Conditions: Tuberculosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the potential of high doses of rifampin (RIF) to shorten treatment for tuberculosis (TB) without causing more adverse events. The hypotheses are that higher doses of RIF will result in higher blood concentrations of RIF; higher blood concentrations will result in tuberculosis bugs being killed more quickly; and, both of these will happen without more adverse events. Patients with active, infectious, drug-susceptible TB who agree to participate will be randomly assigned to 1 of 3 doses of RIF. All patients will also receive standard doses of regular (3) companion drugs for 2 months of daily, supervised therapy. The study will assess the following among the 3 study arms (oral doses of RIF 10, 15 \& 20 mg/kg/day) during the initial 8 weeks of treatment: 1) the amount of RIF in the blood after at least 14 days of treatment; 2) the difference in the number of tuberculosis bugs killed; 3) the frequency of adverse events.

Detailed description:
This is a Phase II, multi-site, dose-ranging trial comparing 3 doses of RIF in a multidrug regimen for treatment of smear-positive, pulmonary TB. The intervention phase of this prospective, randomized, double-blinded trial will last 8 weeks, the duration of the standard "intensive" phase for short-course chemotherapy for TB. During that time, subjects will receive the following companion drugs: isoniazid (INH, 5 mg/kg/day), ethambutol (EMB, 20 mg/kg/day), and pyrazinamide (PZA, 25 mg/kg/day), pyridoxine (50 mg), the standard doses used in treatment. Subjects will also be randomized to receive one of the following weight-based doses of the study drug, rifampin (RIF): 10 mg/kg/day (standard dose, control), 15 mg/kg/day (intervention 1), 20 mg/kg/day (intervention 2). All patients will receive at least standard dose of RIF, the efficacy of which in multidrug-treatment for TB is well established. Placebo will be used to control only the additional RIF capsules provided in the intervention arms. Subjects, clinicians, and laboratory staff will be blinded to study arm. All patients in the same weight band will receive the same total number of tablets (fixed-dose combination plus RIF and/or placebo). Blinding is essential to reduce the probability of biased reporting of adverse events.

After randomization, other covariates that may result in heterogeneity within strata (e.g., presence of cavitation, HIV serostatus), will be adjusted for in analyses. It is important to maintain the ability to measure the effect (if any) of these potential characteristics on treatment outcome. If we were to stratify on these characteristics, we could not estimate their confounding (or interaction) effect. All doses will be delivered orally and fully supervised. All patients will receive weight-based doses of fixed-dose combinations according to package inserts. This will be supplemented by active RIF capsules or placebos, or both, according to weight and treatment arm. They will also all receive 50 mg of pyridoxine to prevent peripheral neuropathy, a common side effect of INH.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Higher-Dose Rifampin
Intervention descriptions: intervention 1: The intervention phase of this trial will last 8 weeks. During that time, subjects will receive the following companion drugs: isoniazid (INH, 5 mg/kg/day), ethambutol (EMB, 20 mg/kg/day), and pyrazinamide (PZA, 25 mg/kg/day), pyridoxine (50 mg), the standard doses used in treatment. Subjects will also be randomized to receive one of the following weight-based doses of the study drug, rifampin (RIF): 10 mg/kg/day (standard dose, control), 15 mg/kg/day (intervention 1), 20 mg/kg/day (intervention 2). All patients will receive at least standard dose of RIF, the efficacy of which in multidrug-treatment for TB is well established. Placebo will be used to control only the additional RIF capsules provided in the intervention arms.

Protocol document: