P1108: A Phase I/II, Open-Label, Single Arm Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Bedaquiline (BDQ) in Combination with Optimized Individualized Multidrug-Resistant Tuberculosis (MDR-TB) Therapy in HIV-Infected and HIV-Uninfected Infants, Children and Adolescents with MDR-TB Disease
This purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of bedaquiline (BDQ) in combination with an optimized background multidrug-resistant tuberculosis (MDR-TB) treatment regimen in HIV-infected and HIV-uninfected infants, children, and adolescents.
The study will enroll HIV-infected and HIV-uninfected children 0 to 18 years of age treated for clinically diagnosed or confirmed intrathoracic (pulmonary) MDR-TB and certain types of extrathoracic MDR-TB. Participants will be assigned to cohorts based on age. Cohort 1 will include children 6 years of age or older but less than 18 years of age; Cohort 2 will include children 2 years of age or older but less than 6 years of age; and Cohort 3 will include children 0 months of age and older but less than 2 years of age. Cohort 1 will be 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.
Study visits will occur at enrollment (Day 0) and at Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 96, and 120. Participants in Cohort 1 will take BDQ once a day during the first 2 weeks. For the next 22 weeks, BDQ will be taken three times a week. Dosing for Cohorts 2 and 3 will be determined based on data from Cohort 1.
Study visits may include physical examinations, blood and urine collection, an electrocardiogram (ECG), medical history reviews, and other assessments.
Ages Eligible for Study: up to 18 Years (Child, Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
- 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: At least 7 kg
- Cohort 3: At least 3 kg
- Documented HIV status as defined in the protocol for HIV-infected participants and HIV-uninfected participants.
- Either confirmed or probable multi-drug resistant tuberculosis (MDR-TB): Confirmed intra-thoracic (pulmonary) MDR-TB, with or without one of the following forms of extrathoracic tuberculosis (TB):
- Peripheral TB lymphadenitis
- Pleural effusion or fibrotic pleural lesions
- Stage 1 TB meningitis
- Miliary and abdominal TB,
- Other non-disseminated forms of TB disease
- More information on this criterion can be found in the protocol.
- Initiated on an optimized background MDR-TB regimen as per routine treatment decision, at least two weeks but not more than 12 weeks prior to enrollment, and tolerating the regimen well at enrollment.
- If HIV-infected: Initiated an acceptable antiretroviral therapy (ART) regimen defined as either zidovudine (ZDV) + lamivudine (3TC) + abacavir (ABC) or nevirapine (NVP) + 2 nucleoside reverse transcriptase inhibitors (NRTIs) at least two weeks prior to enrollment.
- If male and engaging in sexual activity that could lead to pregnancy of the female partner: 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 48 hours prior to enrollment.
- 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.