Tuberculosis Clinical Trials Consortium Study 35

Design: Tuberculosis Trials Consortium Study 35 (TBTC S35) is a Phase I/II, open-label, single arm, exposure-controlled dose finding study using an adaptive design. S35 will evaluate the pharmacokinetics (PK), safety and tolerability of rifapentine given in a new fixed dose combination once-weekly, in combination with isoniazid for 12 weeks, in HIV-infected and HIV-uninfected children aged 0-12 years in whom LTBI treatment is indicated. The study utilizes a modified age de-escalation approach given the extensive PK and safety data already available in children older than 2 years of age. The protocol allows for parallel enrolment of children into cohorts 1 and 2, simultaneously, using a predetermined modeled initial dose for each cohort, separately. Similarly, cohorts 3 and 4 will be enrolled in parallel, using modeled doses for each cohort, based on data from cohorts 1 and 2 and historical data from TBTC trials.

Sample Size: Approximately 72 participants will be required to ensure a minimum number of 60 evaluable participants.

Participants will be enrolled in 4 age cohorts:

Cohort 1: ≥ 4 to ≤ 12 years Cohort 2: ≥ 24 months to \< 4 years Cohort 3: ≥ 12 to \< 24 months Cohort 4: 0 to \<12 months

There will be a minimum of 12 participants each in cohorts 1 and 2, and 18 participants each in cohorts 3 and 4, to allow for 36 participants in the age group below 2 years, given the importance of developmental pharmacology in this youngest age group (Table 1) and the lack of historical data in this age group. Cohorts 3 and 4 will be enrolled once week 1 PK and safety data is available in cohorts 1 and 2.

Up to 18 HIV-infected children overall will be enrolled, with a target of 12 HIV-infected children overall. It is expected that most HIV-infected children will be \> 3 years of age given current international recommendations regarding the use of efavirenz in children in international settings, where the study will be conducted. However, it is expected that integrase inhibitors (e.g. raltegravir) would become more routinely available during the study period, allowing younger HIV-infected children to also be enrolled on study.

Population: HIV-infected and uninfected children aged 0-12 years who could benefit from chemotherapy for LTBI to prevent the development of active tuberculosis, who have documented close recent exposure to a bacteriologically positive drug sensitive adult pulmonary TB source case, or who have proof of M. tuberculosis infection. HIV-infected children will be established on anti-retroviral therapy for at least 12 weeks prior to enrolment.