Tuberculosis

TB Fixed-dose Coformulation Works as Well as Separate Drugs

A 4-drug combination containing rifampicin, isoniazid, pyrazinamide, and ethambutol treats pulmonary tuberculosis (TB) as effectively as individual medications.

Tuberculosis is best treated with a multidrug combination regimen, but a high pill burden can make treatment more difficult and inconvenient for patients, which may interfere with adherence. Good adherence during the full course of therapy is important to prevent the emergence of drug-resistant bacteria.

As reported in an April 13, 2011, special edition of the Journal of the American Medical Association devoted to infectious disease and immunology, Christian Lienhardt and fellow investigators with the Study C Trial Group evaluated the safety and efficacy of a 4-drug fixed-dose combination pill for the treatment of tuberculosis.

Study C was an open-label, randomized, non-inferiority trial conducted at 11 sites in Africa, Asia, and Latin America between 2003 and 2008. The study included 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis.

Participants were randomly assigned (1:1) to receive daily treatment with 4 drugs -- rifampicin, isoniazid, pyrazinamide, and ethambutol -- given either as a fixed-dose combination pill or separately during in the 8-week intensive phase of treatment.

A favorable treatment outcome was defined as a negative TB culture test at 18 months after randomization. In the first model analysis, changing treatment or refusal to continue treatment, for example due to treatment failure or relapse, adverse events, or drug resistance, were considered unfavorable outcomes. The researchers performed a second model analysis in which people who changed treatment but had a negative culture test were considered favorable outcomes. The pre-specified noninferiority margin was 4%.

Results

• In the per-protocol analysis, 93.9% of patients (555 of 591) had a favorable outcome in the fixed-dose combination group, compared with 94.6% (548 of 579) in the separate drugs group (risk difference -0.7%; CI -3.0% to 1.5%, showing non-inferiority).
• In the first model analysis, 83.3% of participants (570 of 684) had a favorable outcome in the fixed-dose group vs 84.8% (563 of 664) in the separate drug group (risk difference -1.5%; CI -4.7% to 1.8%, not meeting non-inferiority criteria).
• In the post-hoc second model analysis, the corresponding favorable outcome rates were 89.8% (591 of 658) vs 91.0% (589 of 647), respectively (risk difference -1.2%; CI -3.9% to 1.5%, again demonstrating non-inferiority).
• Adverse events related to study drugs were similar in both treatment groups.

Based on these findings, the investigators concluded, "Compared with a regimen of separately administered drugs, a 4-drug [fixed-dose combination] regimen for treatment of tuberculosis satisfied pre-specified non-inferiority criteria in 2 of 3 analyses."

"Although the results do not demonstrate full non-inferiority of the [fixed-dose combinations] compared with single drugs given separately using the strict definition applied in this trial," they elaborated in their discussion, "use of [fixed-dose combinations] is preferred because of potential advantages associated with the administration of [fixed-dose combinations] compared with separate-drug formulations."

Patients using a fixed-dose combination would have to take 3-4 pills per day during the intensive treatment phase, instead of 9-16 pills if using separate medications.

"[Fixed-dose combinations] are a full part of the recently revised World Health Organization treatment guidelines," the researchers wrote. "The uptake and acceptance of [fixed-dose combinations] is primarily affected by doubts about the efficacy of [fixed-dose combinations], questions of access and quality, advantages over other formulations or packaging, lack of political will at the country level, and the conflicting policies of funders."

Investigator affiliations: Clinical Trial Division, International Union Against Tuberculosis and Lung Disease, Paris, France; Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico, Albuquerque, NM; Medical Research Council Clinical Trials Unit, London, UK; Mycobacteriology Unit, Institute of Tropical Medicine, Antwerp, Belgium; International Tuberculosis Research Center, Seoul, South Korea; Department of Cellular and Molecular Medicine, St. George's, University of London, London, UK; Stop TB Partnership, World Health Organization, Geneva, Switzerland.

4/15/11

Reference

C Lienhardt, SV Cook, M Burgos, et al. Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of pulmonary tuberculosis: the Study C randomized controlled trial. Journal of the American Medical Association. 305(14):1415-1423 (abstract). April 13, 2011.

Other Source

JAMA. Use of Combination Drug Regimen For Treating TB May Represent an Effective Treatment Option. Media advisory for April 12, 2011.