72 weeks post BDQ discontinuation

Study Arms (3)

Cohort 1 (>=6 to < 18 years)

EXPERIMENTAL

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

Drug: Bedaquiline

Cohort 2 (>=2 to < 6 years)

EXPERIMENTAL

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

Drug: Bedaquiline

Cohort 3 (>=0 to < 2 years)

EXPERIMENTAL

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

Drug: Bedaquiline

Interventions

Bedaquiline DRUG

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.

Also known as: BDQ

Cohort 1 (>=6 to < 18 years); Cohort 2 (>=2 to < 6 years); Cohort 3 (>=0 to < 2 years)

Eligibility Criteria

• Age: 0 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Institute of Mental Health (NIMH): collaborator

Study Sites (4)

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, HT-6110, Haiti

Location

Sizwe CRS

Johannesburg, Gauteng, South Africa

Location

PHRU Matlosana CRS

Klerksdorp, North West, 2574, South Africa

Location

Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS

Cape Town, Western Cape, 7505, South Africa

Location

Related Links

• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, will be used in this study
• "Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010"

MeSH Terms

Conditions

Tuberculosis

Interventions

bedaquiline

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Family Health International (FHI 360)

IMPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• Anneke Hesseling, M.D., Ph.D.

  Desmond Tutu TB Centre, Stellenbosch University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2016
• First Posted: September 19, 2016
• Study Start: September 21, 2017
• Primary Completion: February 7, 2024
• Study Completion: April 30, 2025
• Last Updated: September 4, 2025
• Results First Posted: March 21, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

HA (1); ZA (3)