Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial

Abstract

Summary: Background: Clinical studies suggest that isoniazid contributes rapid bacterial killing during the initial 2 days of tuberculosis treatment, but that the activity of isoniazid declines substantially after day 3 of treatment. In this 14-day, phase 2a, open-label, randomised controlled trial we assessed whether isoniazid is essential in standard tuberculosis therapy. Methods: The study took place at two clinical sites in the South African Western Cape region. Eligible individuals were adult (≥18 years of age) men and women with newly diagnosed, untreated, sputum smear-positive pulmonary tuberculosis. Participants who met the eligibility criteria were enrolled, and permuted block randomisation was used to assign participants to one of four treatment groups at a ratio of 1:1:1:1. All interventions occurred as variations of tuberculosis chemotherapy consisting of rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), and moxifloxacin (M) administered during study days 1–14 while participants were followed as inpatients. The HRZE1–2-RZE3–14 arm received isoniazid only on days 1 and 2; the HRZE1–2-MRZE3–14 arm received isoniazid on days 1 and 2 followed by the substitution of isoniazid for moxifloxacin on days 3–14; the RZE1–14 arm received no isoniazid; and the HRZE1–14 arm was the control group that received standard therapy of isoniazid for all 14 days. The primary endpoint was the daily decrease in log10-transformed colony-forming unit (CFU) counts per mL of sputum calculated by the multiple imputation method between baseline (day 0) and day 14 for all participants with at least one valid CFU count. This study is registered with ClinicalTrials.gov, NCT01589497. Findings: Of 89 patients screened, 69 were enrolled. 62 had at least one valid CFU count and were eligible for the primary endpoint analysis. The early bactericidal activity (EBA) over 14 days was 0·14 log10 units (95% CI 0·11–0·18) for participants receiving isoniazid for 2 days only (HRZE1–2-RZE3–14), 0·13 log10 units (0·09–0·17) for participants receiving isoniazid for 2 days followed by moxifloxacin (HRZE1–2-MRZE3–14), 0·12 log10 units (0·08–0·15) for those not receiving isoniazid (RZE1–14), and 0·13 log10 units (0·09–0·16) for those in the standard therapy group (HRZE1–14). Interpretation: The EBA over 14 days for RZE was not significantly changed by the addition of isoniazid for the first 2 days or for the first 14 days of treatment. In a post-hoc analysis, significantly higher day 2 EBAs were observed for all groups among participants with higher baseline sputum CFU counts. Our finding that isoniazid does not contribute to EBA suggests that isoniazid could be replaced with another drug during standard treatment to improve efficacy and decrease rates of resistance to first-line drugs. Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health, and AIDS Clinical Trials Group Statistical and Data Management Center.