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Fixed-dose combo for TB found noninferior.

A four-drug fixed-dose combination regimen for pulmonary tuberculosis was found noninferior to the standard regimen of four separately administered drugs, according to two of three analyses of data from a clinical trial.

The combo regimen "did not demonstrate full noninferiority" because it met the strict study criteria only in the per-protocol analysis and in a post hoc modified intention-to-treat analysis, but failed to do so in the intention-to-treat analysis. Nevertheless, "the results do support the WHO recommendation for use of fixed-dose combinations because of the potential advantages associated with their administration, compared with separate-drug formulations," said Dr. Christian Lienhardt of the World Health Organization and his associates.

The main advantage is that patients on fixed-dose combo regimens take 3-4 pills per day instead of 9-16 during the first 2 months of treatment. This facilitates adherence, which in turn reduces the risk of developing drug resistance, the researchers noted.

The open-label noninferiority trial was conducted at 11 sites in nine African, Asian, and Latin American countries.

Study subjects were adults with newly diagnosed sputum smear positive pulmonary tuberculosis who were randomly assigned to receive either separate tablets of rifampin, isoniazid, pyrazinamide, and ethambutol or a single combination tablet of the same drugs every day for an 8-week "intensive" phase of the trial. This was followed by 18 weeks of a combination rifampicin plus isoniazid tablet, three times per week, for both study groups.

Every study subject also received pyridoxine with the study drugs throughout the trial.

The patients were required to attend their treatment facilities and take their drugs under supervision of the medical staff. They were also seen at 2, 3, 5, and 6 months during treatment and at 2-month intervals for up to 30 months during follow-up.

The primary efficacy end point was the proportion of patients with an "unfavorable" outcome, which was defined as bacteriologic failure or relapse within 18 months, treatment change after 5 months because of positive sputum smear results or clinical or radiologic deterioration, or death that was possibly or definitely attributable to active tuberculosis.

In the per-protocol analysis of 591 patients on fixed-dose combo therapy and 579 on standard separate drugs, the proportion of unfavorable outcomes was 6.1% in the first group and 5.4% in the second, a difference that met the criteria for noninferiority.

In the post-hoc modified intention-to-treat analysis of 658 patients on fixed-dose combo therapy and 647 on standard separate drugs, the proportion of unfavorable outcomes was 10.2% in the first group and 9% in the second, a difference that also met the criteria for noninferiority.

However, in the intention-to-treat analysis of 684 patients on fixed-dose combo therapy and 664 on standard separate drugs, the proportion of unfavorable outcomes was 16.7% in the first group and 15.2% in the second, a difference which just missed meeting the criteria for noninferiority, the investigators said (JAMA 2011;305:1415-23).

The number of patients who reported adverse events within the first 2 months of starting treatment was small and similar between the two groups. Most of these events were mild or moderate and "reflected the expected undesirable effects of antituberculosis agents," including nausea, vomiting, diarrhea, rash, pruritus, arthralgia, and myalgia.

This trial was supported by the U.S. Agency for International Development. All the drugs used in this trial were man ufactured by Svizera. No financial conflicts of interest were reported.


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Author:Moon, Mary Ann
Publication:Internal Medicine News
Date:May 1, 2011
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