Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid

Abstract

Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.

Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.

Design, setting, and participants: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.

Interventions: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.

Main outcomes and measures: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.

Results: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.

Conclusions and relevance: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.

Trial registration: clinicaltrials.gov Identifier: NCT00023452.

Conflict of interest statement

Conflict of Interest Disclosures: Mr Scott and Dr Moro report being employed by the CDC Foundation, which receives funds for rifapentine research from Sanofi. Dr Weiner reports receiving a grant to perform rifapentine pharmacokinetics studies in children and adults for the University of Texas Health Science Center at San Antonio from Sanofi. Dr Sterling reports giving a 1-day consultation for Sanofi for presentation of PREVENT TB study data to the US Food and Drug Administration and being on the data safety monitoring board for a clinical trial sponsored by Otsuka Pharmaceutical. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Study Participants (Children Aged 2–17 Years): CONSORT Criteria

This flowchart shows the number of participants who were enrolled, received the assigned treatment, and were analyzed for the safety and effectiveness outcomes. Combination drug therapy indicates 3 months of directly observed once-weekly combination of rifapentine and isoniazid; isoniazid therapy, 9 months of self-administered daily isoniazid; DST, drug susceptibility testing; MITT, modified intention-to-treat; TB, tuberculosis; TST, tuberculin skin test. a Eligibility screening data for the randomized clinical trial were obtained from March 31, 2005, onward, with the implementation of an eligibility screening log. This log was implemented in response to the publication of the CONSORT (Consolidated Standards of Reporting Trials) reporting recommendations for randomized clinical trials, which were vetted after the PREVENT TB trial started. b Enrollment of participants was allowed before Mycobacterium tuberculosis culture and susceptibility data were available in the source case of tuberculosis. c Results of TST not confirmed as positive on postenrollment TST repeated at 8 to 12 weeks; enrollment of close contacts was allowed if children were younger than 5 years or human immunodeficiency virus seropositive and enrolling clinicians had the option to discontinue treatment.

Figure 2.. Difference in Tuberculosis Disease Rates Between the 2 Treatment Regimens Over Time (MITT Population)

The figure shows how the noninferiority criterion was met when none of the 471 patients in the combination-therapy arm developed tuberculosis vs 3 of 434 in the isoniazid-only arm (cumulative rate, 0.74%), for a difference of −0.74% and an upper bound of the 97.5% CI of the difference of +0.32%. Per-protocol population effectiveness analysis showed similar results. The difference in cumulative TB disease rate is the rate in the combination-therapy arm minus the rate in the isozanid-only arm. The noninferiority margin was 0.75% for all analyses. Combination drug therapy indicates 3 months of directly observed, once-weekly combination of rifapentine and isoniazid; isoniazid only, 9 months of self-administered daily isoniazid; MITT, modified intention-to-treat; TB, tuberculosis. a None had evidence of re-exposure to infectious TB: (1) one 14-year-old female was diagnosed 72 days after the first dose, with 2 cultures positive for Mycobacterium tuberculosis; (2) one 5-year-old male was clinically diagnosed 818 days after the first dose; and (3) one 2-year-old male was clinically diagnosed 839 days after the first dose. b One-sided 97.5% CI for the difference in cumulative TB disease rates (percentage) using a conservative adjustment for a rare binomial event.