Methodology of clinical trials aimed at assessing interventions for cutaneous leishmaniasis

Piero Olliaro, Michel Vaillant, Byron Arana, Max Grogl, Farrokh Modabber, Alan Magill, Olivier Lapujade, Pierre Buffet, Jorge Alvar, Piero Olliaro, Michel Vaillant, Byron Arana, Max Grogl, Farrokh Modabber, Alan Magill, Olivier Lapujade, Pierre Buffet, Jorge Alvar

Abstract

The 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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. Typical CL lesions.
Figure 1. Typical CL lesions.
Figure 2. Measuring lesions.
Figure 2. Measuring lesions.
Figure 3. Decision tree for the assessment…
Figure 3. Decision tree for the assessment of treatment outcome.
Ø = complete re-epithelialisation; 50% = greater than 50% of the initial size.
Figure 4. Sample size calculations for comparative…
Figure 4. Sample size calculations for comparative superiority trials.
Figure 5. Sample size calculations for comparative…
Figure 5. Sample size calculations for comparative non-inferiority trials.
Figure 6. Boundaries of the one-sided triangular…
Figure 6. Boundaries of the one-sided triangular test.
Left to right; top to bottom: pa = 0.18, pa = 0.20, pa = 0.25, example of sequential analyses with modeled data.
Figure 7. Kaplan-Meier analysis (product-limit estimate of…
Figure 7. Kaplan-Meier analysis (product-limit estimate of time to event).
Figure 8. Differences in sample size for…
Figure 8. Differences in sample size for a non-inferiority trial when calculated using rates or allowing for survival analysis.
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).
Figure 9. Study flow diagram and patient…
Figure 9. Study flow diagram and patient attrition according to the CONSORT statement.

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