Table 1.

Participant inclusion and exclusion criteria for S31/A5349

Inclusion criteria

Individuals must meet all of the following inclusion criteria in order to participate in this study:

A. Suspected pulmonary tuberculosis plus one or both of the following: a) at least one sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing, with semiquantitative result of ‘medium’ or ‘high’ and rifamycin resistance not detected.

B. Age twelve years or older

C. A verifiable address or residence location that is readily accessible for visiting, and willingness to inform the study team of any change of address during the treatment and follow-up period.

D. Women of child-bearing potential who are not surgically sterilized must agree to practice an adequate method of contraception (barrier method or non-hormonal intrauterine device) or abstain from heterosexual intercourse during study drug treatment.

E. Documentation of HIV infection status.

F. For HIV-positive individuals, CD4 T cell count greater than or equal to 100 cells/mm3 based on testing performed at or within 30 days prior to study entry. HIV-positive individuals will be enrolled in a staged approach:

• Group 1 (“EFV1”): receipt of efavirenz-based antiretroviral therapy (ART) for a minimum of 30 days at the time of enrollment AND a documented HIV viral load less than 200 copies/mL at or within 30 days prior to study entry, OR

• Group 2 (“EFV2”): for HIV-positive individuals not on ART at enrollment, planned initiation of efavirenz-based ART before or at study week 8

G. Laboratory parameters done at or within 14 days prior to screening:

• Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal

• Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of normal

• Serum or plasma creatinine level less than or equal to 2 times the upper limit of normal

• Serum or plasma potassium level greater than or equal to 3.5 meq/L

• Hemoglobin level of 7.0 g/dL or greater

• Platelet count of 100,000/mm3 or greater

H. For all women who are not surgically sterilized or who do not meet the study definition of postmenopausal, a negative pregnancy test at or within seven days prior to screening

I. Karnofsky score greater than or equal to 60

J. Written informed consent.

Criteria for exclusion from enrollment

An individual meeting any of the following exclusion criteria at the time of enrollment or initiation of study drugs will be excluded from study participation:

A. Pregnant or breast-feeding

B. Unable to take oral medications

C. Previously enrolled in this study

D. Received any investigational drug in the past 3 months

E. More than five days of treatment directed against active tuberculosis within 6 months preceding initiation of study drugs

F. More than five days of systemic treatment with any one or more of the following drugs within 30 days preceding initiation of study drugs: isoniazid, rifampin, rifabutin, rifapentine, ethambutol, pyrazinamide, kanamycin, amikacin, streptomycin, capreomycin, moxifloxacin, levofloxacin, gatifloxacin, ofloxacin, ciprofloxacin, other fluoroquinolones, ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, linezolid, clofazimine, delamanid or bedaquiline

G. Known history of prolonged QT syndrome

H. Suspected or documented tuberculosis involving the central nervous system and/or bones and/or joints, and/or miliary tuberculosis and/or pericardial tuberculosis

I. Current or planned use within six months following enrollment of one or more of the following medications: HIV protease inhibitors, HIV integrase inhibitors, HIV entry and fusion inhibitors, HIV non-nucleoside reverse transcriptase inhibitors other than efavirenz; quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine.

J. Weight less than 40.0 kg

K. Known allergy or intolerance to any of the study medications

L. Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any one or more of the following: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones.

M. Other medical conditions, that, in the investigator’s judgment, make study participation not in the individual’s best interest.

N. Current or planned incarceration or other involuntary detention.

Criteria for exclusion after enrollment (‘Late exclusion’)

Microbiological confirmation of drug-susceptible tuberculosis is not expected always to be available at the time of enrollment. Enrolled individuals who are subsequently determined to meet either of the following criteria will be classified as ‘late exclusions’ and study treatment will be discontinued:

A. Screening, baseline, and Week 2 study visit sputum cultures all fail to grow M. tuberculosis. M. tuberculosis cultured or detected through molecular assays (Cepheid Xpert MTB/RIF or Hain MTBDRplus assays) from sputum obtained around the time of study entry is determined subsequently to be resistant to one or more of isoniazid, rifampin, or fluoroquinolones.