Ben Salah 2013

Methods	Study design: randomised controlled trial Setting/location: Sidi Bouzid, Tunisia Study period: January 2008 to July 2011 (42 months) Sample size calculation: the sample size of 375 participants was based on estimated rates of final clinical cure of 94% in the paromomycin – gentamicin group and 71% in the vehicle‐control group, as shown in a previous study. On the basis of these rates, a sample size of 125 participants in each of these 2 groups provided a statistical power of 99% to detect a significant difference in the rates of final clinical cure rates (94% vs 71%).
Participants	Type of Leishmania: L major Inclusion criteria: aged 5‐65 years; good health besides cutaneous leishmaniasis if female; absence of pregnancy and lactation; the presence of ≤ 5 lesions, with an index lesion that was ulcerative; lesions measured 1‐5 cm in diameter; lesions confirmed to contain Leishmania by means of culture or microscopical examination of lesion material Exclusion criteria: included clinically significant lymphadenopathy or mucosal involvement, against which a topical agent would not be expected to be effective N randomised: 383 (129 were assigned to paromomycin–gentamicin; 128 were assigned to paromomycin; 126 were assigned to vehicle control) Withdrawals: 8 participants (4, paromomycin–gentamicin; 3, paromomycin; 1, vehicle control) N assessed: 375 participants (125 in each of the 3 groups) Mean age (SD): 24 years (16) (paromomycin–gentamicin, 23 years (16); paromomycin, 25 years (16); vehicle 23 years (15) Sex: male 193 (51%) (paromomycin–gentamicin, 56 (45%); paromomycin, 68 (54%); vehicle control, 69 (55%)) Baseline data: Paromomycin–gentamicin: total N of lesion in group: 243. Mean (SD) area of all lesion ulcers per participants: 126 mm² (121) Paromomycin: total N of lesion in group: 272. Mean (SD) area of all lesion ulcers per participants: 90 mm² (75) Vehicle control: total N of lesion in group: 282. Mean (SD) area of all lesion ulcers per participants: 98 mm² (112)
Interventions	Type of interventions: Group 1: paromomycin‐gentamicin topical cream were manufactured by Teva Pharmaceuticals in accordance with Good Manufacturing Practices Group 2: paromomycin alone topical cream were manufactured by Teva Pharmaceuticals in accordance with Good Manufacturing Practices Group 3: vehicle control manufactured by Teva Pharmaceuticals in accordance with Good Manufacturing Practices Duration of intervention: 20 days
Outcomes	Final cure of index lesion Total re‐epithelialisation of ulcerated lesions at 42 days Adverse effects Time points reported: 168 days
Notes	Study funding sources: the study was sponsored by the Office of the Surgeon General, Department of the Army Possible conflicts of interest: none declared
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A permuted block randomisation schema was generated using nQuery, employing random block sizes, for the first 330 randomisation numbers. As 7 subjects were randomised that did not receive treatment at the time when the new randomisation list was generated, the plan in generating the new list was to balance the assignments in the new list for these 7 subjects to achieve the 1:1:1 allocation balance overall. The second randomisation was performed using SAS Version 9.2."
Allocation concealment (selection bias)	Low risk	The randomisation of the study drugs was done by an independent group.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The placebo consisted of the vehicle without the active components and trace amounts of colorings agents to match the appearance and maintain the blind.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The modified intention‐to‐treat population consisted of patients who received at least one dose of study treatment. We tested two hypotheses using a fixed testing‐sequence procedure with an overall two‐sided alpha level of 0.05 or less."
Selective reporting (reporting bias)	Low risk	ClinicalTrials.gov number, NCT00606580. Pre‐specified outcomes were reported
Other bias	Low risk	Other items assessed correctly reported