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

• Register: ClinicalTrials.gov
• Last refreshed on: 27 February 2024
• Main ID: NCT02906007
• Date of registration: 14/09/2016
• Prospective Registration: Yes
• Primary sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Public title: Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis, Living With or Without HIV
• Scientific 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
• Date of first enrolment: September 21, 2017
• Target sample size: 84
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT02906007
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

Haiti, India, South Africa

Contacts

• Name: Anneke Hesseling, M.D., Ph.D.
• Affiliation: Desmond Tutu TB Centre, Stellenbosch University

Key inclusion & exclusion criteria

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.



Age minimum: 0 Months
Age maximum: 18 Years
Gender: All

Health Condition(s) or Problem(s) studied

Tuberculosis

HIV

Intervention(s)

Drug: Bedaquiline

Primary Outcome(s)

Frequency of unstable dysrhythmias requiring hospitalization and treatment [Time Frame: 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 [Time Frame: Measured through Week 24]

Frequency of participant termination from treatment due to a drug-related adverse event [Time Frame: Measured through Week 24]

Area Under the Curve (AUC0-24h or AUC0-168h) [Time Frame: Week 1 or 2, Week 8, and Week 24]

Frequency of participants with absolute QTcF = 500 msec [Time Frame: Measured through Week 24]

Incidence of death [Time Frame: Measured through Week 24]

Frequency of adverse events of = Grade 3 severity [Time Frame: Measured through Week 24]

Secondary Outcome(s)

Pharmacokinetic parameter maximal concentration [Time Frame: Time frame: Week 1 or 2, Week 8, and Week 24]

Pharmacokinetic parameter oral clearance [Time Frame: Week 24]

Post-treatment bedaquiline concentrations below limit of quantifications [Time Frame: Weeks 32-96]

Frequency of adverse events = Grade 3 severity [Time Frame: Measured through Week 96 or 72 weeks post BDQ discontinuation]

Frequency of unstable dysrhythmias requiring hospitalization and treatment [Time Frame: 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. [Time Frame: Measured through Week 96 or 72 weeks post BDQ discontinuation]

Pharmacokinetic parameter time of maximal concentration [Time Frame: Week 1 or 2]

Pharmacokinetic parameter trough concentration (concentration at the end of an dosing interval) [Time Frame: Week 1 or 2, Week 8, and Week 24]

Incidence of death [Time Frame: Measured through Week 96 or 72 weeks post BDQ discontinuation]

Pharmacokinetic parameter theoretical steady state AUC [Time Frame: Week 24]

Quantitative post-treatment bedaquiline concentrations [Time Frame: Weeks 32-96]

Frequency of participants with absolute QTcF greater than or equal to 500 msec [Time Frame: Measured through Week 96 or 72 weeks post BDQ discontinuation]

Secondary ID(s)

11884

IMPAACT P1108

P1108

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

National Institute of Mental Health (NIMH)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)