Interventions for American cutaneous and mucocutaneous leishmaniasis

 

Characteristics of included studies [ordered by study ID]

Almeida 1999

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Methods	FU: 180 days after treatment onset. D: Randomised clinical trial
Participants	Brazil n=20 Px were recruited at an ambulatory clinic in an endemic region in Brazil. Px of both groups were similar in age, sex, and ulcer size and duration.The majority of the lesions were below the waist and on the lower limbs in 15 (75%) Px. In the GM-CSF group there were 8 males and 2 females whereas in the saline group there were equally divided (5 each). M/F: 13/7. Incl: Age between 10 and 50 years, presence of a single typical CL ulcer for < 60 days duration, and confirmation of CL by compatible histology and either a positive serology or positive intradermal skin test for Leishmania antigen. Excl: pregnancy, other associated acute or chronic illnesses, and history of allergy to GM-CSF and/or antimonial. Leishmania species: Previous studies have shown L. braziliensis to be aetiologic agent in this area.
Interventions	T1:GM-CSF received 2 local injections of 200 μg of hr-GM-CSF at entry and 1 week later + IV SSG at 20 mg/kg/d for 20 days N= 10. MNL: 1. MSL: 18.8 mm. MDLBT: 36.10 days. T2: IVSSG (20 mg/kg daily for 20 days) + Saline (2 local injections of saline at entry and 1 week later N= 10. MNL:1. MSL: 17.9 mm. MDLBT: 25.80 days. Co-treatment: All Px received IVSSG at 20 mg/kg/d for 20 days.
Outcomes	Primary outcome Percentage of Px "cured" 20 days after therapy Secondary outcomes None reported Tertiary outcomes Speed of healing (time taken to be 'cured')
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Double-blinded. The research team was blinded to the administered drug. Two medical doctors examined the Px and questions on possible side effects of the treatment were deferred to a third medical doctor.
Intention-to-treat/Drop-outs?	Yes	ND

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Andersen 2005

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Methods	FU: 6 months D: Randomised clinical trials
Participants	Peru n=80 Px lived in and around the city of Cusco, Peru and presented with clinical diagnosis of CL. The average Px was 30-year-old man weighing 57 kg. The average number of lesions was two (1/3 of which were on the arms and 1/2 of which were on the legs). M/F: 65/15. Incl: An age between 18 and 60 years old; a parasitological diagnosis of CL from a lesion; no evidence of mucosal involvement of oropharynx; no previous use of anti-leishmanial drugs; no previously confirmed leishmaniasis (by scar or clinically compatible history); no use of hypoglycaemic, nephrotoxic, or pancreatitis-inducing drugs; no acute or chronic medical condition; and not being pregnant or not nursing. Leishmania species: culture from 70 Px were typed by isoeanzyme electrophoresis and all were L. braziliensis. They were also identified by stained smears.
Interventions	T1: IVPI 2 mg/kg on alternate days for 7 doses. N= 40. MNL: 2.3. MDLBT: 119 days. T2: IVMA 20 mg (Sb)/kg/day for 20 days. N= 40. MNL: 2.1. MDLBT: 134 days.
Outcomes	Primary outcome Percentage of Px "cured" 6 months after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within six months Adverse effects Tertiary outcomes Microbiological or histopathological cure of skin lesions
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	Yes	6 out of 80 (7.5%)

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Arana 1994

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Methods	FUt: 52 weeks. D: Randomised clinical trials
Participants	Guatemala n=66 They were all Guatemalan male soldiers. Incl: Guatemalan soldiers with parasitologically proven CL Leishmania species: L. braziliensis (33/66; 50%) and L. mexicana (8/66; 12.1%) by cultures.
Interventions	T1: IVMA infusion over 15 minutes, 20 mg Sb/kg body weight/d for 20 days N= 22. MNL: 1.2. MSL: 1 cm2. MDLBT: 56.8 days. T2: IVMA infusion over 15 minutes, 20 mg Sb/kg body weight/d for 10 days + 10 days of a saline infusion N= 22. MNL: 1.2. MSL: 0.8 cm2. MDLBT: 64.1 days. T3: IVMA infusion over 15 minutes, 20 mg Sb/kg body weight/d for 10 days + IFN-γ (1 ml solution containing 0.2 mg of recombinant IFN-γ/ml given subcutaneously in the forearm every other day for 5 doses) N= 22. MNL: 1.4. MSL: 1.4 cm2. MDLBT: 78.4 days.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Adverse effects Tertiary outcomes None reported
Notes	Px whose lesions were not completely reepithelialized by the 13-week examination were removed from the study and treated with additional MA. Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Double-blind: only stated but not reported who was blinded
Intention-to-treat/Drop-outs?	No	3 out of 66 (4.5%)

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Arana 2001

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Methods	FU: 12 months. D: Randomised clinical trials
Participants	Guatemala n=76 Px in the paromomycin group aged 22.3 years and in the placebo group, Px aged 20.3 years. Regarding ethnicity, 47.4% (18/38) of the participants in the paromomycin group were Indian while a 52.5% (20/38) were ladinos. In the placebo group, 42.1% (16/38) and 57.9% (22/38) were Indian and ladinos respectively. Lesions were mainly localized in the extremities (arms and legs) and thorax. Incl: Either male or female sex, aged 10-60 years, and parasitologically confirmed CL. Further, all Px had to provide written informed consent to participate in the study, and they had to be available for FU examinations for 12 months. Excl: > 4 lesions or an active lesion measuring > 5 cm in diameter; previous use of antimony-containing drugs; serious concomitant medical problems; and evidence of mucosal involvement of leishmaniasis. Leishmania species: According to their own previous studies, most of the Px (75%) were infected with L. braziliensis and the rest (25%) with L. mexicana.
Interventions	T1: Topical 15% PR plus 12% MBCL n= 38. MNL: 1.1, MDLBT: 101.2 days. T2: Topical placebo (white soft paraffin) ointment n=38. MNL: 1.3, MDLBT: 105.1 days. Frequency: TD for 20 days across the lesions in 2 different directions at 90º to each other
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 6 months Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	The PR ointment (15% PR sulphate plus 12% MBCL), and the placebo ointment tubes were prepared and randomly numbered by Teva Pharmaceutical Industries, Petach, Tikva, Israel, and provided to the investigators by Dr. F. Modabber (Tropical Diseases Research/World Health organisation [TDR/WHO]. Both active and placebo ointment were identical in appearance and marked only by a consecutive number. These codes were kept in Geneva by the TDR/WHO representative (FM) until completion of the study.
Blinding? All outcomes	Yes	Double-blind (Px and Physicians)
Intention-to-treat/Drop-outs?	No	8 out of 76 (10.5%)

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Armijos 2004

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Methods	FU: at week 52 after the start of treatment. D: Randomised clinical trial
Participants	Ecuador n=120 Px were recruited at the National Leishmaniasis Reference Laboratory clinic located in the Central University of Ecuador School of Medicine (Quito, Ecuador). The subjects reported that they had acquired their CL infections in tropical and subtropical areas of Pichincha, Napo and Sucumbios Provinces. Incl: If the Leishmania parasite was demonstrated to be present in their ulcerated lesions, lesion evolution time was at least 4 months prior to enrolment in the study, they had 1-3 CL lesions, their age was between 5 and 60 years, and they gave their informed written consent. Excl: If they were pregnant or lactating, had at least 3 lesions, lesions that were of a non-ulcerative form, showed evidence of mucocutaneous or disseminated leishmaniasis infection, had active tuberculosis or PPD hyperreactivity (>20 mm induration at 48 h), other serious infections (e.g., malaria, dengue, and fever), chronic illnesses or immunosuppression. had prior CL infection, were being treated with steroid or other immunosuppressant drugs, and had acute malnutrition. Leishmania species: not reported.
Interventions	T1: Topical PR 15% plus 12% MBCL ointment TD for 30 days. N= 40. MNL: 1.5. MSL: 259 mm^2. MDLBT: 3 months. T2: Topical PR 15% plus 10% urea (PR- U) TD for 30 days. N= 40. MNL: 1.8. MSL: 308 mm^2. MDLBT: 3.2 months. T3: IMMA 20 mg of Sb/kg/day for 10 days N= 40. MNL: 1.7. MSL: 418 mm^2. MDLBT: 2.7 months.
Outcomes	Primary outcome Percentage of Px "cured" 2 months after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Adverse effects Tertiary outcomes Speed of healing (time taken to be 'cured')
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Computer-generated random numbers table
Allocation concealment?	Yes	The codes marked on the preparations were kept secured in a locked file cabinet until data analysis
Blinding? All outcomes	Yes	Double-blinded. The 2 preparations were identical in appearance except for codes marked on the outside which were not known to clinicians, laboratory technologists, and other study personnel involved in selection, treatment and follow-up. Double-blind for the two groups treated with PR. It was not possible to blind the control group (MA) whose treatment was administered IM rather than topically
Intention-to-treat/Drop-outs?	No	25 out of 120 (20.83%)

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Arévalo 2007

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Methods	FU: 3 months. D: Randomised clinical trial
Participants	Peru n=20 This study was carried out at Cayetano Heredia Hospital in Lima, Peru. Px were from cities in Peru were CL is endemic. The clinical diagnosis of CL had been confirmed in all Px by direct smear, by culture, and/or by PCR prior to enrolment; 18 (90%) of 20 Px had positive direct smear and PCR results. 11 (55%) had positive Montenegro Skin test results. 9 (45%) had a culture positive for Leishmania. The mean age was 34.9 years (18-87). M/F: 11/9. The majority of Px were farmers. Lesions were nearly equally distributed in the face and upper and lower extremities. 17 of the 20 lesions were ulcerative and the remaining 3 were nodular. Incl: adult Px (>18 years of age) with a confirmed diagnosis of CL and who had newly referred to the outpatient Leishmania clinic were enrolled in the study after signing written informed consent. Excl: Px with mucosal involvement, other known diseases, immunodeficiency, lesions > 25 cm^2 in area, women who were breast-feeding or pregnant, and those with a history of previous treatment for leishmaniasis. Leishmania species: L. braziliensis, L. peruviana, L. mexicana, and L. amazonensis endemic in the area.
Interventions	T1: Topical imiquimod 7.5% cream every other day for 20 days n= 6. MNL: 1.1. MSL: 4.0 cm^2 (0.4-12.5). MDLBT: 4.2 months (1-6). T2: Topical imiquimod 7.5 %cream every other day for 20 days plus IVMA 20 mg/kg/d over a 10-min period for 20 days n= 7. MNL: 1.28. MSL: 8.1 cm^2 (0.9-33). MDLBT: 6.2 months (1.5-26). T3: IVMA 20 mg/kg/d over a 10-min period for 20 days n= 7. MNL: 1.1. MSL: 7.1 cm^2 (0.18-25.5). MDLBT: 5.07 months (1-12).
Outcomes	Primary outcome Percentage of Px "cured" 3 months after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	If bacterial superinfection of a lesion was observed, the Px was administered a regimen of daily cleansing and an oral antibiotic prior to the start of study medication. Only present in 2 Px (1 from the MA group and 1 from the imiquimod plus MA). Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	Yes	ND

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Balou 1987

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	USA n=40 Conducted at the Walter Reed Army Medical Center in Washington. During the study period all active-duty military Px seen at army health care facilities with clinically suspected CL were referred to the centre for diagnosis and treatment. In the P10 group Px were 27.9 years of age and in the P20, 28.5. Lesions were located mainly in the extremities, head and neck and trunk. All were healthy young male soldiers on active duty when they acquired their infections in the Republic of Panama (38 Px) or elsewhere in Central America (2 Px). Incl: Diagnosis established by culture of promastigotes from lesion aspirates or biopsy specimens (26 Px), by identification of amastigotes and granulomatous inflammation in biopsy material (26 Px, including 13 with positive cultures), or by identification of granulomatous inflammation in biopsy material without demonstrable parasites but with a serum IFA titre > 1:8 (1 Px); Excl: No evidence of underlying cardiac, hepatic, or renal diseases; no previous treatment with pentavalent antimonial drugs; at least 18 years of age; and informed consent to participation in the trial. Leishmania species: 22 isolates of L. panamensis and 1 of L. chagasi by isoeanzyme analysis.
Interventions	T1: IVSSG 10 mg Sb/kg (P10) N= 21. MNL: 2.9. MSL: 22.8 mm. MDLBT: 10.8 weeks. T2: IVSSG 20 mg Sb/kg (P20) N= 19. MNL: 2.7. MSL: 22.1 mm. MDLBT: 9.7 weeks. Frequency: OD for 20 consecutive days
Outcomes	Primary outcome Percentage of Px "cured" 1.5 months after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Small/C
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Double-blind: only stated but not reported who was blinded
Intention-to-treat/Drop-outs?	Yes	ND

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Convit 1987

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Methods	FU: 40 weeks of treatment. D: Randomised clinical trial
Participants	Venezuela n=102 In this study, 19/58 (32.76%) and 14/44 (31.8%) were females in the vaccine and IM MA groups respectively. Incl: Over 12 years of age, localised clinical trial form of leishmaniasis < 1 year in evolution, written agreement to participate in the trial, and no contraindication to either chemotherapy or immunotherapy. Leishmania species: L. braziliensis by use of monoclonal and polyclonal antibodies, and restriction fragment polymorphisms of kinetoplast DNA.
Interventions	T1: IMMA 50 mg/kg in series of 20 daily injections, with a maximum of three and a minimum of two series, and with 15 days between series N= 44. T2: Vaccine group: Promastigotes of the strain L. mexicana amazonensis (6.4 x 10E8) in 0.4 ml of PBS per dose, were heat-killed by autoclaving + viable bacille Calmette Guerin (BCG). The amount used in the first dose depended on the response to a previous tuberculin skin test, read at 48 h. The mixture was prepared immediately before use and the vaccine was injected intradermally, half in each deltoid region (0.25 ml in each of two sites). A second dose was given 6-8 weeks after the first and, in a proportion of participants, a third dose 12-18 weeks after the second. N=58
Outcomes	Primary outcome Percentage of Px "cured" 6 months after therapy Secondary outcomes Adverse effects Tertiary outcomes Speed of healing Development of cell-mediated immunity (i.e. positive leishmanin skin test)
Notes	Sample size: Medium/C
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Single-blind. Groups were classified as cured or not, by an experienced dermatologist who did not know to which group they belonged. For this examination the Px were asked to keep their deltoid regions covered and not to mention the kind of treatment they were receiving; health workers were trained to assist in this blinding.
Intention-to-treat/Drop-outs?	No	8 out of 102 (7.8%)

