Interventions for Old World cutaneous leishmaniasis

Julio Heras‐Mosteiro; Begoña Monge‐Maillo; Mariona Pinart; Patricia Lopez Pereira; Emely Garcia‐Carrasco; Pedro Campuzano Cuadrado; Ana Royuela; Irene Mendez Roman; Rogelio López‐Vélez

doi:10.1002/14651858.CD005067.pub4

. 2017 Nov 17;2017(11):CD005067. doi: 10.1002/14651858.CD005067.pub4

Interventions for Old World cutaneous leishmaniasis

Julio Heras‐Mosteiro ^1,^2,^✉, Begoña Monge‐Maillo ³, Mariona Pinart ⁴, Patricia Lopez Pereira ², Emely Garcia‐Carrasco ⁵, Pedro Campuzano Cuadrado ¹, Ana Royuela ⁶, Irene Mendez Roman ⁷, Rogelio López‐Vélez ³

PMCID: PMC6486265 PMID: 29149474

Abstract

Background

Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low‐ and middle‐income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008.

Objectives

To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis.

Search methods

We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co‐ordinators, directors, clinicians, WHO‐EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE.

Selection criteria

Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound.

Data collection and analysis

Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search.

Main results

We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.

Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.

In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow‐up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.

When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow‐up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.

Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons.

Authors' conclusions

There was very low‐certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.

We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well‐designed international studies that evaluate long‐term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.

It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.

Keywords: Animals; Humans; Anti‐Infective Agents; Anti‐Infective Agents/therapeutic use; Antiprotozoal Agents; Antiprotozoal Agents/therapeutic use; Complementary Therapies; Cryotherapy; Hot Temperature; Hot Temperature/therapeutic use; Laser Therapy; Leishmania major; Leishmania tropica; Leishmaniasis, Cutaneous; Leishmaniasis, Cutaneous/therapy; Photochemotherapy; Randomized Controlled Trials as Topic

Treatments for Old World cutaneous leishmaniasis

Background

Old World cutaneus leishmaniasis (OWCL) is an infection caused by the Leishmania parasite, which is passed onto humans by the bite of sandflies. It is a serious skin disease associated with a broad range of signs, symptoms, and degrees of severity. We wanted to assess the competence and safety of all available treatments for OWCL.

Review question

We assessed participants with a healthy immune response who had OWCL diagnosed by laboratory methods. Treatments had to be given alone or in combination with another treatment, and they were compared against no treatment, placebo (an inactive substance) only, or another active treatment. Some of the main outcomes we were interested in included the percentage of wounds cured after the end of treatment, the number of participants completely cured after the end of treatment, speed of healing, side‐effects of treatment, and clearance of parasites (i.e. infection).

Study characteristics

We reviewed 89 clinical trials, which included 10,583 people, in total, with OWCL. We included participants of both sexes and all ages (mean 24.5 years); most participants were over 18 years of age. Most studies were carried out in single centres in different countries, mainly in the Far or Middle East, and lasted between two to six months. We included a variety of treatments, such as antimonials, antifungals, and antibiotics, which were administered either directly onto the skin or into a wound, taken by mouth, or physically applied (e.g. laser treatment, heat therapy, etc.). Most of the included studies assessed OWCL caused by two species of parasites known as Leishmania major (L. major) andLeishmania tropica (L. tropica).

Key results

The evidence is current to November 2016.

Two of the most important treatments that we assessed in this review were itraconazole, an antifungal drug taken by mouth, and paromomycin, an antibiotic applied as an ointment. Trials compared both to a placebo tablet or inactive cream (vehicle).

Participants received 200 mg itraconazole for six to eight weeks or paromomycin ointment at a concentration of 15% plus 10% urea, twice daily for 14 days.

When assessed on average 2.5 months after treatment, more participants were completely cured and cleared of the infection‐causing parasites with itraconazole than placebo, but they also had more side effects (mild stomach pain, sickness, and abnormal liver function, as well as headaches and dizziness).

When paromomycin ointment was compared with placebo, there was no difference in the number of completely cured participants or the number who were found to be cleared of parasites when assessed on average 2.5 months after treatment, but those in the paromomycin treatment group had more contained skin reactions (such as swelling, blistering, pain, redness, or itch).

However, as the certainty of the evidence for these outcomes for these particular comparisons was very low, we are not sure of the accuracy of these results.

Neither of our key treatment comparisons assessed the percentage of wounds cured after the end of treatment and speed of healing (i.e. time taken to be cured).

Quality of the evidence

The overall certainty of the evidence for the different outcomes in the two main comparisons was very low. Important reasons for this were that studies were not blinded, or had a small sample size, making the results less precise. Some of the evidence only focused on young people, and the results greatly varied between each study.

We need more research to fill in the following research gaps: 1) trials of OWCL caused by other types of infection such as L. infantum, L. aethiopica,or L. donovani; 2) involving specific subgroups of people such as children; 3) assessing effectiveness and safety of different anti‐Leishmania drugs compared with placebo in self‐healing forms of leishmaniasis or with traditional first‐choice antimonial treatment in complicated form (defined as more than four lesions over 4 cm in size, located close to an opening or small joints, for which previous treatment has failed); and 4) assessing areas such as wound healing and patient‐reported outcomes, such as quality of life. In addition, few studies assessed relevant issues such as drug resistance. International collaboration is required to improve the quality and standardisation of future trials in order to develop a better evidence‐based approach.

