A four-month gatifloxacin-containing regimen for treating tuberculosis.

BACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.)

A Multicentre Randomized Controlled Trial of the Efficacy and Safety of Single-Dose Praziquantel at 40 mg/kg vs. 60 mg/kg for Treating Intestinal Schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil

Control of urinary and intestinal schistosomiasis is based on mass administration of praziquantel at the World Health Organization (WHO) recommended dose of 40 mg/kg, though some countries use 60 mg/kg. This multi-country randomized clinical trial compared the efficacy (cure and egg reduction rates three weeks post-treatment) and safety of these two doses for treating intestinal schistosomiasis in 856 patients in Brazil, Mauritania and Tanzania (Schistosoma mansoni), and The Philippines (S. japonicum). Transmission and infection intensities varied across the sites, but there was no bias or heterogeneity in efficacy outcomes. The two doses are equally effective in curing intestinal schistosomiasis; the higher dose may be less well tolerated, though effects are generally mild and transient. In endemic areas people can be re-infected; one year post-treatment patients on 60 mg/kg had fewer re-infections but this finding is difficult to explain. This study was conducted to respond to the demand for evidence about the dose of praziquantel when deployed in endemic countries. The results, along with those of systematic reviews, support the current WHO recommendation for using praziquantel at 40 mg/kg and should inform policy decisions in countries. The Philippines has already changed from 60 to 40 mg/kg after this study

Methodology of Clinical Trials Aimed at Assessing Interventions for Cutaneous Leishmaniasis

International audienceThe current evidence-base for recommendations on the treatment of cutaneous leishmaniasis (CL) is generally weak. Systematic reviews have pointed to a general lack of standardization of methods for the conduct and analysis of clinical trials of CL, compounded with poor overall quality of several trials. For CL, there is a specific need for methodologies which can be applied generally, while allowing the flexibility needed to cover the diverse forms of the disease. This paper intends to provide clinical investigators with guidance for the design, conduct, analysis and report of clinical trials of treatments for CL, including the definition of measurable, reproducible and clinically-meaningful outcomes. Having unified criteria will help strengthen evidence, optimize investments, and enhance the capacity for high-quality trials. The limited resources available for CL have to be concentrated in clinical studies of excellence that meet international quality standards

Boundaries of the one-sided triangular test.

<p>Left to right; top to bottom: pa = 0.18, pa = 0.20, pa = 0.25, example of sequential analyses with modeled data.</p

Sample size calculations for comparative superiority trials.

<p>Sample size calculations for comparative superiority trials.</p

Kaplan-Meier analysis (product-limit estimate of time to event).

<p>Kaplan-Meier analysis (product-limit estimate of time to event).</p

Measuring lesions.

<p>Measuring lesions.</p

Sample size calculation for the one-sided triangular test.

<p>pa = 0.18, 0.20 and 0.25; and two-sided test, pa = 0.20.</p

Differences in sample size for a non-inferiority trial when calculated using rates or allowing for survival analysis.

<p>Sample size expressed as % underestimation when calculated using rates vs. survival analysis; delta set at 5, 7, 10%; efficacy of comparator arm (Ref) set at 80% dark blue; 85% pale blue; 90% pale yellow. The size of the bubble is proportional to the sample size (figure next to the bubble).</p

Adoption of inclusion- exclusion criteria based on the type of the study and treatment.

1<p>Depending on available pre-clinical and reproductive toxicity data.</p>2<p>Age limit due to practical difficulties in measuring skin lesions in very small children.</p>3<p>Depending upon the <i>Leishmania</i> species and the type of treatment.</p>4<p>Due to practical difficulties in treating multiple lesions topically.</p>5<p>Due to practical difficulties in treating large lesions topically.</p>6<p>Topical treatment of lesions close to mucosae, eyes and ears is generally difficult and/or may pose safety hazard. Decision to include them in advanced phases of clinical evaluation depends on the risks associated with the specific delivery system or formulation used.</p>7<p>The decision to set a limit for the lesion age should take into consideration a) the <i>Leishmania</i> species –probability that lesions will self-heal within the study time; and b) the difficulty in accurately establishing the age of the lesion from interviewing the patient due to recall bias.</p>8<p>Depending on the risk of systemic toxicity based upon pre-clinical toxicity and clinical data available and the route of administration.</p