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Convit 1989

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Methods	FU: 24-month period. D: Randomised clinical trial
Participants	Venezuela n=217 Px with localized CL from a single endemic focus in Miranda State, Venezuela. Incl: Over 12 years of age, localised clinical trial form of leishmaniasis < 1 year in evolution, written agreement to participate in the trial, and no contraindication to either chemotherapy or immunotherapy. Excl: Pregnant women and Px suffering from malnutrition or other diseases affecting the general state of health. Leishmania species: All isolates of parasites from these Px were identified as L. braziliensis using monoclonal antibodies, enriched polyclonal sera, and kinetoplast DNA hybridisation studies using restriction enzymes and specific DNA probes
Interventions	T1: Combined vaccine was carried out by the intradermal injection of a mixture of 6.4x10E8 heat-killed promastigotes of L. mexicana amazonensis and variable amounts of BCG in a volume of 0.5 ml. The mixture was injected intradermally in two sites in the deltoid regions; 3 doses were applied at 6 to 8-week intervals N= 124. MSL: 21.6 mm. T2: IMMA, 50 mg/kg/day in series of 20 daily injections, with a maximum dose of 3 g/d and with intervals of 15 d between successive series. 2 or 3 series were administered unless otherwise stated N= 51. MSL: 20.4 mm. T3: BCG alone (in a volume of 0.5 ml) intradermally in 2 sites in the deltoid regions, 3 doses at 6 to 8 weeks intervals. N= 42. MSL: 18.6 mm.
Outcomes	Primary outcome Percentage of Px "cured" 6 months after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 3 months to 2.5 years Adverse effects Tertiary outcomes Speed of healing Development of cell-mediated immunity (i.e. positive leishmanin skin test)
Notes	0.2 mg of BCG was used if the reaction to PPD (purified protein derivative of tuberculin) was <10 mm in diameter. 0.02 mg was used in Px with reactions of 10-20 mm. 0.01 mg if reaction was >20 mm. In successive doses, 0.01 mg of BCG was used in all Px. Sample size: Large/C
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Px were given serial numbers and were assigned randomly to one of the three study groups
Blinding? All outcomes	Yes	Single-blind. Outcome assessor blinded.
Intention-to-treat/Drop-outs?	Yes	ND

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Correia 1996

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Methods	FU: 1 year. D: Randomised clinical trial
Participants	Brazil (Corte de Pedra -Bahia) n=46 Px were recruited in a Health Center of Corte de Pedra, Bahia, an endemic area of American tegumentary leishmaniasis (ATL). Age ranged from 12 to 56 years, male sex occurred in 65% (30/46) and females 34.8% (16/46) of the enrolled Px, and most of them worked as farmers 72% (33/46). 78% (36/46) of Px had 1 lesion and 22% (10/46) had 2 lesions. Incl: Primary cutaneous lesions compatibles with ATL, aged between 12 and 60 years, maximum number of 5 ulcers and duration of the disease < 6 months. Leishmania species: L. braziliensis by means of monoclonal antibodies and isoenzymes.
Interventions	T1: IMPI 4 mg/kg/every 2 days, for 8 applications N=15. MNL: 1.2. MDLBT: 40.5 days. T2: IMAS 20 mg/kg/day for 20 days N=15. MNL: 1.33. MDLBT: 35.1 days. T3: IMMA 10 mg/kg/day for 20 days N= 16. MNL: 1.13. MDLBT: 63.8 days.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	Yes	ND

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D'Oliveira 1997

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	El Salvador (Corte de Pedra) n=34 Aged 12 to 45 years. Incl: With leishmania-positive skin test and a maximum of 3 ulcerated lesions (with a minimum lesion diameter of 10 mm and a maximum of 50 mm) who had received no previous treatment. Excl: chronic disease, use of other drugs, history of allergy to allopurinol, pregnancy, breast feeding, or forms of leishmaniasis other than cutaneous. Leishmania species: L. braziliensis by culture and histologic assessment.
Interventions	T1: Oral AL 20 mg/kg 3 times a day for 20 days. N= 18. MNL: 15 Px had 1, 2 had 2 and 1 had 3 lesions. MDLBT: 38 days. T2: IVMA 10 mg/kg OD for 20 days. N= 16. MNL: 10 Px had 1, 5 had 2 and 1 had 3 lesions. MDLBT: 31.9 days.
Outcomes	Primary outcome Percentage of Px "cured" two months (70 days) after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 3 months Tertiary outcomes None reported
Notes	The other 9 Px of the AL group were not included in the evaluation because the protocol was broken and MA was administered before 90 days of treatment. Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	Yes	ND

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Figueiredo 1999

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Methods	FU: 2 years. D: Randomised clinical trial
Participants	Brazil n=43 Px recruited developed CL (26) or mucocutaneous leishmaniasis (17). All cutaneous treatments were performed in health centres of SUCAM, in Caratinga (MC), which is located in the Valley of Rio Doce, and Px were residents in areas situated at 100 km from the city. All mucocutaneous treatments were performed in a hospital (Santa Casa de Misericordia) situated in the city of Belo Horizonte or in the hospital das Clinicas of UFMG, and these Px were mainly residents in regions of the state of Minas Gerais and 3 of other states. All Px diagnosed with CL had ulcerative lesions, and Px diagnosed with MCL had infiltrative or ulcerative lesions located in the nasal mucosae or orofarigean mucosae. Incl: Px were aged between 15 and 60 years, with no history of previous treatment, with no abnormalities in organ functions, negative reaction of Machado-Guerreiro skin test, with cutaneous lesions clinically diagnosed by direct examination, and Px with muco-cutaneous leishmaniasis clinically diagnosed by biopsy, epidemiology, positive Montenegro's Skin test or RIFI and by histopathology. Excl: Pregnancy, history of previous specific treatment, evidence of underlying cardiac, hepatic, or renal diseases, alterations in laboratory data, pregnancy, mucocutaneous lesions, and taking immunosuppressive drugs. Leishmania species: not reported.
Interventions	T1: IVMA (14 mg/kg/day) alternated with placebo N= 24 (10 having mucocutaneous leishmaniasis and 14 CL). T2: IVMA (28 mg/kg/day) for 10 days and the other 10 days with placebo N= 19 (7 having mucocutaneous leishmaniasis and 12 CL). Frequency: in 2 series of 20 days, separated with intervals of 15 days for the CL, and 3 series of 30 days each, separated with intervals of 15 days in the mucocutaneous form
Outcomes	Primary outcome Percentage of Px "cured" two years after therapy Secondary and tertiary outcomes None reported
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Double-blind (Px and physicians). Tubes provided by Rodhia were identical in appearance
Intention-to-treat/Drop-outs?	No	4 out of 43 (9.3%)

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Franke 1994

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Peru n=40 Px were from the villages of Ocongate ad Sicuani in the Department of Cusco, Peru. Men acquired their disease through occupational exposure in the jungles of the Department of Madre de Dios. All Px were male. Leishmania was found in the lips, nose (septum, turbinates), palate-uvula-pharynx, and larynx-epiglottis and was classified as ulcerated, infiltrated, edematous, or erythematous. Incl: If cultures prepared by inoculating aspirates from mucocutaneous lesions into Senekji's blood agar medium were positive for Leishmania. Excl: If they had received antimonials for treatment of leishmaniasis in the previous 12 months, had significant concomitant disease of any organ, or had abnormalities on subsequent baseline tests. Leishmania species: All cultured 35 strains were L. braziliensis by isoenzyme analysis.
Interventions	T1: IVSSG 20 mg Sb/Kg/d for 28 days N= 20. MDLBT: 7.4 years (cutaneous) or 2.9 (mucocutaneous). T2: IVSSG 20 mg Sb/Kg/d for 40 days N= 20. MDLBT: 8.7 years (cutaneous) or 2.9 (mucocutaneous). Frequency: (the daily dose was administered in 50 ml of 5% dextrose in water by intravenous infusion over a 30-45 min period) with no upper limit on the daily dose
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	No	5 out of 40 (12.5%)

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Guderian 1991

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Ecuador n=75 29/61 Px were male. The mean age of all Px was 29 years. The mean ages of Px groups were: AL (25 years), SSG (29 years), and untreated (36 years). Incl: Ecuadorians with cutaneous lesions clinically diagnosed as leishmaniasis and who signed informed consent. Excl: If they had facial or mucocutaneous lesions, significant concomitant disease of any organ, or abnormalities on subsequent baseline laboratory tests. Leishmania species: culture from 23 Px were typed and 12 were L. panamensis, (5) L. guyanensis, (3) L. braziliensis and (3) L. mexicana by monoclonal antibody staining, haemoatoxylin and eosin staining or Giemsa staining.
Interventions	T1: Oral AL ribonucleoside (1.500 mg QID) plus probenecid (500 mg QID) for 28 days N= 30. MNL: 30. MSL: 4.4 cm^2. MDLBT: 3.5 months. T2: IMSSG (20 mg Sb/Kg/day) with no upper limit on daily dose, for 20 days N= 30. MNL: 46. MSL: 3.8 cm^2. MDLBT: 3.9 months. T3: Untreated controls (the end of therapy was defined as 20 days after entering into the study) N= 15. MNL: 16. MSL: 1.2 cm^2. MDLBT: 3.2 months.
Outcomes	Primary outcome Percentage of Px "cured" 1.5 months after therapy Secondary and Tertiary outcomes None reported
Notes	In the AL and the untreated group, the Px that failed to heal, were successfully treated with SSG. Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	No	14 out of 75 (18.67%)

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Hepburn 1994

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Methods	FU: for at least 6 months (mean follow-up period 11.4 months). D: Randomised clinical trial
Participants	Edinburgh n= 34 It was carried out at the army medical facility in Edinburgh, UK. All Px were British soldiers who had contracted CL in Belize. Lesions were located mainly on the limbs. Incl: All Px were British soldiers who had contracted CL in Belize and who had not received any anti-leishmanial therapy for at least 3 months. Leishmania species: In the AS group 53% (9/17) were infected with L. braziliensis and 18% (3/17) with L. mexicana. In the SSG group, 41% (7/17) were infected with L. braziliensis and 18% (3/17) with L. mexicana via culture or histologically. The rest of Px their culture was negative.
Interventions	T1: IVAS 14 mg/kg/day (max 1g daily) N=17. MNL: 1.58 (1-5). MSL: 18.6 mm. MDLBT: 15.7 weeks. T2: IVSSG 20 mg/kg/day N= 17. MNL: 1.76 (1-3). MSL: 11.8 mm. MDLBT: 10.9 weeks. Frequency: for 20 days
Outcomes	Primary outcome Percentage of Px "cured" 1.5 months after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	Yes	ND

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LLanos-Cuentas 1997

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Peru n= 81 Px were recruited from two Px associations and 2 medical centres in Cusco, Peru. The study was divided into 2 phases because the rate of cure of MCL varies with the severity of the disease. Px in phase I had severe lesions and Px in the phase II study had moderate disease. Px were admitted to the Hospital Regional del Cusco during the administration therapy. They were all males with a mean age around 34 years. Incl: Px with severe or moderate MCL who were 15 to 60 years were eligible for study enrolment if they had a documented history of MCL with proven presence of parasites by culture and/or PCR analysis and gave written informed consent. Excl: Clinically similar diseases, serious concomitant diseases, pregnancy, known or suspected allergy to Sb5+ or AL, and use of Sb5+, AL, amphotericin B, or ketoconazole in the last 6 months before the study. Leishmania species: not reported.
Interventions	T1: IVSSG (20 mg of Sb 5+/kg/d) plus oral AL (20 mg/kg/d in 4 divided doses) N= 40 (n=11 in phase I and n=29 in phase II). MNL: 2.8 in the phase I and 2.5 in phase II. MDLBT: 71.9 months in phase I and 75.9 in phase II. T2: IVSSG (20 mg of Sb 5+/kg/d) N= 41 (n=11 in phase I and n=30 in phase II). MNL: 2.1 in the phase I and 2.4 in phase II. MDLBT: 105.1 months in phase I and 79.9 in phase II. Frequency: for 28 days
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/C
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	According to a permuted-blocks scheme with a block size of 10 Px
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	No	11 out of 81 (13.6%)

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Llanos-Cuentas 2007

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Methods	FU: 1 year. D: Randomised clinical trial
Participants	Peru n= 38 All Px were men and the study was conducted in the city of Cuzco, Peru. The mean age of Px was 32.6 years in the AS group and 33.2 years in the MA group. More Px with severe laryngeal and vocal cord involvement were enrolled in the aminosidine group, but the difference did not reach statistical significance. Incl: Adults between 18 and 60 years of age with moderate MCL, defined as involvement of the nasal and pharyngeal mucosa with or without laryngeal affection but without respiratory distress and with proven presence of parasites by culture, histology, and/or PCR on a biopsy specimen. Excl: Px who had received treatment in the previous 6 months with antileishmanial agents or who had failed to a course of treatment with amphotericin B, Px with known or suspected allergy to aminoglycosides or antimonials, pregnant or nursing women, and Px not willing to return for FU evaluations. Also Px with severe concurrent illnesses such as tuberculosis, renal, liver, or heart disease, or alcoholism. Leishmania species: not reported, but they stated that MCL caused by L. braziliensis is a significant health problem in rural areas of Central and South America.
Interventions	T1: IMAS 14 mg/kg body weight OD for 21 days n= 21. T2: IVMA 20 mg/kg body weight in 250 ml 5% dextrose in water infused over a 20-minute period OD for 28 days n= 17.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Small/C
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Computer-generated random table in a 1:1 ratio
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	Yes	ND

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Lobo 2006

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Methods	FU: 28 days after onset of treatment. D: Randomised clinical trial
Participants	Brazil n= 37 The same physician in a health care clinic in Laje attended Px from Laje and neighbourhood towns in the Jirquiriça Valley, in the southwest of Bahia State, Brazil. Age ranged from 18-67 years but mean age was around 35 years. Incl: Px had to be at least 18 years old, have no more than 2 cutaneous lesions and none larger than 10 cm. They had to have no signs and/or symptoms of mucous leishmanial involvement and no previous history of leishmaniasis or specific leishmanial treatment. Px had to be willing to return for clinical and laboratory evaluation 14 and 28 d after initiating treatment and continue for clinical FU. Excl: Pregnant participants, those who had contraindications for MA treatment, such as severe renal or cardiovascular disease. Leishmania species: L. braziliensis endemic in the area.
Interventions	T1: Heat therapy given in a single session. The Thermosurgery instrument placed at the edge of the lesion pointing toward the centre and heat at 50ºC was applied for 30 s, then the applicator was moved to an adjacent area until the lesion had been completely covered, taking 4-5 min. N= 17. Total number of lesions: 16/17 (94%) had 1 lesion. MSL: 23 mm. MDLBT: 45 days (15-180). T2: IVMA 20 mg/kg/d for 20 consecutive days N=20. Total number of lesions: 13/20 (65%) had 1 lesion. MSL: 23 mm. MDLBT: 50 days (20-240). Co-treatment: T2 after day 28 to all Px in the heat therapy group.
Outcomes	Primary outcome Percentage of Px "cured" at the end of therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	No
Intention-to-treat/Drop-outs?	No	1 out of 37 (2.7%)

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M-Verástegui 2005

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Peru n=40 Px with CL were identified in rural health centres in regions of the Peruvian Andes (1500-2500 m above sea level) and the Peruvian jungle where CL is endemic, including the provinces of Churin, Barranca, Yauyos, Satipo, Chachapoyas, Cusco, and Madre de Dios. Subjects were referred for evaluation and treatment at the Instituto de Medicina Tropical Alexander von Humbolt, Unversidad Peruana Cayetano Heredia, in Lima. A total of 75 lesions were evaluated: 35 lesions in the imiquimod group and 40 in the placebo group. The median lesion size was 0.5 cm^2 for both groups, and lesions duration was 8.8 months for the imiquimod group versus 5.2 months for the placebo group. M/F: 17/13. Incl: Each Px must have had parasitologically confirmed CL and a history of > or 1 failed course of treatment with MA. Excl: Mucosal involvement, pregnancy, breast-feeding, > or 1 lesion with the area > 25 cm^2, a history of liver or renal disease, allergy to antimony or imiquimod, or the presence of another significant medical condition (e.g., liver failure, renal failure, AIDS, or tuberculosis). Leishmania species: They considered that Px from the Andean valley regions were infected with L. peruviana and Px from the lower Amazonian jungle regions were infected with L. braziliensis.
Interventions	T1: Topical imiquimod cream 5% applied to each lesion every other day for 20 days + IMMA in children or by slow IV (>15 min) in older subjects for 20 days N= 20. MNL: 1.75. MSL: 1.3 cm^2. MDLBT: 13.4 months. T2: Topical placebo cream applied to each lesion every other day for 20 days + IMMA same as in T1 N= 20. MNL: 2. MSL: 2.3 cm^2. MDLBT: 11.4 months.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Unclear	Double-blind (Px and physicians). Each numbered treatment package had 10 sachets that were identical in appearance and contained either imiquimod or vehicle cream
Intention-to-treat/Drop-outs?	No	2 out of 40 (5%)

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Machado 2007

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Methods	FU: 2 years. D: Randomised clinical trial
Participants	Brazil n=23 Px were living in Corte de Pedra, an endemic area of L. braziliensis. There were M/F: 19/4. Incl: Px who were eligible for enrolment after providing informed consent were aged 18-65 years and had severe mucocutaneous leishmaniasis (defined as the presence of deep mucosal ulcers and/or septal infiltration or perforation). Excl: Px who had superficial mucosal ulcers, prior therapy for mucocutaneous disease, diabetes, or coinfection with HIV, or who were unavailable to FU. Leishmania species: Corte de Pedra is an area of endemicity of L. braziliensis transmission.
Interventions	T1: Oral pentoxifylline 400 mg three times daily for 30 days plus IV SSG 20 mg/kg/d N= 11. MSL: 352 mm^2. MDLBT: 6 months (0.5-120). T2: Oral placebo orally 3 times daily for 30 days plus IVSSG 20 mg/kg/d N= 12. MSL: 451 mm^2. MDLBT: 12 months (2-240).
Outcomes	Primary outcome Percentage of Px "cured" 4 months after therapy Secondary outcomes Adverse effects Tertiary outcomes Speed of healing (time taken to be 'cured')
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Randomisation table
Blinding? All outcomes	Yes	Double-blind (Both the otolaryngologist and Px were blinded to treatment assignment during all the steps of the study)
Intention-to-treat/Drop-outs?	Yes	ND

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Machado-Pinto 2002

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Methods	FU: 12 months D: Randomised clinical trial
Participants	Brazil n= 102 All Px lived in a highly endemic area for ACL in the state of Minas Gerais, Brazil. Baseline characteristics do not include the Px that dropped-out, however: in the vaccine group the median age was 16 years (5-65), mean weight was 47.5 Kg and 53.2% were males. In the MA (control) group the median age was 29 years (7-82), mean weight was 60.3 Kg and 65.3% were males. There was a significant difference between the two groups with regard to age (medians were 16 and 29 years for the vaccine and MA groups respectively). Nonetheless, in multivariate analysis, age had no influence on the outcome. Incl: An age of 5 years, a parasitologically confirmed diagnosis of CL, and an informed consent form signed by the Px or the parents/guardians of those under 16 years of age. Leishmania species: L. braziliensis endemic in the area.
Interventions	T1: Subcutaneous injection of L. amazonensis strain (IFLA/BR/1967/PH8) vaccine (0.5 ml) daily plus IMMA (8.5 mg/kg) for 10 days followed by 10 days of rest. N= 51. MNL: 1 (1-8). MSL: 34.2 mm (25.8). MDLBT: 60 days. T2: Subcutaneous injection of Placebo (0.5 ml) daily plus IMMA (8.5 mg/kg) for 10 days followed by 10 days of rest. N= 51. MNL: 1 (1-7). MSL: 34.5 mm (25.6). MDLBT: 60 days.
Outcomes	Primary outcome Percentage of Px "cured" at the end of therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Adverse effects Tertiary outcomes Speed of healing (time taken to be 'cured')
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Double-blind: only stated but not reported who was blinded
Intention-to-treat/Drop-outs?	No	6 out of 102 (6%)

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Martínez 1992

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Methods	FU: 12 months. D: Randomised clinical trial (Px in the AL alone group and in the no treatment group were not randomised but self-selected)
Participants	Colombia (village called Lopez de Micay on the souther pacific coast and an endemic area of L. panamensis) n=110 Except for 2 girls aged 8 and 10, the Px were male, ranging age from 11 to 40. Most of the Px had 1-3 lesions and only 3 had > 4. Incl: Px who had the disease proved by examination of a smear, culture, or biopsy; who had received no previous therapy and if their lesions were confined to the upper portion of the trunk or the arms. To be enrolled Px had to have a body weight within 20% of the ideal body weight for their height. Excl: If they or their parents did not give written informed consent; if they had a known or suspected allergy to antimony or AL; if they were pregnant or nursing; if they had serious concomitant diseases or any disease other than leishmaniasis requiring treatment; or if they had pre-existing skin rash or another disease of the skin. Leishmania species: L. panamensis by smear or biopsy.
Interventions	T1: Oral AL 20 mg/kg/day in 4 divided doses for 15 days. N= 25 T2: IVMA 20 mg/kg/day for 15 days. N= 33. T3: AL+ MA same dosage. N= 35. T4: No treatment N= 17.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	A master randomisation list was generated by a computer
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	Yes	ND

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Martínez 1997

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Colombia n=100 M/F: 86/14. Their aged ranged from 18 to 57 years. All Px were from the southern Pacific coast of Colombia. Approximately 1/2 (47%) of the Px were farmers, 35% were soldiers, and the remaining 18% had diverse occupations. 2/3 (68/100) were black: 1/4 (24/100) were white; and the remaining 9% (87100) were of native origin. Incl: Evidence of Leishmania in a smear, a biopsy specimen, or a culture was required. To be enrolled Px had to have a body weight within 20% of the ideal body weight for their height. Excl: If they did not give written informed consent; if they had a known or suspected allergy to antimony or AL; if they were pregnant or nursing; if they had serious concomitant diseases or any disease other than leishmaniasis requiring treatment; or if they had pre-existing skin rash or another disease of the skin. Leishmania species: L. braziliensis by smear or culture.
Interventions	T1:Oral AL 20 mg/kg/day in 4 divided doses for 15 days+ IVSSG 20 mg/kg/day for 15 days. N= 51. MDLBT: < 3 months. T2: IVSSG 20 mg/kg/day for 15 days. N= 49. MDLBT: < 3 months.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	A master randomisation list was generated by a computer at the Department of Statistics at Cauca University
Blinding? All outcomes	No	Open
Intention-to-treat/Drop-outs?	Yes	3 out of 100 (3%)

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Navin 1990

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Methods	FU: 52 weeks after the start of therapy. D: Randomised clinical trial
Participants	Guatemala n= 66 Px were all men (average age 20 years). The average weight of Px who received MA was 56.1 Kg; they received an average of 15.2 mg antimony/kg body weight. Px were evenly divided between persons of Indian ancestry and those of mixed or other ancestry. Px had up to 6 lesions at the time of diagnosis, but most (68%) had only one lesion. The mean area of ulceration was 5.2 cm^2. On average, their lesions had been apparent for 58 days when they first came to our clinic. Incl: Px were 18-60 years of age and had diagnoses of leishmaniasis confirmed by positive thin smear or cultures, no previous treatment with antimonials, no serious concomitant medical problems, lesions < 25 cm^2 in size, and no visual evidence of mucosal involvement. Excl: Px with lesions in locations that would have been difficult to treat with the heat device, such as lesions of the ear, near the eye, and on the finger, and unilateral lymphadenopathy or subcutaneous nodules in an area of lymph drainage from the lesion. Leishmania species: Leishmania was isolated in 53 Px by smear or culture; 13 (25%) were L. mexicana and 40 (75%) were L. braziliensis.
Interventions	T1: IMMA 850 mg daily for 15 days N= 22. MNL: 1.7. MSL: 6.2 cm^2. MDLBT: 49 days. T2: Localized heat 50ºC for 30 sec, 3 treatments at 7 day intervals (The apparatus heated the skin to 50ºC in approx 20 sec, and maintained the temperature at 49-51ºC for 30 sec) N= 22. MNL: 1.3. MSL: 4.6 cm^2. MDLBT: 62.3 days. T3: Placebo treatment N= 22. MNL: 1.5. MSL: 4.9 cm^2. MDLBT: 63 days.
Outcomes	Primary outcome Percentage of Px "cured" 2 months after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	They found in a pilot study, that some Px developed what appeared to be bacterial cellulitis after heat treatments. To reduce the risk of subsequent cellulitis in this study, Px who were not allergic to penicillins received 500 mg oral dicloxacillin TD for 14 days before treatment. Px allergic to penicillins received erythromycin at the same dose. All Px received 500 mg of dicloxacillin (or erythromycin) 1 hr before andTD after each heat or placebo treatment. Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Single-blinded. Px did not know whether they were receiving heat or sham treatments.
Intention-to-treat/Drop-outs?	Yes	ND

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Navin 1992

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Methods	FU: 48 weeks after the end of treatment or 52 weeks after the start of therapy. D: Randomised clinical trial
Participants	Guatemala n= 120 The study included 21 civilians and 99 soldiers. In the SSG group 15% (6/40) were infected with an unknown infecting species, 63% (25/40) were infected with L. braziliensis, 18% (7/40) with L. mexicana and 5% (2/40) with both. In the ketoconazole group 16% (6/38) were infected with an unknown infecting species, 61% (23/38) were infected with L. braziliensis, 24% (9/38) with L. mexicana and 0% (0/38) with both. In the placebo group 23% (9/40) were infected with an unknown infecting species, 38% (15/40) were infected with L. braziliensis, 40% (16/40) with L. mexicana and 0% (0/40) with both. Incl: Confirmed diagnosis of leishmaniasis, no previous treatment with antimonials or imidazoles, no serious concomitant medical problems, availability for FU for 12 months, and no visible evidence of mucosal involvement. Leishmania species: L. braziliensis (53%) and L. mexicana (27%) by smear or culture.
Interventions	T1: Oral ketoconazole 600 mg/day for 28 days N=40. MNL: 1.5. MSL: 2.2 cm^2. MDLBT: 68.3 days. T2: IVSSG 20 mg of antimony/kg/day for 20 days N=40. MNL: 1.6. MSL: 1.5 cm^2. MDLBT: 73.7 days. T3: Placebo. Half of the Px assigned to the placebo group received saline infusions similar to the SSG infusions and the other half received tablets similar in form to ketoconazole. N=40. MNL: 1.5. MSL: 2.0 cm^2. MDLBT: 59.1 days.
Outcomes	Primary outcome Percentage of Px "cured" 2 months after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	According to a preexisting list produced by a computer programme that differed from a random number generation only in that it assigned equal number of Px into each treatment group.
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	No	7 out of 120 (5.83%)

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Neva 1997

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Methods	FU: 11 weeks after completion of the 4-week topical treatment . They also stated that the study lasted for 4-5 months. D: Randomised clinical trial
Participants	Honduras ( 2 sites: village of San Juan Bautista, municipality of Pespire, Department of Choluteca and the village of Coyolito, municipality of Ampala, Department of Valle) n=53 26 Px came from San Juan Bautista and 27 from Coyolito. Cases were equally divided by sex and ranged in age from 3 to 36 years (only 4 participants were >20 years old, 1 was 18, and the remainder 16 years or less). 70-90% of the cases had 1 or 2 lesions (multiple lesions were more common in Px from Coyolito: 8/27 having 3 or more). The most prominent lesion on each Px was aspirated and cultured in NNN medium. Incl: Only those Px with positive cultures were enrolled in the study. Leishmania species: L. mexicana and L. chagasi by culture and isoenzyme typing.
Interventions	T1: Topical 15% PR + 10% urea n= 23. (10 Px having L. mexicana and 13 L. chagasi) T2: Topical placebo (white soft paraffin) ointment n=30. (8 Px having L. mexicana and 22 L. chagasi) Frequency: 3 times daily for 4 weeks
Outcomes	Primary outcome Percentage of Px "cured" 2.5 months (11 weeks) after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 4-5 months Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	A list of random numbers generated by Epi-Info software
Allocation concealment?	Yes	The code identifying the contents of each tube was know only to the Geneva participants (FM and PO)
Blinding? All outcomes	Yes	Double-blind. Tubes prepared by Farmitalia Carlo Erba and provided to the WHO TDR programme, containing the drug or placebo were identical in appearance and marked only by a number
Intention-to-treat/Drop-outs?	Yes	ND

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Oliveira-Neto 1997

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Methods	FU: 7 years. D: Randomised clinical trial
Participants	Brazil n= 23 Of the 23 Px proceeding from known endemic foci of ACL in Rio de Janeiro, M/F: 14/9. Ages ranged from 11 to 66 years. All Px presented cutaneous lesions: 16 one single lesion and 7 with multiple lesions. Single lesions were always rounded ones of the ulcerative type with raised borders. In cases of multiple lesions, some were papular and others ulcerative. Lesions were located mainly in exposed areas, face and limbs. Leg lesions were present in 15 Px. Duration of the disease ranged from 1 to 11 months. Incl: Clinical appearance of lesions, positive Montenegro's skin test and the presence of parasites either in in-prints, histological examination or isolation in culture. Leishmania species: L. braziliensis (parasites were found in 18 Px by monoclonal antibodies and zymodeme analysis).
Interventions	T1: IVMA 5 mg/kg/day N= 12. MNL: 1-4 lesions. MSL: 3.73 cm^2. MDLBT: 3.25 months. T2: IVMA 20 mg/kg/day N= 11. MNL: 1-7 lesions. MSL: 3.89 cm^2. MDLBT: 2.54 months. Frequency: during 30 consecutive days
Outcomes	Primary outcome Percentage of Px "cured" at the end of therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Random distribution of high and low doses were in charge of the Chief-nurse only in order to preserve the seal over the dosage employed. Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	Yes	ND