Summary of findings

Summary of findings for the main comparison.

Itraconazole (200 mg for 6 to 8 weeks) versus placebo for Old World cutaneous leishmaniasis

Itraconazole (200 mg for 6‐8 weeks) versus placebo for Old World cutaneous leishmaniasis
Patient or population: patients with Old World cutaneous leishmaniasis Settings: Kuwait, India, and Iran Intervention: itraconazole (200 mg for 6‐8 weeks) Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Itraconazole (200 mg for 6‐8 weeks)
Percentage of lesions cured after the end of treatment	Not measured in this comparison
Percentage of participants with complete cure Follow‐up: mean 2.5 months	Study population		RR 3.70 (0.35 to 38.99)	244 (3 studies)	⊕⊝⊝⊝ Very low^a	—
	454 per 1000	1000 per 1000 (159 to 1000)
	Moderate
	100 per 1000	370 per 1000 (35 to 1000)
Adverse effects Mild abdominal pain and nausea Adverse effects Mild abnormal liver function	40 per 1000 0 per 1000	95 per 1000 (30 to 302) 0 per 1000 (0 to 0)	RR 2.36 (0.74 to 7.47) RR 3.08 (0.53 to 17.98)	204 (3 studies) 84 (3 studies)	⊕⊝⊝⊝ Very low^b ⊕⊝⊝⊝ Very low^c	—
Speed of healing (time taken to be 'cured')	Neither of the studies reported speed of healing (time taken to be 'cured') in this comparison.
Microbiological or histopathological cure of skin lesions Follow‐up: mean 2.5 months	Not estimable	Not estimable	RR 17.00 (0.47 to 612.21)	20 (1 study)	⊕⊝⊝⊝ Very low^d	There were zero events in the placebo group
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence High quality/certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality/certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality/certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality/certainty: we are very uncertain about the estimate.

Paromomycin ointment versus matched vehicle for Old World cutaneous leishmaniasis
Patient or population: patients with Old World cutaneous leishmaniasis Settings: primary health centres, Iran and Tunisia Intervention: paromomycin ointment (15% + 10% urea) twice daily for 14 days Comparison: vehicle
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Vehicle	Paromomycin ointment (15% + 10% urea) twice daily for 14 days
Percentage of lesions cured after the end of treatment	Not measured in this comparison
Percentage of participants with complete cure Follow‐up: mean 2.5 months	Study population		RR 1.00 (0.86 to 1.17)	383 (2 studies)	⊕⊝⊝⊝ Very low^a
	623 per 1000	623 per 1000 (536 to 729)
	Moderate
	619 per 1000	619 per 1000 (532 to 724)
Adverse effects Skin/local reactions	Study population		RR 1.42 (0.67 to 3.01)	713 (4 studies)	⊕⊝⊝⊝ Very low^b
	96 per 1000	136 per 1000 (64 to 287)
	Moderate
	90 per 1000	128 per 1000 (60 to 271)
Speed of healing (time taken to be 'cured')	Not measured in this comparison
Microbiological or histopathological cure of skin lesions Follow‐up: mean 2.5 months	Study population		RR 1.03 (0.88 to 1.2)	383 (2 studies)	⊕⊝⊝⊝ Very low^c
	859 per 1000	884 per 1000 (756 to 1000)
	Moderate
	792 per 1000	816 per 1000 (697 to 950)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; N/A: not applicable.
GRADE Working Group grades of evidence High quality/certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality/certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality/certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality/certainty: we are very uncertain about the estimate.

Term	Definition
Antimonials	Pharmaceutical agents containing antimony. Antimony‐containing compounds (meglumine antimoniate and sodium stibogluconate) are the principal medications used to treat leishmaniases, an infection caused by a protozoan parasite.
Arthralgia	Pain in the joints. The causes of arthralgia are varied and range, from a joints perspective, from degenerative and destructive processes such as osteoarthritis and sports injuries to inflammation of tissues surrounding the joints, such as bursitis.
Cardiac arrhythmia	An arrhythmia is an abnormal heart rhythm. Many types of arrhythmia have no symptoms. When symptoms are present these may include palpitations or feeling a pause between heartbeats. More seriously there may be lightheadedness, passing out, shortness of breath, or chest pain.
Cutaneous necrosis	The death of living tissues in response to disease or injury.
Cytolysis	The degeneration or dissolution of cell caused by the disruption of cell membrane.
Exudate	A fluid with a high content of protein and cellular debris that has escaped from blood vessels and has been deposited in tissues or on tissue surfaces, usually as a result of inflammation.
Human monocytes	Monocytes are the biggest type of white blood cell in the immune system. Originally formed in the bone marrow, they are released into our blood and migrate into the connective tissue where they differentiate into macrophages. When certain germs enter the body, they quickly rush to the site of attack.
Hypotension	A systolic blood pressure reading (the top number) of 90 millimetres of mercury (mmHg) or less a diastolic blood pressure reading (the bottom number) of 60 mmHg or less is generally considered low blood pressure. The causes of low blood pressure can range from dehydration to serious medical or surgical disorders.
Immune response modifier	Any of a broad family of biomolecules that up‐ or down‐regulate, or restore immune responsiveness, which are generated after T cells recognise an antigen present on the surface of a self‐antigen‐presenting cell, which, once activated, produce multiple cytokines.
Immunolabeling	A biochemical process that enables the detection and localisation of an antigen to a particular site within a cell, tissue, or organ. Antigens are organic molecules, usually proteins, capable of binding to an antibody. These antigens can be visualised using a combination of antigen‐specific antibodies as well as a means of detection, called a tag, that is covalently linked to the antibody. If the immunolabeling process is meant to reveal information about a cell or its substructures, the process is called immunocytochemistry. Immunolabeling of larger structures is called immunohistochemistry.
In vitro	Biological processes or reactions made to occur outside the living organism in an artificial environment, such as a culture medium.
Intralesional meglumine antimoniate	Meglumine antimoniate (or Glucantime) is a medicine used for treating leishmaniasis. It belongs to a group of compounds known as the pentavalent antimonials.
Lymphadenopathies	Lymph nodes that have an abnormal in size, number or consistency; often used as a synonym for swollen or enlarged lymph nodes. Common causes of lymphadenopathy are infection, autoimmune disease, or malignancy.
Lymphatic channels	The vessels that transport lymph throughout the body. Lymph is a clear fluid that contains cells important for forming antibodies that fight infection.
Lymphokine	Any of various soluble protein mediators released by sensitised lymphocytes on contact with antigen, and believed to play a role in macrophage activation, lymphocyte transformation, and cell‐mediated immunity. They regulate immune responses through differentiation, amplification, and inhibition of cell functions. Lymphokines may also have a cytotoxic effector function. Used as biologic response modifiers in the treatment of cancer.
Macrophages	White blood cells (activated monocytes) that protect the body against infection and foreign substances by breaking them down into antigenic peptides recognised by circulating T cells.
Miltefosine	An oral alkyl phosphocholine analogue used to treat cutaneous and visceral leishmaniasis. Interacts with lipids and sterols in the Leishmania membrane resulting in inhibition of mitochondria and apoptotic cell death.
Mucous membranes	The mucous membranes (or mucosae or mucosas; singular mucosa) are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs.
Myalgia	Myalgia, or muscle pain, is a symptom of many diseases and disorders. The most common causes are the overuse or over‐stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections. Long‐term myalgias may be indicative of a metabolic myopathy, some nutritional deficiencies or chronic fatigue syndrome.
Nodular lymphangitis	Nodular lymphangitis is a distinct clinical entity, separate from lymphangitis. This disorder is characterised by inflammatory nodules along the lymphatics draining a primary skin infection
Papule	A solid, rounded growth that is elevated from the skin, usually inflammatory but nonsuppurative. A papule is usually less than 1 cm across.
Parenteral	Administration of a medicinal or therapeutic substance, other than through the gastrointestinal or respiratory tracts, e.g. by intravenous, intramuscular or subcuticular injection.
Pentamidine	Pentamidine (e.g. isethionate) is an antiprotozoal and antifungal agent of the class of aromatic diamidines, administered intravenously or intramuscularly in treatment of early African trypanosomiasis and leishmaniasis, and intravenously, intramuscularly, or by oral inhalation in treatment and prophylaxis of Pneumocystis carinii pneumonia.
Pentavalent antimony	Pentavalent antimonials are a group of compounds used for the treatment of leishmaniasis. The first pentavalent antimonial used was urea stibamine: first introduced in the 1930s, it fell out of favour in the 1950s due to higher toxicity compared to sodium stibogluconate. The compounds currently available for clinical use are: sodium stibogluconate (Pentostam; manufactured by GlaxoSmithKline; available in the USA and UK), which is administered by slow intravenous injection, intralesional or intramuscular injection, and meglumine antimoniate (Glucantime; manufactured by Aventis; available in Brazil, France and Italy), which is administered by intramuscular, intralesional, or intravenous injection.
Promastigotes	Term now generally used instead of 'leptomonad' or 'leptomonad stage' to avoid confusion with the flagellate genus Leptomonas. It denotes the flagellate stage of a trypanosomatid protozoan in which the flagellum arises from a kinetoplast in front of the nucleus and emerges from the anterior end of the organism; usually an extracellular phase, as in the insect intermediate host (or in culture) of Leishmania parasites.
Protozoan	Any of a group of single‐celled, usually microscopic, eukaryotic organisms, such as amoebas, ciliates, flagellates, and sporozoans.
ThermoMed device	The ThermoMed is a battery‐operated device that delivers precisely controlled localised current field radiofrequency heat to selectively destroy certain diseased tissue and is recommended by the World Health Organization as an alternative therapy for cutaneus leishmaniasis.
Thermotherapy	The treatment of disease by the application of heat. Thermotherapy may be administered as dry heat with heat lamps, diathermy machines, electric pads, or hot water bottles or as moist heat with warm compresses or immersion in warm water. Warm soaks or compresses may be used to treat local infections, relax muscles and relieve pain in patients with motor problems, and promote circulation in peripheral vascular disorders such as thrombophlebitis.

Drug	Doses
Systemic antimonials
Sodium stibogluconate (Pentostam, Stibanate) Meglumine antimonate (Glucantime) Combined with pentoxifylline	20 mgSb ^v+/kg/d intramuscularly or intravenously for 20‐30 days 400 mg orally 3 times a day for 10–20 days
Intralesional antimonials
Sodium stibogluconate (Pentostam, Stibanate) Meglumine antimonate (Glucantime)	1–5 mL per session every 3–7 days. Up to 10 sessions depending on the clinical response, but most patients require ≤ 5 sessions
Non‐antimonial systemic treatments
Fluconazole	200 mg orally daily for 6 weeks
Miltefosine	50 mg orally three times daily for 28 days
Liposomal amphotericin B	3 mg/kg/d IV on days 1‐5 and 10 (18 mg/kg total dose)
Non‐antimonial topical or intralesional therapies
15% paromomycin/12% methylbenzethonium chloride	Ointment twice daily for 10‐20 days
15% paromomycin/0.5% gentamicin sulphate	Twice a day for 20 days
Physical therapies
Cryotherapy with liquid nitrogen	Frozen for 10‐30 s and thaw applied locally 2‐3 times in each session, repeated every 1‐4 weeks to complete healing (usually 2‐4 sessions)
Local heat therapy	50°‐55ºC for 30 s by: Infrared light Direct current electrical stimulation Ultrasound Laser Radiofrequency waves ThermoMed device

Study	Method of assessment	Timing	Interventions	Adverse effects
Kochar 2000	Quote: "Biochemical tests were done to detect any toxic effects of the drug."	Biochemical tests were done at the end of 1 week, 2 weeks and 4 weeks post‐ treatment.	I1: oral rifampicin 1200 mg/d I2: placebo	Intervention 23 participants evaluated for AEs. Quote: "The drug was well‐tolerated and no side‐effects were seen in any participant." Placebo 23 participants evaluated for AEs. Not reported
Jaffar 2006	Quote: "clinical examination, liver function tests, renal function tests"	Quote: "Before, during, and after completion of treatment"	I1: oral rifampicin 10 mg/kg/d I2: placebo	Intervention 46 participants evaluated for AEs. Elevation liver enzymes: 1 (2%) Placebo 16 participants evaluated for AEs. Not reported
Kochar 2006	Haemoglobin, leukocyte count, and liver test	Biochemical tests were done at the end of 2 week, 4 weeks and 6 weeks post‐treatment	I1: oral rifampicin + omeprazole I2: placebo	Intervention 1 23 participants evaluated for AEs. Intervention 2 21 participants evaluated for AEs. Quote: "All participants tolerated the drug and placebo very well and no side effect was reported."
Layegh 2007	Not described	Azythromycin group: monthly up to 4 months	I1: azithromycin 500 mg/d I2: IMMA 60 mg/kg/d	Intervention 1 22 participants evaluated for AEs (35 lesions). Nausea and vomiting: 2 (9%) Intervention 2 27 participants evaluated for AEs (58 lesions). Myalgia: 3 (11%); Erythema: 1 (3.7%).
Adam 2009	Quote: "Complete haemogram, including haemoglobin and liver and renal function tests Participants were questioned about expected adverse effects for 3 days (Days 5–7) following administration of the doses."	Haemogram: 1 and 2 months Clinical AEs: days 5‐7; 19‐21; 33‐35; 47‐19.	I1: artesunate I2: placebo	Intervention 1 20 participants evaluated for AEs. Placebo 21 participants evaluated for AEs. Skin rash with itching: 1 (4.7%) Quote: "There was no significant difference in biological tests (liver and renal function tests) in all the participants before and after treatment."
Ben Salah 2009	Interview, physical examination, laboratory test, evaluation for pain, standardised questionnaire for the occurrence of systemic side effects (e.g. vertigo, tinnitus). Diminished hearing was verified with audiometer. Laboratory test.	Quote: "Investigators observed each participant each day that the topical creams were administered and at follow‐up study visits (days 50‐100‐180). Clinical and laboratory evidence of side effects was determined on D10 and D20."	I1: WR 279,396 I2: placebo	Intervention 50 participants evaluated for AEs. Erythema at the site of application: 15 (30%); mild pain within 30 minutes of application: 7 (14 %); mild increases and decreases in hearing acuity from baseline: 14 (28%); change hearing acuity: 14 (28%); vertigo: 0 (0%); Increase serum creatinine: 0 (0%); Death: 0 (0%) Placebo 42 participants evaluated for AEs. Erythema at the site of application: 10 (24%); mild pain within 30 minutes of application: 6 (14 %); mild increases and decreases in hearing acuity from baseline: 9 (21%); change hearing acuity: 9 (21%); vertigo: 0 (0%); increase serum creatinine: 0 (0%); death: 0 (0%)
Dastgheib 2012	Quote: "Participants were interviewed and underwent laboratory tests three times"	Quote: "In Allopurinol group, the participants which were visited and received medication underwent laboratory tests three times (before, one month a2fter, and end of the treatment)	I1: azithromycin + allopurinol I2: IMMA	Intervention 1 36 participants evaluated for AEs. Gastrointestinal complaints and headache severe: 1 (2.7%); slight gastrointestinal complications (nausea, heartburn, and epigastric pain): 3 (8.3%) Intervention 2 35 participants evaluated for AEs. Myalgia: 2 (5.7%)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants complete cure	2	148	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.71, 0.96]
2 Adverse effects	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Serious adverse effects	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Skin reaction	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Cardiac toxicity 'QT prolongation'	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Lesions cured	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Adverse effects (itching and burning)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Adverse effects (oedema)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants cured	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Adverse effect (liver enzymes increase)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants complete cure	3	244	Risk Ratio (M‐H, Random, 99% CI)	3.70 [0.35, 38.99]
2 Adverse effects	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 Mild abdominal pain and nausea	3	204	Risk Ratio (M‐H, Random, 95% CI)	2.36 [0.74, 7.47]
2.2 Mild abnormal liver function	3	84	Risk Ratio (M‐H, Random, 95% CI)	3.08 [0.53, 17.98]
2.3 Headache and dizziness	1	20	Risk Ratio (M‐H, Random, 95% CI)	2.63 [0.16, 43.63]
3 Microbiological cure of skin lesions	1		Risk Ratio (M‐H, Random, 99% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants complete Cure	2	160	Risk Ratio (M‐H, Random, 95% CI)	24.08 [1.44, 403.43]
2 Adverse effects	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 Nausea	2	160	Risk Ratio (M‐H, Random, 95% CI)	21.86 [3.04, 157.29]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Secondary infection	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Myalgia	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 ECG changes	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.4 Chest pain	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.5 Pain injection site	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.6 Abscess	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Participants complete cured	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 Abdominal symptoms	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Liver abnormalities	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Myalgia	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.4 Rash	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Participants complete cure (ITT)	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 Hypersensitivity	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Mild pruritus	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Erithema and oedema	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants complete cure	2	383	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.86, 1.17]
2 Adverse effects	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 Skin/local reaction	3	463	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.45, 1.93]
3 Microbiological cure of skin lesions	2	383	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.88, 1.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Lesions cured	1	433	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.53, 1.55]
2 Adverse effects	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Hyperpigmentation and redness	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Hypertrophic scarring	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Systemic symptoms	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Partcipants 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 Erythema	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Date	Event	Description
15 November 2017	New citation required and conclusions have changed	The incorporation of GRADE into this updated review means that compared with the previous version of the review, we are now less certain of the evidence on which we base our conclusions.
15 November 2017	New search has been performed	The corresponding author is now Julio Heras‐Mosteiro. Of the authors from the first review, only Mariona Pinart and Ludovic Reitez have participated in this update. There are seven new authors: Begoña Monge‐Maillo, Patricia Lopez‐Pereira, Emely Garcia‐Carrasco, Pedro Campuzano Cuadrado, Rogelio López‐Vélez, Irene Mendez Roman, and Ana Royuela. We have not searched CINAHL for this update.

Date	Event	Description
17 May 2012	Amended	The lead author's contact details have been edited.
18 April 2008	Amended	Converted to new review format.
21 December 2007	New citation required and conclusions have changed	Substantive amendment

Methods	Study design: randomised, prospective, double‐blind trial Setting/location: Omdurman Hospital for Tropical Diseases, Sudan Study period: August 2007 to March 2008 (7 months) Sample size calculation: not described
Participants	Type of Leishmania: not described Inclusion criteria: people with cutaneous leishmaniasis, confirmed microscopically by finding amastigotes in slit skin smears, if they had not received any previous treatment (Antimonial) Exclusion criteria: pregnant women, people weighing < 10 kg, malnourished people and those with a history of allergy to sulphonamides or artemisinins N randomised: 41 (group 1: n = 20, group 2: n = 21) Withdrawals: 0 N assessed: 41 (100%) (group 1: n = 20, group 2: n = 21) Mean age (SD): group 1: 30.6 years (18.0), group 2: 28.5 years (15.3) Baseline data: N lesions (mean, SD): group 1: 2.1 (1.4); group 2: 2.2 (1.3) Size of lesion (median, IQR): group 1: 3.4 cm (1.5); group 2: 3.2 cm (1.3) Creatinine (mean, SD): group 1: 0.9 mg/dL (0.3), group 2: 0.9 mg/dL (0.2 ) Alanine aminotransferase (mean, SD): group 1: 36.7 IU (9.5), group 2: 37.3 IU (4.5)
Interventions	Type of interventions: Group 1: AS + SMP (100 mg artesunate + 250 mg/12.5 mg sulphamethoxypyrazine/pyrimethamine) (Co‐Arinate®; Dafra Pharma NV, Turnhout, Belgium). 4 tablets on 4 consecutive days were administered and repeated 4 times with 2‐week intervals without treatment Group 2: matched placebo Duration of intervention: 8 weeks Co‐interventions: pentosan was administered to participants who failed treatment with the study drug as well as to participants who had received placebo tablets
Outcomes	Healing rates: disappearance and/or shrinkage of the lesions. Lesions were identified, measured and numbered by their specific location on the participant's body before treatment and after 36 days and 72 days. Reported at the end of treatment. Adverse effects: participants were questioned about expected adverse effects for 3 days (days 5–7) following administration of the doses. These were considered drug‐related if they were not reported at presentation.
Notes	Study funding sources: Dafra Pharma NV/SA, Turnhout, Belgium Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A computer‐generated block‐randomisation, blinded to the treating physician, was used to allocate patients to the two treatment arms"
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "a double‐blind, placebo controlled clinical trial"; "blinded to the treating physician…" Comment: not fully reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Dropouts are unclear
Selective reporting (reporting bias)	Unclear risk	Protocol not available; not registered in a prospective clinical trial registry
Other bias	High risk	Sample size calculation and reporting of Leishmania spp involved was not correctly reported

