Clinical trial NCT02906007: Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis, Living With or Without HIV
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Tuberculosis
HIV
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Mental Health (NIMH)
First posted: 2016-09-19
Enrollment: 54
Sex: ALL
Minimum age (years): 0
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Adverse Events of ≥ Grade 3 Severity
timeFrame: Measured from entry through Week 24
measure: Percentage of Participants With Adverse Events of ≥ Grade 3 Assessed by the Core Team to be at Least Possibly Related to the Study Drug
timeFrame: Measured from entry through Week 24
measure: Percentage of Participants Who Were Terminated From Study Treatment Due to a Drug-related Adverse Event
timeFrame: Measured from entry through Week 24
measure: Percentage of Participants Who Died
timeFrame: Measured from entry through Week 24
measure: Percentage of Participants With Unstable Dysrhythmias Requiring Hospitalization and Treatment
timeFrame: Measured from entry through Week 24
measure: Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec
timeFrame: All participants had ECG performed at Screening and Entry visits and through week 24.
measure: Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h or AUC0-168h) Bedaquiline
timeFrame: 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:
measure: Percentage of Participants With Adverse Events ≥ Grade 3 Severity
timeFrame: Measured through Week 96 or 72 weeks post BDQ discontinuation
measure: Percentage of Participants With Adverse Events ≥ Grade 3 Severity Assessed by the Core Team to be at Least Possibly Related to the Study Drug.
timeFrame: Measured through Week 96 or 72 weeks post BDQ discontinuation
measure: Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec
timeFrame: Measured through Week 96 or 72 weeks post BDQ discontinuation
measure: Percentage of Participants With Unstable Dysrhythmias Requiring Hospitalization and Treatment
timeFrame: Measured through Week 96 or 72 weeks post BDQ discontinuation
measure: Percentage of Participants Who Died
timeFrame: Measured through Week 96 or 72 weeks post BDQ discontinuation
measure: Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h or AUC0-168h) Bedaquiline Mono-desmethyl Metabolite (M2)
timeFrame: 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.
measure: Geometric Mean of Maximal Concentration (Cmax) Bedaquiline
timeFrame: 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.
measure: Geometric Mean of Maximal Concentration (Cmax) Bedaquiline Mono-desmethyl Metabolite (M2)
timeFrame: 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.
measure: Geometric Mean of Trough Concentration (Ctrough) Bedaquiline
timeFrame: Intensive PK (Week 1 or 2) 24h post dose and Weeks 8 and 24 48-72h post dose
measure: Geometric Mean of Trough Concentration (Ctrough) Bedaquiline Mono-desmethyl Metabolite (M2)
timeFrame: Intensive PK (Week 1 or 2) 24h post dose and Weeks 8 and 24 48-72h post dose
measure: Median of Time of Maximal Concentration (Tmax) Bedaquiline
timeFrame: Intensive PK (Week 1 or 2) pre-dose and 2, 4, 6, 8 hours post dose
measure: Median of Time of Maximal Concentration (Tmax) Bedaquiline Mono-desmethyl Metabolite (M2)
timeFrame: Intensive PK (Week 1 or 2) pre dose and 2, 4, 6, 8 hours post dose
measure: Geometric Mean of Oral Clearance (CL/F) Bedaquiline
timeFrame: Week 24
measure: Geometric Mean of Theoretical Steady State AUC (AUC0-168h)
timeFrame: Week 24
measure: Quantitative Post-treatment Bedaquiline Concentrations
timeFrame: Weeks 32-96
measure: Post-treatment Bedaquiline Concentrations Below Limit of Quantifications
timeFrame: Weeks 32-96
Other outcomes:
Locations:
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
city: Johannesburg
country: South Africa
facility: Sizwe CRS
state: Gauteng
city: Klerksdorp
country: South Africa
facility: PHRU Matlosana CRS
state: North West Province
city: Cape Town
country: South Africa
facility: Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS
state: Western Cape Province
Study officials:
affiliation: Desmond Tutu TB Centre, Stellenbosch University
name: Anneke Hesseling, M.D., Ph.D.
role: STUDY_CHAIR
References: