Study 33: Adherence to Latent Tuberculosis Infection Treatment 3HP SAT Versus 3HP DOT

The World Health Organization (WHO) estimates that approximately 2.3 billion people are
infected with Mycobacterium tuberculosis. Approximately 1.7 million people die of TB each
year, the second most common infectious cause of death in the world. In order to improve TB
control worldwide, an affordable, effective, short course treatment for latent TB infection
(LTBI) is a global priority.

Candidates for LTBI treatment are those persons with a positive TST or IGRA, particularly if
they also have risk factors for progressing to active TB, including individuals likely to be
recently infected. The Prevent TB Study (TBTC Study 26) was an open-label, randomized, phase
III controlled clinical trial with over 8,000 high risk TST reactors enrolled. The study
compared rifapentine and INH (3RPT/INH) given once-weekly by directly observed treatment
(DOT) for 3 months (12 doses) compared with 9 months of daily, self-administered INH. The
results demonstrated the safety and efficacy of the shorter regimen. Moreover, the once
weekly therapy had significantly higher treatment completion rates than the standard 9 INH
regimen.

One of the most effective strategies for assuring adherence with therapy is to have each
dose of medication directly administered by a health care worker who observes and records
the ingestion of the drugs. DOT for active TB has been successfully used in many settings to
improve treatment completion, however cost and logistical constraints of DOT remain. The
estimated cost of giving 12 weekly DOT doses to all LTBI patients is likely prohibitive for
TB control programs worldwide. This may lead to a decreased uptake of the new regimen or
implementation using SAT where adherence has not been studied. Therefore, to apply the
Prevent TB study results more broadly, a new study evaluating treatment completion of 3
RPT/INH given as SAT is conducted.

Medication adherence is defined by whether patients take a treatment as prescribed. The
effectiveness of any treatment is determined largely by adherence. In clinical practice and
research, indirect measures of adherence are commonly used. Indirect measures of adherence
include patient self-report, evaluation of pharmacy dispensation records, pill counts, and
the use of electronic prescription bottle monitors. Patient self-reported adherence is
accurate when non-adherence is reported but tends to overestimate true adherence.
Self-report is not discerning enough to be utilized as a sole measure of adherence in
research settings where adherence is the primary outcome. Pill counts have been utilized
successfully in research and clinical settings for real-time assessment but also tend to
overestimate adherence. Electronic drug monitors such as the Medication Event Monitoring
System (MEMS) are the best available tools to assess the timing and patterns of adherence.
This study uses a combination of indirect measures including MEMS, pill counts, and
self-report to provide the most accurate assessment of adherence to once weekly,
self-administered RPT/INH.

The number of cellular phone users globally has increased dramatically in the last decade.
Cell phones and SMS reminders have been used successfully in randomized controlled clinical
trials to improve adherence to vaccines, HIV medications, and asthma treatment. SMS appear
to be cost-effective ways to reach patients in remote locations. This study examines effect
of SMS on medication adherence.

The goal of this open label clinical trial is to compare the adherence to 3RPT/INH given by
DOT versus SAT or SAT with a weekly SMS reminder. The primary assessment of adherence will
be treatment completion which is defined as taking at least 90% of the doses (11/12 doses of
each drug) within 16 weeks of initiation. Secondary objectives include evaluating the
patterns of adherence in participants who fail to complete, determining the feasibility and
impact of using SMS reminders on treatment completion with SAT, evaluating the tolerability
and any adverse events associated with each treatment arm, monitoring for the development of
active TB, determining the drug susceptibility for participants who develop active TB, and
measuring important patient-related expenditures associated with each study arm. The trial
will be conducted in patients diagnosed with LTBI and recommended for treatment.

Inclusion Criteria:

- Males and non-pregnant, non-nursing females

- Age > 18 years

- Weight > 45kg and considered appropriate to receive RPT 900mg and INH 900mg once
weekly by the local site investigator

- Willingness to provide signed informed consent.

- Clinical indication for LTBI treatment such as: 1) persons with a positive tuberculin
skin test (TST) as defined by CDC criteria or a positive interferon-gamma release
assay (IGRA) defined per the manufacturers' guidelines AND one of the following:
close contact to someone with culture confirmed TB, HIV infection, or > 2 cm2 of
pulmonary parenchymal fibrosis on chest X-ray and no prior history of TB treatment;
2) TST or IGRA converters defined as a documented change from negative to positive
within a two-year period; 3) Persons with any other clinical indication for LTBI
treatment as locally defined including persons with a negative TST and/or IGRA (e.g.
HIV-infected close contacts to an active pulmonary TB cases)

Exclusion Criteria:

- Confirmed or suspected active TB

- Contacts to a source case with known resistance to isoniazid or rifampin

- Persons with a history (by written documentation or self-report) of ever receiving >
1 week of treatment for active or latent TB, regardless of whether the course was
completed, because adherence may be different in people who previously took TB
treatment

- Persons who are not considered candidates for SAT by the local investigator

- History of sensitivity or intolerance to isoniazid or rifamycins

- Serum alanine aminotransferase (ALT, SGPT) > 5x upper limit of normal among persons
in whom an ALT is determined

- Persons with HIV-infection who 1) have a CD4 < 350 or 2) are currently receiving or
planning to receive antiretroviral therapy in the first 120 days after study
initiation (e.g., HIV-1 protease inhibitors, nucleoside or non-nucleoside reverse
transcriptase inhibitors, CCR5 inhibitors or integrase inhibitors)