Methods	Study design: randomised, prospective clinical trial Setting/location: outpatient clinic of Basra teaching hospital, south Iraq Study period: April 2004 to March 2005 (11 months) Sample size calculation: not described
Participants	Type of Leishmania: Leishmania major and L tropica Inclusion criteria: all patients with cutaneous leishmaniasis who were diagnosed clinically by the same dermatologist Exclusion criteria: ≥ 20 lesions; pregnancy, lactation; hypersensitivity to pentavalent antimonials or local anaesthetic; serious medical illness, lesion in proximity to mucous membranes, face, or cartilage; implanted metallic devices; unwillingness to avoid procreation for at least 2 months N randomised: 38 participants, 70 lesions: group 1 = 35, group 2 = 35 Withdrawals: group 1: 14 lesions; group 2: 8 lesions N assessed: lesions assessed: group 1: 21 (60%); group 2: 27 (77%) Age range: 1.5 to 64 years (1.5–45 years in group 1 and 3–64 years in group 2) with a mean of 21.1 years Sex: 52.5% males, 47.5% females Baseline data: N lesions treated at start of study: group 1, 35; group 2, 35 N lesions per participant: group 1 ‐ 1:7, 2:5, 3:1, > 3:7; group 2 ‐ 1:7, 2:8, 3:2, > 3:5 N lesions by site ‐ face and neck: group 1: 8, group 2: 3; upper limbs: group 1: 19, group : 10; lower limbs: group 1: 7, group 2: 18; trunk group 1: 1, group 2: 4 Mean lesion size before study: group 1, 1.74 cm, group 2, 1.70 cm Range of lesion duration before study: group 1: 1 month–1 year; group 2: 1 month–5 years
Interventions	Type of interventions: Group 1: hypertonic sodium chloride solution (HSCS) (7%) (7 g dissolved in 100 mL distilled water and autoclaved) Group 2: ciprofloxacin solution (2 mg/mL) Both drugs were injected into the lesions in amounts of 0.1–0.5 mL according to the size of the lesion Duration of intervention: 8 weeks
Outcomes	Clinical cure: resolution of active lesion with or without scarring. A scoring system was specially designed as follows. The diameter of lesions was recorded in mm using a ruler and scored as: 0 (total healing); 1 (0 cm to < 0.5 cm); 2 (0.5 cm to < 1 cm); 3 (1 cm to < 1.5 cm); 4 (1.5 cm to < 2 cm); 5 (2 cm to < 2.5 cm); or 6 (≥ 2.5 cm). The degree of induration was assessed by palpation in comparison with the participant's normal skin and given the following scores: 0, 0.5, 1, 1.5, 2, or 3. The degree of erythema was assessed visually and scored as: 0, 0.5, 1, 1.5, 2, or 3. Ulceration was scored as: 1 (present) or 0 (absent). The scores of these 4 parameters were added to give a total score for each lesion. Time points reported: the changes in total score between weeks: lesions were assessed at the start and again at 2‐week intervals after treatment for 8 weeks: 0, 2, 4, 6, and 8 weeks of treatment. Follow‐up continued for 8 weeks until complete healing took place
Notes	Study funding sources: none reported Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: insufficient detail was reported about the method used to generate the allocation sequence
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not reported; probably an open trial
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not reported; probably an open trial. No information on how lesions were assessed
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	After excluding participants who defaulted on treatment, 21/35 lesions were analysed in group 1 (HSCS) and 27/35 in group 2 (ciprofloxacin)
Selective reporting (reporting bias)	Unclear risk	Protocol not available. Not registered in a clinical trial registry. Pre‐specified outcomes of the review were reported. Tables were not available in the links of the journal, and .pdf does not work. No adverse effects reported in the text
Other bias	Unclear risk	There was not enough information in the publication to assess if there were other biases present.

