Essentiality of INH in TB Therapy

This was a Phase IIa open label, randomized clinical trial comparing the early bactericidal activity (EBA) of four anti-tuberculosis regimens. Participants with acid fast bacilli (AFB) smear-positive pulmonary tuberculosis were hospitalized from screening through Day 15 of the study, during which time, sputum, blood, and urine were collected. Participants returned to the clinic on Day 28 for the final visit. The study duration was 29 days.

The purpose of the study was to estimate the primary outcome within each study arm and the study was not designed for between arm comparisons.

Inclusion criteria

• Absence of HIV-1 infection within 30 days prior to study entry OR
• HIV-1 infection
• Sputum positive for acid fast bacilli (AFB) by smear-microscopy ≥1+ on the WHO/IUALTD scale within 1 day prior to study entry.
• Isoniazid and rifampin sensitivity, based on Hain GenoType MTBDR Plus assay performed within 7 days prior to study entry.
• Body weight: 40 kg to 90 kg, inclusive
• Age ≥ 18 years at study entry.
• Certain laboratory values, as defined in the protocol, obtained within 30 days prior to entry
• For HIV-positive candidates only: CD4+ cell count of > 200 cells/mm^3, determined within 7 days prior to study entry at a DAIDS approved laboratory.
• For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to entry.
• Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (ie, condoms, with a spermicidal agent; a diaphragm, or cervical cap with spermicide; or an IUD) while receiving study medications.
• Radiographic findings consistent with pulmonary TB from a chest x-ray performed within 14 days prior to entry.
• Ability and willingness of study candidate or legal guardian/representative to provide informed consent.
• Willingness to be hospitalized for approximately 3 weeks.
• Ability to provide at least 10mL of sputum during an overnight collection prior to study entry.

NOTE: Candidates who do not produce an overnight sputum sample of sufficient quality and quantity will be considered screen failures. However, if a candidate's failure to produce sufficient sputum appears to be due to poor technique rather than low volume of sputum production, this evaluation may be repeated.

Exclusion criteria

• Receipt of INH prophylaxis or any tuberculosis therapy within 7 days prior to study entry or for more than 7 cumulative days in the last 6 months, or receipt of any fluoroquinolone in the 1 month prior to entry.
• Currently on anti-retroviral treatment (ART), has been on ART within 30 days, or is expected to initiate ART within 2 weeks after study entry.
• Breastfeeding.
• Known intolerance to any of the study drugs.
• Resistance to rifampicin determined by GeneXpert within 7 days prior to study entry.
• Known history of resistance to isoniazid or rifampin or known close exposure (i.e., household exposure) to someone with MDR TB or known study candidate default on previous TB treatment (ie, the study candidate was diagnosed with TB, started TB treatment but did not complete that treatment).
• Known allergy to any fluoroquinolone antibiotic.
• History of prolonged QT syndrome or a QTc of > 450 ms (using Fridericia's correction)..
• Current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during the 2 weeks of on-study tuberculosis treatment.
• Current or prior diagnosis of pulmonary silicosis.
• Advanced disease as defined by Karnofsky score ≤ 70 at screening.
• Any of the following current comorbidities, complications, or underlying medical conditions:

• poorly controlled diabetes, as determined by the site investigator
• currently uncontrolled hypertension (ie, requiring acute medical treatment or immediate hospitalization)
• miliary TB
• neurological TB (including TB of the spine, TB meningitis)
• peripheral neuropathy ≥ Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Estimated overnight sputum production of < 10 mL.
• Requirement for concomitant medications that may potentially interact with study drugs.