Conditions: Tuberculosis
Keywords: Latent TB infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8053
Healthy volunteers: no

Brief summary:
Open-label, multi-center, Phase III clinical trial to compare the effectiveness and tolerability of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose)regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI).

Detailed description:
The PRIMARY objective of this open-label Phase III clinical trial is to compare the effectiveness of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose) regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI). The 3RPT/INH regimen will be given under direct observation and the 9INH regimen will be self-administered.

SECONDARY Objectives:

* Compare the rates of drug discontinuation due to adverse drug reactions associated with 3RPT/INH and 9INH.
* Compare the rates of drug discontinuation for any reason associated with 3RPT/INH and 9INH.
* Compare the rates of any grade 3, 4, or 5 drug toxicity associated with 3RPT/INH and 9INH.
* Compare treatment completion rates of 3RPT/INH and 9INH. Compare the efficacy (i.e., among persons who complete study-phase therapy) of 3RPT/INH and 9INH.
* Compare the effectiveness and tolerability of 3RPT/INH and 9INH in HIV-infected persons.
* Compare the effectiveness and tolerability of 3RPT/INH and 9INH in children \< 18 years old.
* Compare the rates of methadone withdrawal associated with 3RPT/INH and 9INH among persons concomitantly receiving methadone.
* Describe patterns of antibiotic resistance among M. tuberculosis isolates in patients who develop TB despite treatment of latent infection.

Amendment of the study protocol to allow extension of enrollment to children \< 12 years old and HIV-infected persons:

For assessment of the primary outcome, development of TB, a sample size of approximately 4,000 persons per arm will be required. To assess tolerability (one of the secondary outcomes) in sub-groups, children less than 12 years old and HIV-infected persons, a sample size of 644 per strata will be required. A sample size of 8,053 patients for the primary outcome was reached on February 15, 2008 (with expected follow-up completion time in 2010), leaving approximately 454 additional young children and 200 HIV-infected persons to be enrolled to achieve the targets of 644 for each group. The additional data on tolerability in those sub-groups will available for analysis in 2013.

Arms:
arm 1: Isoniazid (INH) daily for 9 months (240 to 270 total doses). arm 2: Isoniazid / Rifapentine (RPT/INH) weekly for 3 months (11 to 12 total doses) given by Directly Observed Therapy (DOT)

Interventions: intervention 1: RPT + INH once weekly for 3 months given by DOT intervention 2: Isoniazid (INH) daily for 9 months
Intervention descriptions: intervention 1: Rifapentine (RPT) 900 mg once-weekly x 12 doses (3 months) for persons \> 50.0 kg. For persons \< 50.0 kg, the following doses will be given (Weight/Dose): 10.0-14.0 kg / 300 mg; 14.1-25.0 kg / 450 mg; 25.1-32.0 kg / 600 mg; 32.1-50.0 kg / 750 mg.

PLUS

Isoniazid (INH) 15 mg/kg (rounded up to nearest 50 or 100 mg; 900 mg max) once weekly x 12 doses if \> 12 years old. INH 25 mg/kg (round up to nearest 50 or 100 mg; 900 mg max) if 2-11 years old.

Therapy will be given by Directly Observed Therapy (DOT). intervention 2: Isoniazid (INH) 5 mg/kg (rounded up to nearest 50 or 100 mg; 300 mg max) daily x 270 doses (9 months) For children age 2 - 11, INH 10-15 mg/kg (round up to nearest 50 or 100 mg; 300 mg max) will be given.

Protocol document: