Tuberculosis Clinical Trials Consortium Study 35
Tuberculosis Clinical Trials Consortium Study 35
Hypotheses: Rifapentine (given as water-dispersible monolayer and/or fixed dose combination
 with isoniazid) dosing in HIV-infected and uninfected children ≤ 12 years of age with latent
 TB infection (LTBI) or with exposure to Mycobacterium tuberculosis (M. tuberculosis) will
 require higher mg/kg rifapentine dosing than adults to achieve adult- exposures which are
 correlated with efficacy in trials of TB prevention. Investigators further hypothesize that
 rifapentine will be safe and well-tolerated in HIV-infected and uninfected children who
 require treatment for LTBI.
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.

 Sites:

 TBTC Site 33, Desmond Tutu TB Centre, Department of Paediatrics and Child Health,
 Stellenbosch University, South Africa TBTC Site 34, Baragwaneth, Perinatal HIV Research Unit
 (PHRU), Wits Health Consortium, Soweto, Johannesburg, South Africa

 Study Duration: Child participants will be on study for a total of 24 weeks, including a
 12-week rifapentine and isoniazid dosing period, with an additional follow-up period of 12
 weeks. The overall study accrual period will be approximately 18 months and the total study
 duration will be approximately 36 months.

 Description of Agent or Intervention:

 Participants will receive 12 once-weekly doses of water-dispersible rifapentine and
 isoniazid; the initial rifapentine dose in each age cohort will be determined based on
 historical population models and will be adjusted as data become available in paediatric
 cohorts in this study. Cohorts 1 and 2 will open up with a pre-selected modeled dose. Dose
 selection for cohorts 3 and 4 will be modeled from data emerging from cohorts 1 and 2 and
 historical data. Doses in cohorts will be adjusted as required based on interim PK and safety
 analyses. Isoniazid will be given at doses of up to 25 mg/kg, once weekly, in combination
 with pyridoxine (Vitamin B6) 25 mg/kg.
Inclusion Criteria:

 1. Aged 0 - 12 years

 2. Documented close (household or other close exposure) for at least an average 4 hours a
 day over the past 6 months to a bacteriologically confirmed adult (18 years or older)
 source case with pulmonary TB. The adult TB source case should have confirmed drug
 sensitive (sputum culture confirmed or XPERT MTB/Rif [Cepheid] positive TB and without
 any evidence of drug resistance, i.e., at least XPERT MTB/Rif rifampicin susceptible
 or an alternative molecular or phenotypic test indicating rifampicin susceptible M.
 tb) OR:

 3. Evidence of M. tb infection (positive TST ≥ 10 mm in HIV-uninfected and TST ≥ 5 mm in
 HIV-infected participants or a positive commercial interferon-gamma release assay, as
 defined by the manufacturer)

 4. Confirmed HIV status:

 HIV status will be confirmed by DNA PCR and Plasma HIV-RNA if the participant is <18
 months of age.

 In participants ≥18 month of age HIV-ELISA testing will be completed. If any HIV test
 is positive in a child participant, regardless of age, the test result needs to be
 confirmed with a second HIV test, using HIV DNA or RNA PCR, from an independent
 sample.

 5. HIV-infected participants should be on an ART regimen for at least 12 weeks prior to
 enrolment and should be clinically stable before entering the study, regardless of CD
 4 count and HIV viral load. While on study, participants must be on an efavirenz- or
 raltegravir-based ART regimen which should have been given for at least 14 days prior
 to enrolment.

 6. Caregiver (parent or legal guardian) gives written informed consent and assent from
 the child where applicable

 7. Weight > 2.5 kg but < 40 kg

 Exclusion Criteria:

 1. Active TB disease (evidenced by: symptoms suggestive of TB, or suggestive findings on
 clinical examination, or suggestive chest radiographic findings, or positive
 mycobacterial culture/molecular TB tests -if culture/molecular testing was clinically
 indicated and was completed-, or currently on TB treatment for active disease).

 2. Any documented drug resistant TB (DR TB) in an identified adult source case, defined
 as rifampicin resistance on Xpert or any other relevant approved molecular test, or
 phenotypic evidence of rifampicin resistance.

 3. Receipt of a once-daily isoniazid regimen for > 30 days which was given for at least
 14 consecutive days in the 30 days prior to enrolment.

 4. Hb < 10 mg/dl

 5. Weight for age z score below 2 or severe clinical malnutrition

 6. Known allergy or hypersensitivity to isoniazid or rifapentine

 7. Documented hepatic disorder including > 5 fold elevated upper limit of normal (ULN)
 ALT and/or bilirubin

 8. Lansky play score < 50

 9. Documentation of Hepatitis A or B infection

 10. Female adolescents who have reached menarche will not be eligible.