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Oster 1985

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	USA n= 36 Incl: The diagnosis was confirmed by demonstrating amastigotes in histological sections of skin biopsies and/or by culturing promastigotes from lesion aspirates or biopsies; the Px had not previously been treated with antileishmanial drugs; and the Px was at least 18 years of age and gave informed consent to participate in the trial. Leishmania species: Only in 26 Px Leishmania parasite was identified by cultire or biopsies: 14 Px were infected with L. braziliensis, 9 with L. mexicana and 3 with L. chagasi.
Interventions	T1: IVSSG 600 mg OD for 10 days N=12. MSL: 3.0 cm. T2: IVSSG loading dose of 600 mg followed by 600mg/day continuous infusion for 9 days. N=12. MSL: 2.8 cm. T3: IVSSG loading dose of 600 mg followed by 200mg every 8 hour for 9 days N=12. MSL: 2.5 cm.
Outcomes	Primary outcome Percentage of Px "cured" at the end of therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Px who had initially been randomised to one of the three experimental treatment groups and were not cured, were randomised for re-treatment with one of the two treatment regimens they had not received, and Px failing this second course of therapy were then treated with the regimen they had not yet received. Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	They stated that assignment to one of the three treatment groups was made according to predetermined randomised schedule which was balanced for every three Px
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	Yes	ND

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Palacios 2001

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Methods	FU: 52 weeks after initiation of treatment. D: Randomised clinical trial
Participants	Colombia n= 136 Carried out at the Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM) in Cali and Tumaco. Tumaco is an endemic area on the Colombian Pacific Coast where most of the recruited Px live in rural areas. Cali is the largest city in the southwestern region, and Px residing in non-endemic areas are often referred to Cali for diagnostic tests and medical attention. The 2 groups were comparable in socio-demographic and principal clinical characteristics, although Px randomised to receive 20 days of treatment bore lesions with median areas that were significantly larger and had less frequent regional adenopathies than Px who received 10 days of treatment. Incl: Px who had a parasitological diagnosis of cutaneous leishmaniasis. Excl: Px who had been treated previously with antimonials, ketoconazole, or another imidazole, amphotericin B or pentamidine, as well as those with mucocutaneous leishmaniasis, severe cardiovascular, renal, hepatic, or pancreatic disease, and pregnant or nursing women. Leishmania species: Of the 88 parasite isolates obtained, 84 were due to L. panamensis, and 4 cases were due to L. braziliensis by means of monoclonal antibodies and/or isoenzyme analysis.
Interventions	T1: IMMA 20 mg/kg/day (with no upper limit on the daily dose) OD during 10 days. N= 68. MNL: 2. MDLBT: 2 months. T2: IMMA 20 mg/kg/day (with no upper limit on the daily dose) OD during 20 days. N=68. MNL: 2. MDLBT: 2 months.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/C
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Randomisation was performed using permuted block randomisation as described previously (Spilker 1991)
Blinding? All outcomes	Yes	Single-blinded. Masked examiners evaluated clinical responses
Intention-to-treat/Drop-outs?	Yes	54 out of 136 (39.7%)

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Saenz 1987

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Panama n= 59 Most of the Px came from rural areas of the provinces of Panama and Colon, and were male. M/F was higher in the MA-treated group than the SSG-treated group (9:1 versus 2:1). Mean age in the MA group was 29.6 and 26.4 years in the SSG group. Lesions were ulcerative in all Px. Number of lesions in the SSG was 30 and in the MA was 29. Incl: Px were included if Leishmania organisms were cultured from lesion material or seen in smears of lesion material, and had not received previous antileishmanial therapy. Leishmania species: L. panamensis by culture or biopsy.
Interventions	T1: IMSSG 20 mg/kg/d N= 30. MDLBT: 7.5 weeks. T2: IMMA 20 mg/kg/d N= 29. MDLBT: 8.3 weeks. Frequency: (maximum daily dose of 850 mg) for 20 days
Outcomes	Primary outcome Percentage of Px "cured" at the end of therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 6 to 1 year Adverse effects Tertiary outcomes Microbiological or histopathological cure of skin lesions
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	No	9 out of 59 (15.3%)

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Saenz 1990

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Panama n= 52 They were all male. For the Ketoconazole group the age range was 16 to 48 years and the mean age was 25. For the MA group the age range was 17 to 67 years and the mean age was 34. The weight range for the ketoconazole group was 36 to 74 kg and 41 to 77 kg for the MA group. 66% (23/35) and 51% (25/49) of lesions were on the upper extremities in the ketoconazole and the MA groups respectively. The placebo-treated group were between 16 and 43 years of age and the mean age was 31 years old. 61% of lesions were in the upper extremities). Incl: Panamians with cutaneous lesions clinically diagnosed as leishmaniasis and who gave informed consent. Px were included if Leishmania organisms were cultured from lesion material or seen in smears of lesion material. Excl: If they had facial or mucocutaneous lesions, significant concomitant disease of any organ, or abnormalities on subsequent baseline tests. Leishmania species: L. panamensis. Except one isolate in the ketoconazole group that was L. mexicana by culture or smear.
Interventions	T1: Oral ketoconazole 3 (200-mg tablets) before sleep each day (600 mg/kg/day) for 28 days N= 22. MNL: 2.1. MSL: 333 mm^2. MDLBT: 8.2 weeks. T2: IMMA 20 mg/Kg with a maximum of 850 mg/day for 20 days N=19. MNL: 2.6. MSL: 350 mm^2. MDLBT: 12.5 weeks. T3: Oral placebo 3 tablets each night for 28 days. N=11. MNL: 2.1. MSL: 95 mm^2. MDLBT: 7.4 weeks.
Outcomes	Primary outcome Percentage of Px "cured" 3 month after therapy Secondary outcomes Adverse effects Tertiary outcomes Speed of healing Microbiological or histopathological cure of skin lesions
Notes	Px in whom ketoconazole MA or placebo therapy failed were retreated with the local standard of care, pentavalent antimony in the form of Glucantime or Pentostam (20 mg Sb/Kg, with a maximum of 850 mg Sb/day, IM for 12 days) and all were cured. Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	By card drawing
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	Yes	ND

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Santos 2004

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Methods	FU: 1 year. D: Randomised clinical trial
Participants	Brazil n=22 Px were referred to the health post of Corte de Pedra, Bahia, Brazil, an area where L. braziliensis infection is endemic. In this study there were M/F: 16/4. The average age was approx 29 years. Incl: An age of 15-50 years and a diagnosis of CL within 60 days of the beginning of the cutaneous lesion, confirmed either by parasitologic (culture or histopathologic) examination or by positive results of at least 2 of the following: compatible histopathologic examination, serologic examination, or delayed-type hypersensitivity test (Montenegro skin test) to Leishmania antigen. Excl: Pregnancy, an age of < 15 or > 50 years, other associated acute or chronic illness, and a history of allergy to GM-CSF and/or antimony. Leishmania species: L. braziliensis is endemic in the area.
Interventions	T1: GM-CSF (final concentration of 10 μg/ml). The GM-CSF working solution was reapplied and dressings changed 3 times/week, on Mondays, Wednesdays, and Fridays, for 3 weeks (for a total of 9 GM-CSF applications) + IV MA 20 mg/kg/d for 20 days N= 11. MSL: 25 mm. MDLBT: 28 days. T2: Placebo (saline applied locally instead of GM-CSF) + IVMA 20 mg/kg/d for 20 days N= 11. MSL: 24 mm. MDLBT: 34 days.
Outcomes	Primary outcome Percentage of Px "cured" one month (40 days) after therapy Secondary outcomes Adverse effects Tertiary outcomes Speed of healing (time taken to be 'cured')
Notes	Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	By use of a randomisation table performed by a statistician
Blinding? All outcomes	Yes	Double-blind (Both the Px and the physicians). Two independent physicians examined the Px on all visits and questions on possible side effects of the treatment were deferred to a third medical doctor who was conversant with the known side effects of GM-CSF.
Intention-to-treat/Drop-outs?	No	2 out of 22 (9%)

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Soto 1994

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Colombia n=90 Members of Colombian army. The Px were infected during military duty in the regions of Uraba and LLanos Orientales, Colombia. 90 consecutive Px who met eligibility requirements, presented with disease when standard antileishmanial agents were no longer in stock at the field medical dispensary, and received permission from the local commander to relocate to Bogota for treatment, constituted the study population. All treatment was performed at Bogota Military Hospital. Incl: If they were 18-60 years old, had CL proven parasitologically, had not used putative antileishmanial compounds in the previous 9 months, and gave written informed consent to participate. Excl: If there were serious concomitant problems in their medical history or abnormalities in baseline laboratory tests. Leishmania species: 30/90 of the Px had L . panamensis by Giemsa smears, monoclonal antibody. Also a separate biopsy was taken to be cultured in NNN and Schneider's media and further identified by isoenzyme electrophoresis.
Interventions	T1: IMAS 12 mg/Kg/day (maximum 850 mg/day) for 7 days. N= 30. Total number of lesions: 69. MSL: 143 mm^2. T2: IMAS 12 mg/Kg/day (maximum 850 mg/day) for 14 days. N= 30. Total number of lesions: 55. MSL: 305 mm^2. T3: IMAS 18 mg/Kg/day (maximum 850 mg/day) for 14 days. N=30. Total number of lesions: 48. MSL: 288 mm^2.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	The original intention was to compare AS 12 mg base for 7 days with AS for 14 days, the first 60 Px were randomly allocated equally between the 2 groups. When 50 Px had been entered, it became clear the AS efficacy was less than expected. Therefore a 3rd group was added and the final 40 Px were randomly allocated to the three groups in the ratio 5:5:30
Blinding? All outcomes	Unclear	Not mentioned
Intention-to-treat/Drop-outs?	Unclear	1 out of 90 (1.1%)

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Soto 1998

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Colombia n=150 The Px acquired their disease in the Colombian regions of Uraba, Magdalena Medio, and LLanos Orientales. Incl: If they were 18-60 years old, had cutaneous leishmaniasis proven parasitologically by visualization or culture of organisms, and were otherwise healthy. Excl: If there were serious concomitant problems in their medical history or abnormalities in baseline laboratory tests (in the levels of white blood cells and haemoglobin, serum levels of aspartate aminotransferase, and concentrations of glucose and blood urea nitrogen). Leishmania species: Of the 69/150 cultures strains, 49 were L. panamensis, and 20 were L. braziliensis by isoenzyme electrophoresis.
Interventions	T1: Topical 15% PR sulphateTD for 10 days+ 12% MBCL and a short course of IV MA for 7 days N= 59. MNL: 1.4. MSL: 224 mm^2. T2: Topical placebo TD for 10 days plus IVMA for 7 days N= 30. MNL: 1.4. MSL: 202 mm^2. T3: Topical 15% PR sulphate TD for 10 days+ 12% MBCL and a short course of IVMA for 3 days N= 30. MNL: 1.4. MSL: 302 mm^2. T4: IVMA for 20 days N= 31. MNL: 1.2. MSL: 267 mm^2.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary and tertiary outcomes None reported
Notes	The inclusion and exclusion criteria definitions were identical to those reported in our previous study (Soto et al., 1995) Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	Px were randomly assigned in unequal allocation (2:1:1:1) to four groups
Blinding? All outcomes	Yes	Partially double-blinded: only stated but not reported who was blinded
Intention-to-treat/Drop-outs?	Yes	2 out of 150 (1.3%)

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Soto 2002

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Methods	FU: 6 months after initiation of treatment. D: Randomised clinical trial
Participants	Colombia n=45 Colombian soldiers acquired their disease in the Colombian regions of Uraba and Magdalena Medio. Most Px were evacuated to the Central Military Hospital in Bogota for diagnosis and treatment. Some Px were diagnosed and treated at the Instituto Colombiano de Medicina Tropical in Uraba. All Px were men aged approx. 25 years. The pre-therapy lesion sizes were a mean of 166 mm^2. The mean number of lesions was 1.6 per Px. Incl: If the total ulcer lesion size was < 2000 mm^2, lymphadenopathy was < 1 cm in diameter, there was no disease of the oronasal mucosa, screening laboratory values (serum levels of creatinine) were within normal limits and the Px had not concomitant medical problems. Leishmania species: determination of Leishmania was successfully detected in 5 of the 45 Px, and they were all L. panamensis via Giemsa smears or monoclonal antibody staining.
Interventions	T1: Topical WR279396 with 0.0005 ml/mm^2 TD for 20 days N= 33. MNL: 1.70. MSL: 155 mm^2. T2: Topical placebo with 0.0005 ml/mm^2 TD for 20 days N= 12. MNL: 1.42. MSL: 203 mm^2.
Outcomes	Primary outcome Percentage of Px "cured" 2 months (70 days) after therapy Secondary outcomes Adverse effects Tertiary outcomes Speed of healing (time taken to be 'cured')
Notes	The reason for the lack of exact 2:1 assignment was that randomisation was performed for a possible total of 60 Px to allow for drop-outs, and a relatively large number of active treatments were randomised to the first 45 Px. Sample size: Small/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	Randomly assigned in a 2:1 allocation
Blinding? All outcomes	Yes	Single-blind. Outcome assessor (determination of lesion cure and failure was made by a clinician blinded as to the treatment group of the Px)
Intention-to-treat/Drop-outs?	No	8 out of 45 (17.8%)

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Soto 2004A

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Methods	FU: 6 months. D: Randomised clinical trial
Participants	Bolivia and Colombia n= 114 45 consecutive Bolivian Px from the province of La Paz had parasitologically proven CL and 69 consecutive Colombian Px from the provinces of Urabá and Carmen de Chucurí, aged at least 18 years (age range 18-65) were eligible for the study. Diagnosis and treatment were performed in local hospitals in Apartade and Carmen de Chucurí, Colombia. In 45 Bolivian Px, the mean number of lesions per Px was 1.8 and the mean lesion size was 397 mm^2. In 69 Colombian Px, the mean number of lesions per Px was 1.9 and the mean lesion size was 328 mm^2. Incl: Parasitologically proven CL and Px who were at least 18 years of age. Excl: Mucocutaneous disease, previous treatment with antimonials, concurrent treatment with hepatotoxic, pancreaticotoxic, or cardiotoxic drugs, and any concurrent systemic medications except common drugs for symptomatic relief. Leishmania species: L. panamensis by direct Giemsa stain of the smear. In Colombia when motile promastigotes were seen, the parasite was determined by monoclonal antibody binding.
Interventions	T1: IMSSG 20 mg/Kg/day N= 48. MNL: 49.5. MSL: 366.5 mm^2. T2: IMSSG (Pentostam) 20 mg/Kg/day N= 16. MNL: 14. MSL: 474.5 mm^2. T3: IMMA 20 mg/Kg/day N= 50. MNL: 48. MSL: 307 mm^2. Frequency: for 20 consecutive days (there was no upper limit on the daily dose)
Outcomes	Primary outcome Percentage of Px "cured" 6 months after therapy Secondary outcomes Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Px were randomised by playing cards
Allocation concealment?	Yes	The Colombian allocation ratios were chosen to achieve a final allocation ratio for both sites for generic stibogluconate, Pentostam, and Glucantime of approximately 3:1:3. The Px code was broken only after all efficacy and toxicity evaluations had been completed
Blinding? All outcomes	Yes	Double-blind (neither Px, administering medical personnel, or evaluator knew the identity of the agent)
Intention-to-treat/Drop-outs?	Yes	10 out of 114 (8.8%)

