Study of Daily Rifapentine for Pulmonary Tuberculosis

The goal of this Phase 2 study is to determine the microbiological activity and safety of rifapentine when given as a component of multidrug intensive phase treatment of smear-positive pulmonary tuberculosis (TB).

Funding Source- FDA Office of Orphan Products Development (OOPD)

Prospective phase II, open-label, single center study in which each experimental rifapentine regimen is evaluated using a two-stage design. Adults (HIV-negative, or HIV-positive with CD4 \> 200 cells/cu mm) suspected to have pulmonary tuberculosis who meet eligibility criteria will be randomized to receive one of three intensive phase regimens. Intensive phase regimens will consist of once daily isoniazid, pyrazinamide, and ethambutol, plus one of the following: rifampin 600 mg once daily OR rifapentine 450 mg once daily OR rifapentine 600 mg once daily. Randomization will be stratified by presence/absence of cavitation on baseline chest radiograph. In Stage 1, 15 subjects will be randomized to each arm, following which there will be an enrollment pause for efficacy and safety assessment. Any rifapentine regimen for which fewer than 6 of 11 evaluable participants have week 8 culture conversion will be discarded.

Stage 2 will randomize subjects into the remaining "accepted arms" with a maximum of 36 additional subjects per arm.

All subjects will continue TB treatment with a conventional continuation phase treatment.

Study Site

Study subjects will be recruited from the University of Cape Town inpatient wards and outpatient clinics.

Estimated Study Duration

It is estimated that 18 months will be required for recruitment and enrollment of study subjects. The estimated duration of participation for each study subject is 18 months, including 2 months of experimental intensive phase TB treatment, 4 months of non-experimental conventional continuation phase TB treatment, and an additional 12 months for follow-up for TB relapse.

Study Management

Study subjects will have study visits on days 0, 7, 14, 21, 28, 35, 42, 49, and 56 for sputum collection and adverse event assessment. Safety laboratory monitoring will be performed on days 14, 28, 42, and 56 and will consist of complete blood count, serum alanine aminotransferase, serum total bilirubin, and serum creatinine. Steady state pharmacokinetic analysis will be performed on approximately day 28. Subjects will have additional study visits at week 10 and at months 4, 6, 12, and 18.

Eligibility Criteria:
Inclusion Criteria:

1. Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated sputum. Patients having extra-pulmonary manifestations of tuberculosis, in addition to smear-positive pulmonary disease, are eligible for enrollment.
2. No prior history of tuberculosis disease or tuberculosis treatment
3. No treatment with fluoroquinolones in the 2 months preceding initiation of study drugs.
4. Age \> 18 years
5. Weight ≥ 50 kg and ≤ 80 kg
6. Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs; see Appendix)
7. Signed informed consent
8. Ability to adhere with study follow-up
9. Women with child-bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy.
10. HIV negative, or HIV-positive with CD4 \> 200 cells/cu mm
11. Laboratory parameters done at, or 14 days prior to, screening (with results available for review by study personnel):

    * Serum alanine aminotransferase (ALT) activity ≤ 2 times the upper limit of normal
    * Serum total bilirubin level ≤ 2 times the upper limit of normal
    * Serum creatinine level less than or equal to the upper limit of normal
    * Hemoglobin level of at least 7.0 g/dL
    * Platelet count of at least 100,000/mm3
    * Negative pregnancy test (women of childbearing potential)

Exclusion Criteria:

1. Pregnant or breast-feeding
2. Known intolerance or allergy to any of the study drugs
3. Concomitant disorders or conditions for which isoniazid (INH), rifamycins, pyrazinamide (PZA), or ethambutol (EMB) are contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis.
4. Current or planned therapy, during the intensive phase of TB therapy with cyclosporine or tacrolimus, or HIV antiretroviral (ARV) therapy, which have unacceptable interactions with rifamycins.
5. Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable.
6. Pulmonary silicosis
7. Central nervous system TB