Attachment_2_Appendix_B_S35_Summary.pdf

Appendix B_S35 Summary

1.1 Protocol Summary

Title: Phase I/II Dose Finding and Safety Study of Rifapentine and Isoniazid in HIV-

Infected and HIV-Uninfected Children with Latent Tuberculosis Infection

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 of rifapentine in trials of TB prevention. We 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, water-dispersible fixed dose combination formulation with isoniazid once-weekly, 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, respectively, 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 data and safety data through week 12 are available in cohorts 1 and 2.

Up to 18 HIV-infected children overall will be enrolled (all cohorts)with a minimum 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 and dolutegravir) would become more routinely available during the study period, allowing for younger HIV-infected children (<3 years of age) 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 (positive test of M.tuberculosis infection). HIV-infected children will be established on anti-retroviral therapy for at least 12 weeks prior to enrolment.

*The availability of integrase inhibitors during the study implementation may affect the age distribution of HIV-infected children enrolled (i.e. inclusion of children < 3 years)

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 12-18 months and the total study duration will be approximately 36 months.

Table 1. Minimum evaluable number of participants per age group and by HIV status.

Cohort Age Total number

Number HIV-infected*

Number HIV-uninfected

1 ≥ 4 to ≤ 12 years 12 6 6

2 ≥ 24 months to < 4 years 12 6 6

3 ≥ 12 to < 24 months 18 - 18

4 0 to < 12 months 18 - 18

Total 60 12 48

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, results of relative bioavailability evaluation of the new formulations to be tested 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 given to participants as clinically indicated.

Objectives

In HIV-infected and HIV-uninfected children aged 0-12 years receiving a new water-dispersible formulation of rifapentine in combination with isoniazid for the prevention of TB:

Primary

1. To establish, through population PK modeling, the dose(s) of rifapentine that will achieve the target adult exposures [median area under the curve24 (AUC 0-24) no more than 25% lower than, and no more than 75% higher than, the target adult AUC of 522 mcg*h/L] from TBTC Study 26, when rifapentine was given once-weekly, in a fixed dose combination with isoniazid, for 12 weeks.

Secondary

1. To document the safety of rifapentine given in combination with isoniazid once-weekly over 12 weeks.

2. To document the tolerability of rifapentine given in combination with isoniazid once-weekly for

12 weeks.

3. To characterize the PK of rifapentine, given in model-predicted doses, in combination with isoniazid once-weekly for 12 weeks, taking into account covariates that may influence the PK of rifapentine, such as age, weight, sex, HIV status, nutritional status and pharmacogenomics (e.g.

SLCO1B1).

4. To document the palatability and acceptability of rifapentine given in combination with isoniazid once-weekly for 12 weeks.

5. To characterize incident TB over a total of 24 weeks follow-up from enrolment in children treated for TB exposure or infection.

6. To characterize the PK of isoniazid given once weekly in combination with rifapentine, taking into account N-acetyltransferase 2 (NAT2) metabolizer genotype.

Exploratory

1. In HIV-infected children, to characterize the effects of once-weekly rifapentine and isoniazid on efavirenz taking into account CYP2B6 efavirenz metabolizer status. In addition, the potential effects of once-weekly rifapentine and isoniazid on dolutegravir/raltegravir PK parameters will be studied if dolutegravir/raltegravir are routinely used in the trial population during the study.

End points

Primary

1. Dosing algorithm derived by simulation of optimal rifapentine doses (based on the target adult AUC levels from TBTC Study 26) in children, using nonlinear mixed effects models, using an age and/or weight banding approach.

Secondary

1. The cumulative number and proportion of children with grade 3 and 4 adverse events over the 12 week dosing period.

2. The cumulative number and proportion of children who discontinue study drug due to an adverse event during the 12 week dosing period.

3. Primary population PK parameters including absorption rate constant (ka), volume of distribution

(Vd), and oral clearance (Cl/F) and between-subject variability terms; post-hoc Bayesian predictions of secondary PK parameters of rifapentine including (Cmax), time to Cmax (Tmax), area-under-the-curve (AUC0-24) and t ½ for rifapentine (and its 25-desacetyl metabolite).

4. Palatability scores and acceptability over the 12 week rifapentine dosing period.

5. Frequency of incident tuberculosis over 24 weeks’ follow-up from enrollment.

6. PK parameters of isoniazid, taking into account NAT2 genotype.

Exploratory

PK parameters of efavirenz in HIV-infected children when taking concomitant rifapentine versus not taking rifapentine, taking into account the CYP2B6 genotype. PK parameters of other ART will be explored, including dolutegravir/raltegravir, if they are routinely used in the trial population during the study.