Three Months of Weekly Rifapentine and Isoniazid for M. Tuberculosis Infection

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.

INCLUSION criteria:

- Males or nonpregnant, non-nursing females > 2 years old.

- Tuberculin (PPD) skin test reactors at high risk for developing TB but without
evidence of active TB. High-risk reactors are defined as:

1. Household and other close contacts of persons with culture-confirmed TB who are
TST-positive as part of a contact investigation conducted within two years of the
date of enrollment. Close contact is defined as > 4 hours in a shared airspace
during a one-week period. Among close contacts, a positive TST is defined as > 5
mm induration after 5 TU of PPD placed intradermally using the Mantoux technique.

2. TST converters--converting from a documented negative to positive TST within a
two-year period. This is defined as persons with a tuberculin skin test of > 10
mm within two years of a nonreactive test or persons with an increase of > 10 mm
within a two-year period.

3. HIV-seropositive, TST positive (> 5 mm induration) persons.

4. Persons with > 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray, no prior
history of TB treatment, > 5 mm induration on TST, and 3 sputum cultures negative
for M. tuberculosis on final report.

- HIV-seropositive close contacts of persons with culture-confirmed TB, regardless of
TST status. In addition, HIV-seropositive close contacts of persons with
culture-confirmed TB who have a documented history of completing an adequate course of
treatment for active TB or latent TB infection, are also eligible.

- Willing to provide signed informed consent, or parental consent and participant
assent.

EXCLUSION criteria:

- Current confirmed culture-positive or clinical TB

- Suspected TB (as defined by the site investigator)

- Tuberculosis resistant to isoniazid or rifampin in the source case

- A history of treatment for > 14 consecutive days with a rifamycin or > 30 consecutive
days with INH during the previous 2 years.

- A documented history of a completing an adequate course of treatment for active TB or
latent TB infection in a person who is HIV-seronegative.

- History of sensitivity/intolerance to isoniazid or rifamycins

- Serum aminotransferase aspartate (AST, SGOT) > 5x upper limit of normal among persons
in whom AST is determined

- Pregnant or nursing females

- Persons currently receiving or planning to receive HIV-1 protease inhibitors or
nonnucleoside reverse transcriptase inhibitors in the first 90 days after enrollment.

- Weight < 10.0 kg