Methods	Study design: randomised controlled trial Setting/location: Kuwait Study period: not described Sample size calculation: not described
Participants	Type of Leishmania: L tropica or L major in the area Inclusion criteria: positive for leishmanial parasites (amastigotes) on microscopic examination. Women of childbearing age were instructed to use potent and adequate contraceptive measures before the initiation of treatment. Exclusion criteria: not described N randomised: 24. Oral itraconazole: 15; placebo: 9 Withdrawals: 0 N assessed: N = 24. Oral itraconazole: 15; placebo: 9 Age range: 12‐52 years Sex: male/female: 13/11 Baseline data: single or multiple lesions, active being nodule, nodule‐ulcerative, or ulcerative. The site of lesions including both groups was 75% on upper limbs; 46% on lower limbs; 25% on the face, and 4% on the trunk. The duration of the lesion varied between 1 and 14 months.
Interventions	Type of interventions: Group 1: oral itraconazole 200 mg twice daily. There was a 12‐year‐old boy who was given a dose of 100 mg once daily (3 mg/kg per day) Group 2: placebo capsules twice daily during meals. Duration of intervention: 6‐8 weeks Duration of follow‐up: 12 weeks post‐treatment
Outcomes	Primary outcome: percentage of participants 'cured' 2 months after treatment. The response to treatment was graded as excellent (reduction in size of lesion by 80% up to complete clearance); good (reduction in size of lesion by 50%) and poor when there is minimal or no change of lesion. Secondary outcomes: duration of remission and percentage of people with treated lesions that recur within 6 months and 1, 2, and 3 years (for a period up to 3 months after suspension of the drug) Adverse effects Time points reported: 8 weeks and 12 weeks post‐treatment
Notes	Study funding sources: none reported Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The participants were randomly divided into two groups" Comment: insufficient detail was reported about the method used to generate the allocation sequence.
Allocation concealment (selection bias)	Unclear risk	Quote: "The patients were randomly divided into two groups" No further information about allocation concealment was provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The drug and the placebo were supplied in capsules with the same shape. No information about blinding of personnel was provided but it is not likely to add risk of bias being oral administration
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No blinding of outcome assessment was described
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	Relevant outcomes were reported
Other bias	High risk	Sample size calculation and reporting of Leishmania spp involved was not correctly reported

PERMALINK

Interventions for Old World cutaneous leishmaniasis

Julio Heras‐Mosteiro

Begoña Monge‐Maillo

Mariona Pinart

Patricia Lopez Pereira

Emely Garcia‐Carrasco

Pedro Campuzano Cuadrado

Ana Royuela

Irene Mendez Roman

Rogelio López‐Vélez

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Treatments for Old World cutaneous leishmaniasis

Summary of findings

Summary of findings for the main comparison.

Summary of findings 2.

Background

Table 1.

Description of the condition

Definition

Epidemiology and impact

Aetiology and transmission

Clinical manifestations

Localised leishmaniasis

Leishmaniasis recidivans

Diffuse leishmaniasis

Mucosal leishmaniasis

Post‐kala‐azar dermal leishmaniasis

Diagnosis

Description of the intervention

Table 2.

Systemic and intralesional antimonials

Meglumine antimoniate and sodium stibogluconate

Non‐antimonial systemic treatments

Oral antifungal

Oral dapsone

Oral allopurinol

Oral antibiotics

Oral pentoxifylline

Oral miltefosine

Oral zinc sulphate

Oral artesunate

Other oral drugs

Parenteral liposomal amphotericin B

Non‐antimonial topical or intralesional therapies

Topical antifungals

Topical paromomycin (aminosidine)

Intralesional zinc sulphate

Topical imiquimod

Intralesional hypertonic sodium chloride

Intralesional interferon‐gamma (IFN‐γ)

Topical aminoglycoside ointment (WR279,396)

Intralesional metronidazole

Topical miltefosine

Topical dapsone

Topical 0.045% pharmaceutical chlorite (DAC N‐055)

Topical Thio‐Ben

Physical therapies

Laser

Trichloroacetic acid (TCA)

Cryotherapy

Thermotherapy

Topical photodynamic therapy

Mesotherapy

Methods for promoting healing

Alternative therapies

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Methods	Study design: randomised, phase I, open‐label, clinical trial Setting/location: Department of Dermatology at SP Medical College and PBM Hospital, Bikaner, India Study period: June 2009 to December 2010 (19 months) Sample size calculation: not described
Participants	Type of Leishmania: L tropica Inclusion criteria: aged ≥ 4 years, 4 or fewer lesions, a parasitologically confirmed diagnosis of CL by demonstration of organisms (L tropica bodies) in the lesion smear or biopsy Exclusion criteria: included lesion size > 5 cm diameter, prior treatment failure with SSG, treatment for CL within 2 months of enrolment into the study, any chronic condition that might prevent the patient from completing the study therapy and subsequent follow‐up N randomised: 100; radiofrequency‐induced heat therapy (RFHT): 50; ILSSG: 50 Withdrawals: not described N assessed: 100 Median (range) age: RFHT: 20 years (4‐70); ILSSG: 20.5 years (4‐85) Sex: RFHT: male 27, female 23; ILSSG: male 20, female 30 Baseline data: Number of lesions: median (range); RFHT: 1 (1‐7); ILSSG: 1 (1‐4) Number of lesions per participant (%): 1 lesion: RFHT, 30 (60); ILSSG: 32 (64). 2 lesions: RFHT, 14 (28); ILSSG: 13 (26). > 2 lesions: RFHT, 6 (12); ILSSG, 5 (10) Median size of lesions (range): RFHT, 2 cm (0.5‐5); ILSSG, 2 cm (0.5‐14) Median duration of illness (range): RFHT, 3 months (1‐9); ILSSG, 3 months (1‐18)
Interventions	Type of interventions: Group 1: the RFHT group received a single application of a controlled and localised delivery of radiofrequencies into lesions for 30–60 s depending on the thickness of the lesion. The application was performed under local anaesthesia (1% lidocaine) using a current field radiofrequency generator (ThermoMed 1.8) Group 2: ILSSG group, the participants were treated with an intralesional injection of SSG (50 mg/cm² of lesion), twice a week for 7 injections Duration of intervention: RFHT, 5 days; ILSSG, 4 weeks Co‐interventions: all participants were prescribed oral nonsteroidal anti‐inflammatory drugs and topical antibacterial cream (fusidic acid cream) for 5 days
Outcomes	Cure rate, assessed as follows: Complete cure: the total re‐epithelialisation of the lesions Partial cure: decreased induration and erythema Time points reported: 6, 8, 10, 12, 16, and 20 weeks after the initiation of treatment, and at 5, 6, 9, 12 and 18 months post‐treatment
Notes	Study funding sources: none reported Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The patients were N randomised in a 1:1 ratio" Comment: insufficient detail was reported about the method used to generate the allocation sequence.
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The clinician who recorded healing was blinded to the modality of treatment." Comment: not clear how the assessor was blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	No information about numbers or reasons for withdrawals during treatment. It seems that there was withdrawals only in the follow‐up: 44% at 18 months in RFHT group and 16% at 18 months in the SSG group. Losses to follow‐up were heterogeneous between groups and no ITT analyses were performed.
Selective reporting (reporting bias)	Low risk	Outcomes of interest were reported in results
Other bias	Unclear risk	There was not enough information in the publication to assess if there were other biases present.