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Soto 2004B

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Methods	FU: 6 months. D: Randomised clinical trial
Participants	Colombia and Guatemala n= 133 In Colombia, the Px were both civilians and soldiers who acquired infection in the provinces of provinces of Uraba and Carmen de Chucuri and who were evaluated in local hospitals for diagnosis and treatments. In Guatemala, the Px were civilians who presented, received diagnoses, and were treated at 2 clinics operated by the Universidad del Valle de Guatemala, which is located in Poptun, El Peten, Guatemala. On average, Px were in the third decade of life, weighed approx. 60 kg, and had 1 lesion. The ulcer size was approx. 200 mm^2. M/F: 119/ 14. Incl: Px were of either sex, aged > 12 years, had parasitologically confirmed CL, and did not have mucosal involvement. Previous treatment for the disease was permitted if the therapy had stopped > or 4 weeks earlier and the lesions were not improving. Normal complete blood cell counts, liver transaminase levels, and kidney function test results. Excl: Pregancy and lactation, and significant concomitant diseases. Leishmania species: In Colombia, all parasites were L. panamensis via monoclonal antibody binding. In Guatemala, 63% were L. braziliensis, and 37% of speciated parasites were L. mexicana via PCR. Compliance assessment: Drugs were administered under observation of study staff. 6/133 (4.5%) treated Px did not receive the full 28 days of medication. All 6 partially treated Px are included with the 127 fully treated Px in the efficacy and tolerance evaluations below.
Interventions	Colombia: T1: Miltefosine orally (50 mg) for 28 days. N= 49. MNL: 1 (1-8). MSL: 171 (72-1775) mm^2. T2: Placebo administered like miltefosine for 28 days N= 24. MNL: 1 (1-5). MSL: 238 (6-2110) mm^2. Guatemala: T1: same as in Colombia N= 40. MNL: 1 (1-10). MSL: 165 (6-1650) mm^2. T2: same as in Colombia N= 20. MNL: 1 (1-3). MSL: 154 (6-3300) mm^2.
Outcomes	Primary outcome Percentage of Px "cured" 6 months after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 6 months Adverse effects Tertiary outcomes None reported
Notes	Sample size: Medium/NC
Risk of bias
Item	Authors' judgement	Description
Blinding? All outcomes	Yes	Double-blind: only stated but not reported who was blinded
Intention-to-treat/Drop-outs?	Yes	8 out of 133 (6%)

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Vélez 1997

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Methods	FU: 12 months. D: Randomised clinical trial
Participants	Colombia ( 11 regions of Colombia in which cutaneous leishmaniasis is endemic: Arma, Dabeiba, Herveo, La Mesa, Marquetalia, Medellin, San Carlos, San Luis, Taraza, Valdivia and Victoria) n=187 Incl: If they were 6 to 60 years of age, had CL as confirmed by the presence of parasites, had not received treatment for leishmaniasis with recognised agents during the previous 6 months, did not have lesions close to the eyes or on the mucosa, had body weight that was appropriate for height, and were amenable to prolonged FU. Excl: The presence of concomitant diseases that required medical intervention, abnormalities in the complete blood count, abnormal glutamate oxoacetate aminotransferase levels, abnormal creatinine levels, abnormal uric acid levels, and pregnancy. Leishmania species: For the 182 analysable Px, 84% (153/182) had documented infection with L. panamensis and 16% (29/182) had infection with L. braziliensis by culture or Gimesa staining. Compliance assessment: Oral therapy was self-administered and compliance self-recorded. At each monitoring session, a 10-day supply of pills was dispensed and the Px's compliance record was checked and verified by counting the number of pills. MA was administered by medical support personnel. However, figures are not reported.
Interventions	T1: Oral AL 300 mg ( three 100-mg tablets) 4 times daily for 28 days, (dosage given was approx 5 mg/kg). N= 60. MNL: 2.8. MDLBT: 3.1 months. T2: Oral placebo, 3 tablets 4 times daily for 28 days. N= 56 (60 ITT). MNL: 3.3. MDLBT: 2.7 months. T3: IMMA, 20 mg/kg/day (no maximum daily dose) for 20 days. N= 66 (67 ITT). MNL: 2.9. MDLBT: 2.6 months.
Outcomes	Primary outcome Percentage of Px "cured" one year after therapy Secondary outcomes Recurrence: duration of remission and/or percentage of people with treated lesions that recur within 1 year Adverse effects Tertiary outcomes None reported
Notes	Sample size: Large/NC
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	After the end of follow-up for the last Px, 3 independent, blinded evaluators determined the efficacy and reached consensus for each Px. The randomisation code was then broken. Toxicity was determined by one evaluator before the code was broken
Blinding? All outcomes	Yes	Partially double-blinded (only Px in the allopurinol and placebo groups were assigned to treatment in a double-blinded manner (Px, study investigators and monitors were blinded)
Intention-to-treat/Drop-outs?	No	30 out of 187 (16%)

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 FU: follow-up; D: design; Px: participants; M/F: male/female ratio; Incl: inclusion criteria; Excl: exclusion criteria; m/f:male/female; T1: treatment 1; T2: Treatment 2; T3: treatment 3; T4: treatment 4; IM: intramuscular; IL: intralesional; IV: intravenous; OD: once daily; TD: twice daily; MNL: Median number of lesions; MSL: Median size of lesions; MDLBT: Median duration of lesions before therapy; GM-CSF: Granulocyte macrophage colony-stimulating factor; MA: meglumine antimoniate; SSG: sodium stibogluconate; AL: allopurinol; PR: paromomycin; MBCL: methylbenzethonium chloride; AS: aminosidine sulphate; PI: pentamidine isethionate; Drop-outs: ND= no drop-outs; Sample size: Small= <50 participants; Medium= 51-150 participants; Large= >150 participants; C: Calculated; NC: Not calculated

 

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Armijos 2004B	Use of vaccines alone
De Luca 1999	Use of vaccines alone
De Luca 2001	Use of vaccines alone
De Luca 2003	Use of vaccines alone
Deps 2000	Method of randomisation inadequate (order of arrival)
Fagundes 2007	A therapeutic but not a clinical trial
Hepburn 1994B	No mention about clinical cure rates but hepatotoxic parameters
Laguna-Torres 1999	In the text they mentioned that 10 Px were randomly distributed into 2 groups. Authors were contacted and clarified that 5 random Px were picked up and assigned to group 1 and another 5 Px picked up randomly were assigned to the other group. Thus, this is a quasi-randomised clinical trial.
Llanos 1991	No mention about clinical cure rates but nephrotoxic parameters
Monjour 1994	Use of vaccines alone
Nascimento 1990	Use of vaccines alone
Oliveira-Neto 2000	Non-comparative although randomised study
Rodriguez 1995	This RCT did not provide cure rates.
Saldanha 2000	No mention about clinical cure rates but hepatotoxic parameters
Soto 1993	Randomisation method of generation of allocation sequence was inadequate. Randomisation of the first 80 Px was accomplished by assigning Px 1, 5, 9, etc., to receive MA; Px 2, 6, 10, etc., to receive pentamidine; Px 3, 7, 11, etc., to receive itraconazole; and Px 4, 8, 12, etc., to receive no treatment. Px 81-92 were randomly assigned to receive MA or pentamidine but we were unable to distinguish the outcomes from these participants.
Soto 1994 A	Method of randomisation inadequate: the first 94 consecutive Px were entered. The first 38 Px constituted group 1. The other 56 Px constituted group 2.
Velez 2005	Use of vaccines alone
Wortmann 2002	Mixed Old World and New World forms of CL

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Characteristics of studies awaiting assessment [ordered by study ID]

Krolewiecki 2007

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Methods	Follow up: one year after completion of treatment
Participants	45 Px from Argentina Species of Leishmania: L. braziliensis was identified in all of them
Interventions	T1: Oral azithromycin, 500 mg/day n=22. T2: IM MA 10 mg Sb/kg/day n=23. Frequency: for 28 days, with a second cycle of 15 days if necessary. All Px who failed treatment with azithromycin were treated with MA and clinically cured.
Outcomes	Efficacy, defined as complete re-epithelization without relapse for 12 months after completing therapy, was 82.6% (95% confidence interval [CI] = 67-98%) for MA and 45.5% (95% CI = 25-66%) for azithromycin. Azithromycin was well tolerated; MA caused arthralgias and local symptoms in 78% of the Px.
Notes	Efficacy, defined as complete healing of all lesions by 6 months after completing therapy, was miltefosine 82% (36/44) and IM MA 83% (15/18). During therapy, the primary adverse event for the miltefosine group was gastrointestinal symptoms, experienced by 27/44 (61%) of Px for a median of 3 days (range 1-10 days). For the MA group, 13/18 (72%) of Px reported arthralgias and/or local pain at the injection site for a median of 7 days (range 5-14 days).

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Soto 2008

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Methods	Follow up: one year after completion of treatment
Participants	62 Px from Bolivia 25-30 years of age with a median of 1 ulcer per Px with an average area of 300mm^2. Species of Leishmania: L. braziliensis in the area Drop-outs: 5/62 (8%)
Interventions	T1: Miltefosine orally 2.5 mg/kg daily for 28 days n=44 T2: IMMA at 20 mg/kg/d for 20 days n=18
Outcomes	Six months after end of therapy, cure rates were of 88% (36/41) in the miltefosine group and of 94% (15/16) in the IMMA group. Speed of healing: more rapid in the IMMA group. Adverse effects: gastrointestinal in the miltefosine group and arthralgias and/or local pain in the injection site in the IMMA group.
Notes

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 Px= participants

 

Characteristics of ongoing studies [ordered by study ID]

NCT00004755

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Trial name or title	Phase II Randomized Study of Allopurinol Versus Glucantime Versus Allopurinol/Glucantime for Cutaneous Leishmaniasis in Brazil
Methods	Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study
Participants	Total Enrollment: 375 Participants are followed at 3, 6, and 9 months, then annually for at least 5 years. Ages Eligible for Study: 12 Years and above, Genders Eligible for Study: Both Criteria PROTOCOL ENTRY CRITERIA: --Disease Characteristics-- Parasitologically confirmed cutaneous leishmaniasis (lesion of < 3 months duration) No mucocutaneous leishmaniasis No prior leishmaniasis --Prior/Concurrent Therapy-- No prior treatment for leishmaniasis --Px Characteristics-- Hepatic: No clinical or laboratory evidence of hepatic disease Renal: No clinical or laboratory evidence of renal disease No hyperuricaemia or gout Cardiovascular: No clinical, electrocardiographic, or laboratory evidence of cardiac disease Other: No allergy or other contraindication to allopurinol or glucantime; No concurrent medication that might interact with study drugs, e.g.: probenecid, warfarin, azathioprine; No skin rash; No malnutrition; No other medical contraindication to protocol therapy; No pregnant or nursing women
Interventions	Group 1: IMMA daily. Px with less than a complete response on Day 21 continue treatment until lesions heal completely or for a maximum of 60 days. Px with progressive disease on Day 40 are removed from study. Group 2: Daily oral allopurinol. Px with a partial response on Day 21 continue treatment until lesions heal completely. Px with stable or progressive disease on Day 21 or unhealed lesions on Day 56 cross to glucantime therapy. Accrual into this group was closed in 6/96. Group 3: Oral allopurinol plus IMMA
Outcomes	Not reported
Starting date	Study start: September 1995 Study completed
Contact information	James H. Maguire, Study Chair, Harvard School of Public Health More Information Study ID Numbers: 199/11679; HSPH-11679 Last Updated: June 23, 2005 Record first received: February 24, 2000 ClinicalTrials.gov Identifier: NCT00004755 Health Authority: United States: Federal Government
Notes

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NCT00111514

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Trial name or title	A Phase 1, Randomised, Double-Blind, Placebo-Controlled, Dose-Escalating Study to Evaluate Safety, Tolerability, and Immunogenicity of Leish-111f + MPL-SE Vaccine in Combination With Pentavalent Antimony in Treatment of Mucocutaneous Leishmaniasis
Methods	Treatment, Randomised, Double-Blind, Placebo Control, Parallel Assignment, Safety Study
Participants	Total Enrollment: 48 Ages Eligible for Study: 18 Years - 60 Years, Genders Eligible for Study: Both Inclusion Criteria: Px with mucocutaneous leishmaniasis confirmed by a positive smear, in vitro culture or PCR test Exclusion Criteria: Mucocutaneous leishmaniasis must not involve the vocal cords or cause respiratory distress, and there must be no evidence of other disease
Interventions	This study is a phase 1, randomised, double-blind, placebo controlled, sequential dose-escalating trial to evaluate the safety and immunogenicity of three injections of 5, 10, or 20 µg of Leish-111f protein + 25 µg of MPL-SE adjuvant given at 4 week intervals as an adjunct to standard chemotherapy with pentavalent antimony (20 mg/kg/day for 28 days) in Px with mucocutaneous leishmaniasis
Outcomes	Further study details as provided by Infectious Disease Research Institute: Primary Outcome Measures: Occurrence of dose-limiting toxicity Adverse events Secondary Outcome Measures: IgG and T-cell response to Leish-111f vaccine Leish-111f skin test reactivity Safety of the vaccine with respect to the clinical course of mucocutaneous leishmaniasis
Starting date	Study start: July 2004 Study completed
Contact information	Universidad Peruana Cayetano Heredia, Lima, 100, Peru Clínica de Leishmaniasis, Hospital Nacional Sur Este EsSalud, Cusco, Peru Study chairs or principal investigators Alejandro Llanos-Cuentas, MD, Principal Investigator, Universidad Peruana Cayetano Heredia Franco M Piazza, MD, MPh, Study Director, Infectious Disease Research Institute More Information Study ID Numbers: IDRI-LMVTC-102 Last Updated: February 13, 2007 Record first received: May 20, 2005 ClinicalTrials.gov Identifier: NCT00111514 Health Authority: Peru: General Directorate of Pharmaceuticals, Devices, and Drugs; United States: Food and Drug Administration
Notes

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NCT00111553

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Trial name or title	Randomised, Double-Blind, Adjuvant- and Placebo-Controlled, Dose-Escalating Study to Evaluate Safety, Tolerability, and Immunogenicity of Leish-111f + MPL-SE Vaccine With Meglumine Antimoniate (Glucantime) in Cutaneous Leishmaniasis
Methods	Treatment, Randomised, Double-Blind, Active Control, Parallel Assignment, Safety Study
Participants	Total Enrollment: 45 Ages Eligible for Study: 18 Years - 60 Years, Genders Eligible for Study: Both Inclusion Criteria: Confirmed diagnosis of cutaneous leishmaniasis defined as positive identification of parasite from lesion biopsy Normal lab values and electrocardiogram (ECG) Negative for HIV, hepatitis B and C, and Chagas disease Exclusion Criteria: Nine or more active cutaneous lesions Lesion diameter >60 mm Previous exposure to Leishmania vaccines or to MPL-SE Pregnant or breast feeding female
Interventions	This study is a phase 1, randomised, double-blind, placebo controlled, sequential dose-escalating trial to evaluate the safety and immunogenicity of three injections of 5, 10, or 20 µg of Leish-111f protein + 25 µg of MPL-SE adjuvant given at 4 week intervals as an adjunct to the standard chemotherapy with Glucantime cycles, as described above in Px with CL.
Outcomes	Further study details as provided by Infectious Disease Research Institute: Primary Outcome Measures: Occurrence of dose limiting toxicity Adverse events Secondary Outcome Measures: IgG and T-cell response to Leish-111f vaccine Leish-111f skin test reactivity Safety of the vaccine with respect to the clinical course of cutaneous leishmaniasis
Starting date	Study start: October 2004 Study completed
Contact information	Study chairs or principal investigators Evaldo Nascimento, MD, Principal Investigator, Universidade Federal de Minas Gerais Franco M Piazza, MD, MPH, Study Director, Infectious Disease Research Institute (IDRI) More Information Study ID Numbers: IDRI-LCVTC-101 Last Updated: February 13, 2007 Record first received: May 23, 2005 ClinicalTrials.gov Identifier: NCT00111553 Health Authority: United States: Food and Drug Administration; Brazil: Committee of Ethics in Research
Notes

