Assessing PA-824 for Tuberculosis (the APT Trial)
Assessing PA-824 for Tuberculosis (the APT Trial)
Assess the mycobactericidal activity of PA-824 (given at 200 mg daily) when added to
 first-line tuberculosis (TB) treatment (isoniazid, pyrazinamide, and a rifamycin antibiotic)
 over 12 weeks of treatment. Funding Source - FDA OOPD
Phase IIB, 12-week, open-label, single-site, randomized clinical trial with three treatment
 groups. Patients with drug-sensitive TB will all receive once daily isoniazid and
 pyrazinamide for 8 weeks followed by 4 weeks of daily isoniazid. In addition, Arm 1
 participants will receive PA-824 200 mg daily and rifampin 600 mg daily for 12 weeks. Arm 2
 participants will receive PA-824 200 mg daily and rifabutin 300 mg daily for 12 weeks. Arm 3
 participants (control group) will receive rifampin for 12 weeks and ethambutol for 8 weeks.
 Patients will be screened within 1 week of TB diagnosis, will receive 12 weeks of study
 treatment and will return for follow-up visits at 4, 12, and 36 weeks after study treatment
 completion. All patients will be referred to the local TB treatment program after completion
 of study treatment to finish their 24-week TB treatment course.
Inclusion Criteria:

 1. Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of
 expectorated sputum or Gene Xpert positive sputum sample. Patients having
 extra-pulmonary manifestations of tuberculosis, in addition to smear-positive
 pulmonary disease, are eligible for enrollment.

 2. Age > 18 years

 3. . Weight ≥ 40 kg and ≤ 80 kg

 4. Karnofsky score of at least 60 (requires occasional assistance but is able to care for
 most of his/her needs)

 5. . Signed informed consent

 6. . HIV negative, or positive with CD4 ≥350 cells/cu mm and not currently taking or
 planning to take combination antiretroviral therapy for HIV during the study.

 7. Ability to adhere with study follow-up

 8 Agrees to adhere to contraceptive requirements

 -

 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, rifampin, rifabutin,
 pyrazinamide, or ethambutol is contraindicated. These include severe hepatic damage,
 acute liver disease of any cause, allergy to the drug, and acute uncontrolled gouty
 arthritis.

 4. Current or planned therapy, during the intensive phase of TB therapy with cyclosporine
 or tacrolimus, 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

 8. ECG at screening with corrected QT interval (QTc) (Fridericia correction) interval
 >450 ms or any clinically-significant, in the opinion of the investigator, ECG
 abnormality

 9. History and/or presence (or evidence) of neuropathy or epilepsy.

 10. History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic
 examination with a value of 1.0 or higher on age-related eye disease scale 2 (AREDS2)
 Clinical Lens Opacity Classification and Grading System scale.

 11. Infection with an isolate known to be resistant to a first-line TB drug (for example,
 patients with Gene Xpert screening through the local TB program with results
 suggesting resistance to rifampin)

 12. Laboratory parameters done at, or 14 days prior to, screening (with results available
 for review by study personnel) demonstrating any of the following:

 -  Serum alanine aminotransferase (ALT) activity > 3 times the upper limit of normal

 -  Serum total bilirubin level > 2 times the upper limit of normal

 -  Serum creatinine greater than the upper limit of normal

 -  Hemoglobin level less than 7.0 g/dL

 -  Platelet count less than 100,000/mm3

 -  Positive pregnancy test (women of childbearing potential)

 13. More than five days of treatment directed against active tuberculosis in the past 6
 months -