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.
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
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
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%.
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%,
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).
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).
events related to study drugs were similar in both treatment
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
"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.
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."
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,
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.
JAMA. Use of Combination Drug Regimen For Treating TB May
Represent an Effective Treatment Option. Media advisory for
April 12, 2011.