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NCT00121862

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Trial name or title	A Study to Evaluate the Safety, Tolerability, and Immunogenicity of the Leish-111f + MPL-SE Vaccine Compared to the Leish-111f Protein Alone in Montenegro Skin Test-Negative Healthy Adults
Methods	Prevention, Randomised, Double-Blind, Placebo Control, Parallel Assignment, Safety Study
Participants	Total Enrollment: 60 Ages Eligible for Study: 18 Years - 40 Years, Genders Eligible for Study: Both Accepts Healthy Volunteers Inclusion Criteria: Must have negative Montenegro skin test (0 mm) Must be in good general health with normal lab values Negative for HIV, hepatitis B and C Exclusion Criteria: History of leishmaniasis or exposure to Leishmania vaccine or MPL-SE Nursing or pregnant female
Interventions	The vaccine, identified as Leish-111f + MPL-SE, consists of a recombinant three-antigen Leishmania polyprotein (Leish-111f, 10 µg) together with the adjuvant MPL-SE (25 µg). In addition, the safety and immunogenicity of the vaccine will be compared to that of the Leish-111f protein (10 µg) given alone. The vaccine, Leish-111f protein alone or placebo will be given to each study subject three times at 4 week intervals.
Outcomes	Further study details as provided by Infectious Disease Research Institute: Primary Outcome Measures: Adverse events Dose-limiting toxicities: hematology and serum chemistry evaluations at Screening, Days 7, 35, 63, 84 T-cell IFN-γ response to the Leish-111f protein: immunology evaluations at Days 0, 84, 168 Secondary Outcome Measures: T-cell IL-5 response to the Leish-111f protein Antibody responses to the Leish-111f protein Skin test reactivity to the Leish-111f protein at Days 84, 168
Starting date	Study start: August 2005 Study completed
Contact information	Franco M Piazza, MD, MPH, Study Director, Infectious Disease Research Institute More Information Study ID Numbers: IDRI-LCVPX-201 Last Updated: May 4, 2006 Record first received: July 18, 2005 ClinicalTrials.gov Identifier: NCT00121862 Health Authority: United States: Food and Drug Administration; Colombia: INVIMA Instituto Nacional de Medicamentos y Alimentos
Notes

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NCT00233545

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Trial name or title	Miltefosine to Treat Cutaneous Leishmaniasis in Bolivia
Methods	Treatment, Randomised, Open Label, Active Control, Parallel Assignment, Efficacy Study
Participants	Puesto de Salud, Campamento OSCAR,, Palos Blancos,, Bolivia Total Enrollment: 80 Ages Eligible for Study: 3 Years and above, Genders Eligible for Study: Both Criteria Presentation: At least 1 lesion must be ulcerative. Parasitology: Parasitological confirmation of 1 lesion will be made by visualization or culture of leishmania from the biopsy or aspirate of the lesion. Previous RX: No specific or putatively specific therapy for leishmaniasis (Sb, pentamidine, amphotericin B, imidazoles, allopurinol) Other diseases: No concomitant diseases by history and by approximately normal complete blood counts (white blood count, haemoglobin, platelet count), values of liver transaminases (SGOT) and kidney function tests (creatinine).
Interventions	Standard dose regimens will be used for both drugs.
Outcomes	Primary Outcome Measures: cure rate
Starting date	Study start: September 2005
Contact information	J Soto, MD, Principal Investigator, FADER More Information Study ID Numbers: 01-2005 Last Updated: September 18, 2006 Record first received: September 28, 2005 ClinicalTrials.gov Identifier: NCT00233545 Health Authority: Bolivia: Ethics Committee
Notes

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NCT00257530

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Trial name or title	Randomised Double Blind Clinical Trial of Imiquimod (Aldara) Versus Placebo Used in Combination With Pentavalent Antimony (Glucantime) in Peruvian Cutaneous Leishmaniasis Patients
Methods	Treatment, Randomised, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study
Participants	Total Enrollment: 80 Ages Eligible for Study: 5 Years - 65 Years, Genders Eligible for Study: Both Inclusion Criteria: Males/Females between 5 and 65 yrs CL diagnosis confirmed >4 weeks time disease no prior anti-leishmanial therapy for CL negative pregnancy test informed written consent or parent consent for <18yrs Px Exclusion Criteria: >25cm2 lesion(s) >6 cutaneous lesions mucocutaneous lesion previous exposure to Imiquimod or anti-leish treatment participation in another protocol within 30 days prior study other acute or chronic illness / medication that may interfere significant psychiatric illness anaphylaxis or severe allergic reaction to proposed drugs Px unlikely to cooperate concomitant infection pregnancy or breast feeding
Interventions	Not reported
Outcomes	Further study details as provided by Drugs for Neglected Diseases: Primary Outcome Measures: Time to healing Reduction of scaring Secondary Outcome Measures: Safety (measured by AE reporting) during treatment and follow up to 12 months
Starting date	Study start: November 2005 Study completed
Contact information	Please refer to this study by ClinicalTrials.gov identifier NCT00257530 Alejandro Llanos-Cuentas, Dr [phone] [e-mail] Peru UPCH, Cusco, Peru Alejandro Llanos-Cuentas, Dr [phone] IMT Alexander Von Humboldt, Lima, Peru Alejandro Llanos-Cuentas, Dr [phone] Study ID Numbers: DNDi-IMQ-05 Last Updated: November 22, 2005 Record first received: November 22, 2005 ClinicalTrials.gov Identifier: NCT00257530 Health Authority: Peru: UPHC (Universidad Peruana Cayetano Heredia); Canada: McGill University; Switzerland: Drugs for Neglected Diseases initiative
Notes

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NCT00317629

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Trial name or title	Double Blind, Randomised Controlled Trial, to Evaluate the Effectiveness of a Controlled Nitric Oxide Releasing Patch Versus Meglumine Antimoniate in the Treatment of Cutaneous Leishmaniasis
Methods
Participants	Double Blind, Randomised Controlled Trial, to Evaluate the Effectiveness of a Controlled Nitric Oxide Releasing Patch Versus MA in the Treatment of CL
Interventions	Group 1: During 20 days this group will receive simultaneously IMMA (Glucantime® 20 mg/kg/day with a maximum dose of 3 ampoules per day); and a NOP placebo. Group 2: During 20 days this group will receive simultaneously placebo of IMMA (5-15cc/day) and an active NOP.
Outcomes	Further study details as provided by Fundación Cardiovascular de Colombia: Primary Outcome Measures: Complete reepithelization three months after the beginning of the treatment Absence of reactivation and affections of the mucous membranes during the 6 months of the study Secondary Outcome Measures: Incomplete reepithelization three months after the beginning of the treatment Increase in the size of the ulcer by more than 50% in relation to the last clinical evaluation Reactivation and/or affections of the mucous membranes during the 6 months of the study
Starting date	Study start: May, 2006
Contact information	Please refer to this study by ClinicalTrials.gov identifier NCT00317629 Patricio López-Jaramillo, MD, PhD [phone] Ext. 331 [e-mail] Federico A Silva, MD [phone] Ext. 345 [e-mail] Study ID Numbers: fcv137 Last Updated: May 31, 2006 Record first received: April 21, 2006 ClinicalTrials.gov Identifier: NCT00317629 Health Authority: Colombia: Cardiovascular Foundation of Colombia; United States: University of Akron; Colombia: University of Antioquia; Colombia: University of Santander
Notes

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NCT00317980

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Trial name or title	Phase IV Randomised Controlled Clinical Trial to Evaluate the Safety and Efficacy of Low-Dose Pentavalent Antimony Compared to the Standard Dose in Patients With Cutaneous Leishmaniasis Caused by Leishmania (Viannia)Braziliensis
Methods	Treatment, Randomised, Single Blind, Active Control, Parallel Assignment, Safety/Efficacy Study
Participants	Total Enrollment: 324 Ages Eligible for Study: 7 Years - 50 Years, Genders Eligible for Study: Both Accepts Healthy Volunteers Inclusion Criteria: Presence of 1 to 9 cutaneous lesions clinically compatible with leishmaniasis Disease duration of 2 to 20 weeks Positive leishmanin skin test Parasitological diagnosis confirmed through culture or genus-specific polymerase chain reaction (PCR) for Leishmania spp Exclusion Criteria: History of past episode of leishmaniasis Mucocutaneous disease Disseminated disease Use of drugs with anti-leishmanial activity Contraindications for using pentavalent antimony: pregnancy renal failure heart failure hepatic failure Other diseases: active tuberculosis, hanseniasis
Interventions	Group1: IVMA (calculated dose based on the concentration of pentavalent antimony) 5 mg/kg/d Group2: IVMA (calculated dose based on the concentration of pentavalent antimony) 15 mg/kg/d Frequency: for 20 days.
Outcomes	The clinical outcomes of cure or failure will be evaluated until the third month of follow-up Primary Outcome Measures: Proportion of clinically cured Px at the third month after treatment Proportion of Px with early failure during the first 3 months after treatment Secondary Outcome Measures: Proportion of Px with adherence to the protocol prescribed drug Proportion of Px with adverse events Proportion of Px with late failure after the first 3 months of follow-up
Starting date	Study start: February 2006 Study completed
Contact information	Gustavo S Romero, MD, Principal Investigator, University of Brasilia Study ID Numbers: NMT-LD-CP-2006 Last Updated: February 5, 2007 Record first received: April 21, 2006 ClinicalTrials.gov Identifier: NCT00317980 Health Authority: Brazil: National Health Surveillance Agency
Notes

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NCT00469495

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Trial name or title	Empiric Antihelminthic Therapy Combined With Antimony in the Treatment of Cutaneous Leishmaniasis: A Randomised Controlled Trial in Subjects Co-Infected With Helminths and Leishmania Brasiliensis
Methods	Treatment, Randomised, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study
Participants	Number of arms in study: 2 Total Enrollment: 90 Ages Eligible for Study: 13 Years - 50 Years, Genders Eligible for Study: Both Inclusion Criteria: Subjects with a diagnosis of CL based on the presence of typical skin lesions and a positive Montenegro skin test Evidence of helminthic infection by parasitological examination of first stool sample Males or females between 13 and 50 years of age Maximum of 3 ulcers with no more than 2 body regions involved Period of 15 to 60 days from the onset of the first ulcer Subject agreement to follow-up visits and therapy Ability to give informed consent Exclusion Criteria: Pregnancy Breast feeding mothers Presence of mucocutaneous disease History of prior treatment with antimonial drugs. History of prior treatment with anthelminthic drugs within the last 6 months. History of allergy to pentavalent antimony or antihelminthic Presence of underlying disease which affects the immune response, such as HIV and diabetes mellitus
Interventions	Not reported
Outcomes	Further study details as provided by Hospital Universitário Professor Edgard Santos: Primary Outcome Measures: Bidirectional measurements will be taken of the subjects’ lesions at each visit and will be categorized as active or healed by a dermatologist. [Time Frame: 90 days]
Starting date	Study start: February 2007
Contact information	Please refer to this study by ClinicalTrials.gov identifier NCT00469495 Edgar M Carvalho, MD 212-746-6320 [e-mail] Marshall J Glesby, MD, PhD 212-746-6320 [e-mail] Study ID Numbers: 0701008939 Last Updated: May 2, 2007 Record first received: May 2, 2007 ClinicalTrials.gov Identifier: NCT00469495 Health Authority: Brazil: Committee of Ethics in Research; United States: Institutional Review Board
Notes

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NCT00471705

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Trial name or title	Phase 3 Open-Label Study of Efficacy and Safety of Miltefosine vs Glucantime for Cutaneous Leishmaniasis in Colombia.
Methods	Treatment, Randomised, Open Label, Active Control, Single Group Assignment, Safety/Efficacy Study In this phase III, randomised open trial, subjects meeting inclusion criteria of the trial will be randomly allocated into two groups according to a randomisation list.
Participants	Number of arms in study: 2 Total Enrollment: 288 Sample size The sample was calculated using a power of 80%, confidence of 95% establishing important differences from 12%. We expect a successful rate of 90% meglumine antimoniate (Glucantime®) and 78% for miltefosine. We calculated that 288 will be needed. Population CL in is a remerging disease in Colombia affecting civilian and military population as well, sharing the same epidemiologic characteristics. The selected population will be composed from National Army of Colombia soldiers from CL endemic areas (Caquetá, Meta, Guaviare, Putumayo, Córdoba, Antioquia and Chocó). Withdrawal criteria: A serious adverse event occurs Withdrawal of the consent Withdrawn cases will be treated according to the investigators opinion and beneficial of the participants at no cost. All withdrawn Px will be evaluated in final analysis (intent-to-treat analysis). Ages Eligible for Study: 18 Years - 40 Years, Genders Eligible for Study: Male Inclusion Criteria: Parasitologically proven cases of CL based on positive smear and/or culture. Px belonging to the National Colombian Army. Otherwise healthy subjects on the basis of medical history, physical examination and results of blood test (if seemed necessary by the physician) Age 18-40 years. Willing to participate in the study, sign the informed consent , to go to the scheduled visits and to the follow-up visits. Abstain to receive any other treatment for CL during the trial and follow-up periods. Non purulent lesions. Mentally sane volunteers. No Leishmaniasis treatment in the six months prior to the recruitment. Number of lesions no more than 5 Exclusion criteria: None of the lesions must be close to the anal, oral and nasal mucosa, or next to the urogenital and anal canal. Serious systemic illnesses (as judged by the physician) Px with mucocutaneous compromise. Px with diffuse Leishmaniasis (defined as 10 or more cutaneous lesions and negative Montenegro's test)
Interventions	Group 1:150 mg/day of oral miltefosine for 28 days Group 2: 20 mg/kg/day IMMA for 20 days.
Outcomes	Primary Outcome Measures: Clinical response:Complete re-epithelization of all lesions with disappearance of induration (with or without scar). No parasitological evaluation will be done on clinically cured lesions determined until 45 days posttreatment. [Time Frame: Until 45 days posttreatment] Secondary Outcome Measures: Treatment failure: No change or increase in the size of induration and ulcer. [Time Frame: Until 45 days posttreatment] Absence of clinical response: Induration and ulcer area =50% compared with the immediately previous evaluation. [Time Frame: Until 45 days posttreatment]
Starting date	Study start: June 2006
Contact information	Please refer to this study by ClinicalTrials.gov identifier NCT00471705 Laureano Mestra, MD. [phone] [e-mail] Liliana López, BSc. [phone] [e-mail] Study ID Numbers: PECET001 Last Updated: May 8, 2007 Record first received: May 7, 2007 ClinicalTrials.gov Identifier: NCT00471705 Health Authority: Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos; Colombia: Ministry of Social Protection.
Notes

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NCT00487253

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Trial name or title	Randomized Clinical Trial of the Efficacy and Tolerability of Oral Miltefosine Versus Parenteral Antimony for the Treatment of Pediatric Cutaneous Leishmaniasis in Colombia
Methods	Interventional Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Participants	Ages Eligible for Study: 2 Years - 12 Years, Genders Eligible for Study: Both, Accepts Healthy Volunteers: No Inclusion Criteria: 2 to 12 years of age (inclusive) Parasitologically confirmed CL Availability to receive supervised treatment for 28 days (i.e., directly observed therapy, to ensure the therapy is appropriately administered and received - e.g., the miltefosine is "swallowed") Availability to return for follow-up visits for at least 6 months after treatment is initiated Exclusion Criteria: Weight under 10kg Previous use of SbV, miltefosine or other antileishmanial therapy Simultaneous mucosal lesions suggestive of or proven to be mucosal leishmaniasis If a girl, ability to reproduce (history of menarche) Relative or absolute contraindications for the use of SbV drugs or miltefosine, including history of cardiac, renal or hepatic disease Patients with pretreatment haemoglobin <10g/dl or blood urea nitrogen (BUN), serum creatinine, ALT, AST or amylase values that exceed the upper limit of normal If living in Malaria endemic areas (eg. Tumaco) only: A positive malaria thick smear
Interventions	Estimated Enrollment: 150
Outcomes	Primary Outcome Measures: The primary outcome measure will be the proportion of "Therapeutic Failures" diagnosed during the final (week 26) visit or before, according to defined clinical criteria. [ Time Frame: 26 weeks (6 months) ] Evidence of clinical or laboratory toxicity during the treatment period. [ Time Frame: During the treatment period (20 or 28 days) ] Secondary Outcome Measures: Proportion of patients with "parasitologic" response 26 weeks after the initiation of treatment. [ Time Frame: 26 weeks ]
Starting date	Study Start Date: July 2007
Contact information	Please refer to this study by ClinicalTrials.gov identifier NCT00487253 Maria Consuelo Miranda, MD, MSc (571)6682164 ext 216 [e-mail]; Isabel Rodriguez, MD (571)6682164 ext 307 [e-mail]; Study ID Numbers: 50100119; Study First Received: June 14, 2007; Last Updated: July 26, 2007; ClinicalTrials.gov Identifier: NCT00487253; Health Authority: Colombia: Institutional Review Board
Notes

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NCT00537953

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Trial name or title	EFFICACY AND SAFETY OF A SHORT COURSE OF THE COMBINATION OF MILTEFOSINE AND ANTIMONY TO TREAT CUTANEOUS LEISHMANIASIS IN BOLIVIA
Methods	Interventional Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Participants	Ages Eligible for Study: 18Years - 65 Years, Genders Eligible for Study: Male, Accepts Healthy Volunteers: No Inclusion Criteria: Gender: Male Age: Adults Presentation: At least 1 lesion must be ulcerative. Parasitology: Parasitological confirmation of 1 lesion will be made by visualization or culture of leishmania from the biopsy or aspirate of the lesion. Exclusion Criteria: Previous treatment for leishmaniasis, specific or putatively specific therapy (Sb, pentamidine, amphotericin B, imidazoles, allopurinol) Other concomitant diseases by history and by approximately normal complete blood counts (white blood count, hemoglobin, platelet count), values of liver transaminases (SGOT), values of pancreatic function (lipase), kidney function tests (creatinine), and EKG.
Interventions	Not reported
Outcomes	Not reported
Starting date	Not reported
Contact information	Jaime Soto, MD 571 348 2171 [e-mail] Julia Toledo, MD 571 347 6093 [e-mail] Study ID Numbers: 2007-Bol/LC-1339 Study First Received and Last updated: September 28, 2007 ClinicalTrials.gov Identifier: NCT00537953 Health Authority: Bolivia: Ministry of Health
Notes

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NCT00600548

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Trial name or title	Clinical Trial to Assess Efficacy and Safety of Orally Administered Miltefosine in Brazilian Patients With Cutaneous Leishmaniasis Compared to the Standard Care as Active Control
Methods	Interventional Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Participants	Estimated Enrollment: 180 Ages Eligible for Study: 2 Years - 65 Years, Genders Eligible for Study: Both, Accepts Healthy Volunteers: No Inclusion Criteria: Newly diagnosed (untreated) cutaneous leishmaniasis with localized lesions and visualization of amastigotes in tissue samples or a positive culture or diagnosed by polymerase chain reaction (PCR) methods or by intradermal skin testing (Montenegro test). Number of lesions: 1 to 5 ulcerative lesions. Lesion´s diameter: 1 to 5 cm. Disease duration: up to three months. Exclusion Criteria: Safety concerns: Thrombocyte count <30 x 109/l Leukocyte count <1 x 109/l Hemoglobin <5 g/100 ml ASAT, ALAT, AP >3 times upper limit of normal range Bilirubin >2 times upper limit of normal range Serum creatinine or BUN >1.5 times upper limit of normal range Evidence of serious underlying disease (cardiac, renal, hepatic or pulmonary) Immunodeficiency or antibody to HIV Any non-compensated or uncontrolled condition, such as active tuberculosis, malignant disease, severe malaria, HIV, or other major infectious diseases Lactation, pregnancy (to be determined by adequate test) or inadequate contraception in females of childbearing potential for treatment period plus 2 months Lack of suitability for the trial: Negative parasitology (aspirate/smear)or negative Montenegro test Any history of prior anti-leishmania therapy Any condition which compromises ability to comply with the study procedures Concomitant serious infection other than cutaneous Administrative reasons: Lack of ability or willingness to give informed consent (patient and/or parent / legal representative) Anticipated non-availability for study visits/procedure
Interventions	Cutaneous leishmaniasis patients in Manaus-Amazonas: Group1: Miltefosine: Capsules containing 10 mg or 50 mg miltefosine; administered orally for 28 days at dosage of 2.5 mg/kg body weight per day. Group 2: Meglumine antimoniate administered by intravenous route for 20 days at the dosage of 20mg/kg/day. Cutaneous leishmaniasis patients in Corte de Pedra-Bahia: Group 1: same as above Group2: same as above
Outcomes	Primary Outcome Measures: Cure rate or complete cicatrization of the ulcer. [ Time Frame: 6 months after treatment. ] [ Designated as safety issue: Yes ] Secondary Outcome Measures: Inicial cure rate or complete cicatrization of the ulcer. [ Time Frame: 2 months after treatment. ] [ Designated as safety issue: Yes ]
Starting date	Study Start Date: March 2007
Contact information	Principal Investigator: Paulo RL Machado, MD, PhD Responsible Party: Universidade Federal da Bahia Study ID Numbers: D-18506, 410559/2006-7 Study First Received: January 2, 2008 Last Updated: November 12, 2008 ClinicalTrials.gov Identifier: NCT00600548 Health Authority: Brazil: Universidade Federal da Bahia;   Brazil: Fundação de Medicina Tropical do Amazonas;   Brazil: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq);   Brazil: Ministério da Ciência e Tecnologia
Notes

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NCT00682656

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Trial name or title	Open Label Randomized Study to Assess Safety and Efficacy of Azithromycin Versus Meglumine Antimoniate to Treat Cutaneous Leishmaniasis
Methods	Interventional Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Participants	Ages Eligible for Study: 14 Years - 65 Years, Genders Eligible for Study: Both, Accepts Healthy Volunteers: No Estimated Enrollment: 620 Inclusion Criteria: Patients older than 14 and younger than 65 years old Skin lesions with clinical suggestion of cutaneous leishmaniasis and positive leishmanin skin test (Montenegro test) Agreement to participate in the study and signed the informed consent Exclusion Criteria: Diabetes mellitus, kidney diseases, liver or cardiac diseases, tuberculosis, malaria. Pregnancy Breast feeding Cutaneous lesion with bacterial infection for which antibiotics need to be prescribed More than six cutaneous lesions Previous history of cutaneous or mucosal leishmaniasis Use of drugs with potential pharmacological interactions with antimonials as anti-arrhythmic or tricycle anti-depressives Previous intolerance to azithromycin or other macrolides or N-metilglucamine Abusive alcohol ingestion according to the CAGE questionnaire
Interventions	Group1: metil glucamine (Glucantime®-Aventis) 15mg Sb+5/Kg/day, during 20 days. Maximum dose: 15ml/day Group 2: Azithromycin (Zitromax®/ Pfizer) 500 mg per os 1x day, during 20 days
Outcomes	Primary Outcome Measures: Proportion of clinically cured patients [ Time Frame: at the third month after treatment ] [ Designated as safety issue: No ] Secondary Outcome Measures: Proportion of patients with failure [ Time Frame: twelve months after treatment ] [ Designated as safety issue: No ] Occurrence of mucosal lesions after treatment [ Time Frame: twelve months after treatment ] [ Designated as safety issue: No ] Proportion of patients presenting new lesions [ Time Frame: 1st 2nd 3rd 6th 12th month after treatment ] [ Designated as safety issue: No ] Proportion of adverse events on each treatment group [ Time Frame: 1st 2nd 3rd 6th 12th month after treatment. ] [ Designated as safety issue: Yes ]
Starting date	Study Start Date: June 2008
Contact information	Ana Rabello, MD, PhD 55-31-3349-7708 [e-mail] Mariana Pedras 55-31-3349-7712 [e-mail] Responsible Party: Fundação Oswaldo Cruz Study ID Numbers:CEPSH/CPqRR 21/2006 Study First Received:May 20, 2008 Last Updated: October 8, 2008 ClinicalTrials.gov Identifier: NCT00682656 Health Authority: Brazil: National Health Surveillance Agency
Notes

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 Px= participants

 

Comparison 1. IMMA (20 mg/kg/d for 20 d) vs placebo (3 tablets/4 times a day for 28 d) in L. braziliensis and L. panamensis; FU: 3 months and 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	2	157	Risk Ratio (M-H, Random, 95% CI)	4.23 [0.84, 21.38]

---

 

Comparison 2. 10-day IMMA versus 20-day IMMA in L. braziliensis and L. panamensis; FU: 1 year

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Anorexia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Headache

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Myalgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Malaise

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.5 Arthralgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 3. IVMA 20 mg/kg/d for 15 d vs no treatment in L. panamensis; FU: 12 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Relapses	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 4. IVMA for 7 days + placebo topically TD for 10 d vs IVMA for 20 d in L. braziliensis & L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 5. IVMA 15% (14 mg/kg/d) vs IVMA 30% (28 mg/kg/d) ; FU: 2 years

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure (CL plus MCL)	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Complete cure CL form	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
3 complete cure MCL form	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 6. 10-day IVMA+ 10-day placebo versus 20-day IVMA in L. braziliensis and L. mexicana; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 7. IMSSG 20 mg/kg/d for 20d vs IMMA (20 mg/kg/d for 20d) in L. panamensis; FU: 6 months

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Myalgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Headache

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Metallic taste

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Abdominal pain

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 8. IMSSG (branded) vs IMSSG (generic). Dose: 20 mg/kg/d for 20 d in L .panamensis; FU: 6 months

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Myalgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Headache

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Metallic taste

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Abdominal pain

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 9. IVSSG for 28 days versus IVSSG for 40 days in L. braziliensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 10. Oral ketoconazole for 28 days versus IMMA for 20 days in L. panamensis and L. mexicana; FU: 3 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 11. Oral ketoconazole versus oral placebo for 28 days in L. panamensis and L. mexicana; FU: 3 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 12. Oral AL 20 mg/kg/d (4 doses) for 15d vs. AL + IVMA (same regimen) in L. panamensis; FU: 12 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Relapses	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 13. Oral AL 20 mg/kg/d (4 doses) x 15d vs. IVMA (same regimen) in L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Relapses	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 14. Oral AL + IVMA (20 mg/kg/d (4 doses) for 15d) vs. IVMA (same regimen) in L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Relapses	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 15. Oral AL for 28d vs IMMA 20mg/kg/d for 20 d in L braziliensis and L. panamensis ; FU: 12 month

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 16. Oral AL + IVSSG (20 mg/kg/d (4 doses) x 15d) vs IVSSG (same dose) in L. braziliensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Oral AL plus IV antimonials vs. IV antimonials	2	168	Risk Ratio (M-H, Random, 95% CI)	1.90 [1.40, 2.59]

---

 

Comparison 17. Oral AL + IVSSG (20 mg/kg/d (4 doses) for 28d) vs IVSSG (same dose); FU: 12 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 18. Oral AL 20 mg/kg/d (4 doses) for 15 d vs no treatment in L. panamensis; FU: 12 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Relapses	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 19. Oral AL 28 days versus placebo in L. braziliensis and L. panamensis; FU: 12 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 20. Oral AL + IVMA (20 mg/kg/ d in 4 doses for 15d) vs no treatment in L. panamensis; FU: 12 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 Relapses	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 21. Oral miltefosine 50 mg for 28 d vs. placebo (same regimen) in L. mexicana, L. panamensis and L. braziliensis; FU: 6 months

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

1.1 Colombia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

1.2 Guatemala

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Nausea

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Motion sickness

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Headache

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Vomiting

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.5 Diarrhoea

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.6 Creatinine

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.7 Aspartate aminotransferase

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.8 Alanine aminotransferase

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 22. Different regimens of IMAS in L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 AS 12-g base x 7 days versus AS 12-g base x 14 days	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 AS 12-g base x 7d versus AS 18-g base for 14 d	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
3 AS 12-g base x 14 d versus AS 18-g base x 14 d	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 23. IMAS for 20 days versus IMMA for 20 days in L. braziliensis; FU: 1 year

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Myalgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Anorexia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Asthenia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Arthralgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 24. IMAS for 20 days versus IMPI x 8 applications in L. braziliensis; FU: 1 year

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Myalgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Anorexia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Asthenia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Arthralgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 25. IM Aminosidine20 mg/kg/d for 28 d vs IVMA 20 mg/kg for 28 d; L. braziliensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 26. IVPI for seven doses versus IVMA for 20 days in L. braziliensis; FU: 6 months

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Gastrointestinal events

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Musculoskeletal events

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Headache

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 27. IMPI versus IMMA for 20 days in L. braziliensis; FU: 1 year

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Myalgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Anorexia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Asthenia

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Arthralgias

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 28. Topical PR-MBCL TD for 20d vs placebo TD for 20d in L. panamensis and L. mexicana; FU: 12 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 29. Topical PR-MBCL (TD x 10d) + IVMA x 7 d vs Placebo + IVMA x 7 d in L. braziliensis and L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 30. Topical PR-MBCL (TD x 10d) + IVMA x 7 d vs PR-MBCL + IVMA x 3 d in L. braziliensis and L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 31. Topical PR-MBCL (TD x 10d) + IVMA x 3 d vs Placebo + IVMA x 7 d in L. braziliensis and L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 32. Topical PR-MBCL (TD x 10d) + IVMA x 7 d vs IVMA for 20 d in L. braziliensis and L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 33. Topical PR-MBCL (TD x 10d) + IVMA x 3 d vs IVMA for 20 d in L. braziliensis and L. panamensis; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 34. Vaccine vs IMMA (50 mg/kg in 2-3 series of 20 daily injections) in L. braziliensis; FU: 6 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	2	277	Risk Ratio (M-H, Random, 95% CI)	0.96 [0.90, 1.04]

---

 

Comparison 35. BCG vs. IMMA in L. braziliensis; FU: 6 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 36. Oral pentoxifylline 400 mg 3 times daily for 30d + IVSSG 20 mg/kg /d vs. placebo + IVSSG in L. braziliensis; FU: 4 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 37. 7.5% imiquimod cream x 20 days plus IVMA for 20 days versus IVMA x 20 days in L. braziliensis, L. peruviana, L. mexicana and L. amazonensis; FU: 3 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 38. Topical imiquimod 5% + IVMA vs placebo + IM/IVMA in L. braziliensis and L. peruviana; FU: 1 year

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 Complete cure

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

 2 Adverse effects

1

Risk Ratio (M-H, Random, 95% CI)

Totals not selected

---

2.1 Edema

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.2 Itching

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.3 Burning

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

2.4 Erythema

1

Risk Ratio (M-H, Random, 95% CI)

Not estimable

---

 

Comparison 39. 7.5% imiquimod cream x 20 days versus IVMA x 20 days in L. braziliensis, L. peruviana, L. mexicana and L. amazonensis; FU: 3 months

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete cure	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Comparison 40. IVMA combined or in different regimens in L. braziliensis and L. mexicana; FU: 1 year

---

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 10-day IV MA+10-day IFN-γ versus 10-day IV MA+10-day placebo	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected
2 10-day IV MA+ 10-day IFN-γ versus 20-day IV MA	1		Risk Ratio (M-H, Random, 95% CI)	Totals not selected

---

 

Table 1. Quasi-randomised and non-randomised controlled trials

---

Authors	Title of the study	Journal citation	Observations
Arevalo I, Ward B, Miller R, Meng TC, Najar E, Alvarez E, Matlashewski G, Llanos-Cuentas A	Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator	CID 2001; 33 (11): 1847-1851	Non-randomised trial
de Paula CD, Sampaio JH and Cardoso DR	A comparative study between the efficacy of pentamidine isethionate given in three doses for one week and N-methyl-glucamine in a dose of 20 mgSbV/kg/day for 20 days to treat cutaneous leishmaniasis	Rev Soc Bras Med Trop 2003; 36 (3): 365-371	Non-randomised trial
Harms G, Zwingenberger K, Chehade AK, Talhari S, Racz P, Mouakeh A, Douba M, Näkel L, Naiff RD, Kremsner PG, Feldmeier H and Bienzle U	Effects of intradermal gamma-interferon in cutaneous leishmaniasis	Lancet 1989; 10: 1287-1292	Non-randomised and mixed Old and New World cutaneous leishmaniasis
Monjour L, Silva OA, Vouldoukis I, Neogy AB, Brito ME, Filho SP and Jardim ML	Immunoprophylaxis in cutaneous leishmaniasis	Lancet 1992; 340 (8827): 1098-9	Non-randomised trial
Saldanha AC, Romero GA, Merchan-Hamann E, Magalhaes AV and Macedo V de O	Comparative study between sodium stibogluconate BP 88R and meglumine antimoniate for cutaneous leishmaniasis treatment: I. Efficacy and safety	Rev Soc Bras Med Trop 1999; 32 (4): 383-387	Non-randomised trial
Soto J, Toledo J, Valda L, Balderrama M, Rea I, Parra R, Ardiles J, Soto P, Gomez A, Molleda F, Fuentelsaz C, Anders H, Sindermann H, Engel J, Berman J	Treatment of Bolivian mucosal leishmaniasis with miltefosine	CID 2007; 44(3): 350-356	Non-randomised trial
Saenz RE, Paz HM, Johnson CM, Marr JJ, Nelson DJ, Pattishall KH and Rogers MD	Treatment of American cutaneous leishmaniasis with orally administered allopurinol riboside	J Infect Dis 1989; 160: 153-158	Non-randomised and non-comparative trial
Toledo VPCP, Mayrink W, Gollob KJ, Oliveira MA, Costa, CA DA, Genaro O, Pinto JA, Alfonso LCC	Immunochemotherapy in American cutaneous leishmaniasis: immunological aspects before and after treatment	Mem Inst Oswaldo Cruz 2001; 96 (1): 89-98	Non-randomised trial
Romero, Gustavo Adolfo Sierra.	Study of the cutaneous illness caused by leishmania (Viannia) Braziliensis and Leishmania (Viannia) Guyanensis/ Estudo da doença cutânea causada por leishmania (Viannia) Braziliensis e Leishmania (Viannia) Guyanensis	Brasília; s.n; 2000. 222 p. mapas, tab. (doctoral thesis)	Non-randomised trial

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 CL: cutaneous leishmaniasis; MCL: mucocutaneous leishmaniasis; OD: once daily; TD; twice daily

 

Table 2. Geographic distribution of Leishmania

---

Reference	Country	Form of Leishmania	Type of parasite	Interventions
Soto 2004A	Bolivia & Colombia	CL	L. panamensis (confirmed)	T1: IMSSG 20 mg/Kg/day; T2: IMMA 20 mg/Kg/day (for 20 days)
Almeida 1999	Brazil	CL	L. braziliensis (previous studies)	T1: GM-CSF (2 injections of 200 μg at entry and 1 week later) + IVSSG at 20 mg/kg/d for 20 days; T2: IVSSG (20 mg/kg daily for 20 days) + Saline
Correia 1996	Brazil	CL	L. braziliensis (confirmed)	T1: IMPI 4 mg/kg/every 2 days for 8 applications; T2: IMAS 20 mg/kg/day for 20 days; T3: IMMA 10 mg/kg/day for 20 days
Figueiredo 1999	Brazil	CL+ MCL	NR	T1: MA 15% (14 mg SBV/kg/day) + placebo; T2: MA 30% (28 mg SBV/kg/day) for 10 days +10 days placebo *CL: 2 series of 20 days; MCL: 3 series of 30 days
Lobo 2006	Brazil	CL	L. braziliensis  (endemic)	T1: Single session heat therapy; T2: IVMA 20 mg/kg/d for 20 days
Machado 2007	Brazil	MCL	L. braziliensis  (NR but stated that MCL is caused by L. brasiliensis)	T1: Oral pentoxifylline 400 mg 3 times/day for 30 days + IVSSG 20 mg/kg/d; T2: Oral placebo + IVSSG 20 mg/kg/d
Oliveira-Neto 1997	Brazil	CL	L. braziliensis (confirmed)	T1: IVMA 5 mg/kg/day; T2: IVMA 20 mg/kg/day *during 30 days
Santos 2004	Brazil	CL	L. braziliensis  (endemic)	T1: GM-CSF+ IV MA 20 mg/kg/d for 20 days; T2: Placebo + IVMA 20 mg/kg/d for 20 days
Machado-Pinto 2002	Brazil	CL	L. braziliensis (endemic)	T1: Subcutaneous injection of L. amazonensis strain vaccine (0.5 ml) daily + IMMA; T2: Subcutaneous injection of Placebo daily+ IMMA *(8.5 mg/kg) for 10 d and 10 d of rest
Martínez 1992	Colombia	CL	L. panamensis (confirmed)	T1: Oral AL 20 mg/kg/day in 4 doses for 15 d; T2: IVMA 20 mg/kg/day for 15 d; T3: AL+ MA same doses; T3: no treatment
Martínez 1997	Colombia	CL	L. braziliensis (confirmed)	T1: Oral AL 20 mg/kg/day in 4 doses for 15 days+ IVSSG; T2: IVSSG *20 mg/kg/day for 15 days
Palacios 2001	Colombia	CL	L. braziliensis; L. panamensis (confirmed)	T1: IMMA 20 mg/kg/day OD for 10 days; T2: IMMA 20 mg/kg/day OD for 20 days
Soto 2002	Colombia	CL	L. panamensis (confirmed)	T1: Topical WR279396 TD for 20 days; T2: Topical placebo
Soto 1994	Colombia	CL	L. panamensis (confirmed)	T1: AS 12 mg/Kg/day for 7 d; T2: AS 12 mg/Kg/day for 14 d; T3: AS 18 mg/Kg/day for 14 d
Soto 1998	Colombia	CL	L. braziliensis; L. panamensis (confirmed)	T1: Topical 15% PR sulphate 12% MBCL TD for 10 days + IVMA for 7 days; T2: Topical placebo TD for 10 days + IVMA for 7 days; T3: Topical 15% PR sulphate 12% MBCL TD for 10 days+ IV MA for 3 days; T4: IVMA for 20 days
Vélez 1997	Colombia	CL	L. braziliensis; L. panamensis (confirmed)	T1: Oral AL 300 mg 4 times daily for 28 days; T2: IMMA 20 mg/kg/day for 20 days; T3: Oral placebo 4 times daily for 28 days
Soto 2004B	Colombia & Guatemala	CL	L. panamensis; L. braziliensis; L. mexicana (confirmed)	T1: Oral miltefosine orally for 28 days; T2: Placebo
Armijos 2004	Ecuador	CL	NR	T1: Topical PR 15%+12% MBCL TD for 30 d; T2: Topical PR 15%+10% urea TD for 30 d; T3: IMMA 20 mg/kg/day for 10 d
Guderian 1991	Ecuador	CL	L. panamensis; L. guyanensis; L. braziliensis; L. mexicana (confirmed)	T1: Oral AL ribonucleoside (1.500 mg QID) plus probenecid (500 mg QID) for 28 days; T2: IMSSG (20 mg/Kg/day) for 20 days; T3: no treatment
Hepburn 1994	Edinburgh(Belize)	CL	L. braziliensis; L. mexicana (confirmed)	T1: IVAS 14 mg/kg/day; T2: IVSSG 20 mg/kg/day for 20 day
D'Oliveira 1997	El Salvador	CL	L. braziliensis (confirmed)	T1: Oral AL 20 mg/kg 3 times/day for 20 days; T2: IVMA 10 mg/kg OD for 20 days
Arana 2001	Guatemala	CL	L.braziliensis; L.mexicana (previous studies)	T1: Topical 15% PR plus 12% MBCL; T2: Topical placebo *TD for 20 days
Arana 1994	Guatemala	CL	L. braziliensis; L. mexicana (confirmed)	T1: IVMA 20 mg/kg/d for 20 days; T2: IVMA 20 mg/kg/d for 10 days + 10 days of a saline infusion; T3: IVMA 20 mg/kg/d for 10 days + IFN-γ
Navin 1990	Guatemala	CL	L. braziliensis; L. mexicana (confirmed)	T1: IMMA 850 mg daily for 15 days; T2: Localized heat 50ºC for 30 sec, 3 treatments at 7 day intervals; T3: Placebo
Navin 1992	Guatemala	CL	L. braziliensis; L. mexicana (confirmed)	T1: Oral ketoconazole 600 mg/day for 28 days; T2: IVSSG 20 mg/kg/day for 20 days; T3: Placebo
Neva 1997	Honduras	CL	L. chagasi; L. mexicana (confirmed)	T1: Topical 15% PR + 10% urea; T2: Topical placebo *3 times/day for 4 weeks
Saenz 1987	Panama	CL	L. panamensis (confirmed)	T1: IMSSG 20 mg/kg/d; T2: IMMA 20 mg/kg/d *for 20 days
Saenz 1990	Panama	CL	L. panamensis; L. mexicana (confirmed)	T1: Oral ketoconazole 3 (200-mg tablets) each day for 28 d; T2: IMMA 20 mg/Kg for 20 days; T3: Oral placebo 3 tablets for 28 d
Andersen 2005	Peru	CL	L. braziliensis (confirmed)	T1: IVPI 2 mg/kg on alternate days for 7 doses; T2: IVMA 20 mg/kg/day for 20 days
Arévalo 2007	Peru	CL	L. braziliensis; L. peruviana; L. mexicana; L. amazonensis (endemic)	T1: Topical imiquimod 7.5% every other day for 20 days; T2: Topical imiquimod 7.5 % + IVMA 20 mg/kg/d for 20 days; T3: IVMA 20 mg/kg/d for 20 days
Franke 1994	Peru	MCL	L. braziliensis  (confirmed)	T1: IVSSG 20 mg Sb/Kg/d for 28 d; T2: IVSSG 20 mg/Kg/d for 40d
Llanos-Cuentas 2007	Peru	MCL	L. braziliensis (endemic)	T1: IMAS 14 mg/kg OD for 21 d; T2: IVMA 20 mg/kg OD for 28 d
LLanos-Cuentas 1997	Peru	MCL	NR	T1: IVSSG (20 mg/kg/d)+ oral AL (20 mg/kg/d in 4 doses); T2: IVSSG (20 mg/kg/d) for 28 days
M-Verástegui 2005	Peru	CL	L. braziliensis; L. peruviana  (endemic)	T1: Topical imiquimod cream 5% every other day for 20 days + IMMA; T2: Topical placebo + IMMA as in T1
Balou 1987	USA (mainly Panama)	CL	L. panamensis; L. chagasi (confirmed)	T1: IVSSG 10 mg/kg (P10); T2: IVSSG 20 mg/kg (P20) *OD for 20 days
Oster 1985	USA(Panama or Brazil)	CL	L. braziliensis; L. mexicana; L. chagasi(confirmed)	T1: IVSSG 600 mg OD for 10 days; T2: IVSSG loading dose of 600 mg SB + continuous infusion of 600 mg 24 h/9 days; T3: IVSSG loading dose of 600 mg SB + continuous infusion of 200 mg 8 h/day for 27 doses/9 days
Convit 1987	Venezuela	CL	L. braziliensis (confirmed)	T1: IMMA 50 mg/kg in series (2-3) of 20 daily injections with 15 days between series; T2: Vaccine
Convit 1989	Venezuela	CL	L. braziliensis (confirmed)	T1: Vaccine+BCG; T2: BCG alone intradermally in 2 sites 3 doses at 6-8 weeks intervals; T2: IMMA 50 mg/kg/day in series of 20 daily injections with intervals of 15 days

---

 CL: cutaneous leishmaniasis; MCL: mucocutaneous leishmaniasis; NR: not reported; OD: once daily; TD; twice daily; T1,2,3,4: Treatment groups; *: dosage schedule for all groups