Methods	Study design: randomised single blind parallel clinical trial Setting/location: Leishmaniasis Center in Dadbin Health Care Clinic in Kerman, Iran Study period: 15 months. Participants recruitment: 8 months (December 2012 to August 2013) Sample size calculation: based on the data from previous study, and by considering the confidence interval of 95%, sample size was determined as 23 lesions per group. Regarding to a possible loss in follow‐up period, finally 32 lesions were allocated in each group
Participants	Type of Leishmania: L amastigote (Leishman‐Donovan bodies) Inclusion criteria: positive direct smear or documented skin biopsy for L amastigote (Leishman‐Donovan bodies), > 2 years of age, no previous therapy for leishmaniasis, ulcerated lesions for those lesions that were included in Thio‐Ben + cryotherapy (TC) group Exclusion criteria: pregnancy, lesions on the eyelids and lips, having more than 5 lesions, positive history of confirmed immunodeficiency disorders or immunosuppression, disease duration for more than a year, positive history of allergy or hypersensitivity to thioxolone, benzoxonium chloride, or pentavalent antimony compounds. N randomised: 64 lesions of 47 participants, Thio‐Ben + cryotherapy (TC) group (32 lesions, 22 participants), ILMA (32 lesions, 25 participants) Withdrawals: 16 lesions of 9 participants (10 lesions from TC and 6 from ILMA group) were removed from the study arms because of their poor adherence to the trial protocol and lost to follow‐up. Additionally, one participant (with one lesion) was excluded because of developing a hypersensitive reaction to MA in the course of the treatment. Lesions assessed: 48 lesions in 47 participants. TC: 22, ILMA: 25 Mean age (SD): TC 23.5 years (16.4), ILMA 25.4 years (19.4) Sex (n (%)): TC: male 6 (27.2%), female: 16 (72.7%); ILMA: male 19 (76%), female: 6 (24%) Baseline data: Location of lesion: TC: face 5 (22.7%), elbow 1 (4.5%), hand 13 (59.1%), foot 1 (4.5%), ear 1 (4.5%), arm 1 (4.5%), neck 0. ILMA: face 6 (24%), elbow 3 (12%), hand 10 (40%), foot 2 (8%), ear 1 (4%), arm 2 (8%), neck 1 (4%) Mean (SD) duration of disease: TC, 4.1 months (2.9); ILMA, 3.1 months (2.4)
Interventions	Type of interventions: Group 1: 1–2 mL of tincture of Thio‐Ben (depending on the size of the lesion) topically by a cotton swab that was held with a mild pressure on the lesion for about 3–4 min, every other day Group 2: ILMA containing 8.1% Sb5+ (81 mg/mL), once a week with the dose of 0.5–2 mL per lesion Co‐intervention: in addition, at the beginning, and then every 2 weeks, cryotherapy with liquid nitrogen (−195°C) was performed for all lesions in both groups Duration of intervention: 3 months or until the lesion was cured, whichever came first Duration of follow‐up: 6 months after the termination of the treatment to evaluate the incidence of relapse (reported at 1 month, 2 months, 5 months)
Outcomes	Clinical cure of the lesions: Complete cure: complete subsidence of induration and re‐epithelialisation of the lesion Partial cure: reduction of the size of lesion by 50% and more Improvement: reduction of the size of lesion by less than 50% No response: no significant reduction of the size of lesion Deterioration: any increase in the size of the lesion Adverse effects Relapse: participants that developed with relapse of the lesions at the previously involved area Time points reported: clinical cure was reported when it occurs or for a maximum of 3 months. Adverse effects were assessed at follow‐up during therapy; they were the safety endpoints of the treatments, and 6 months after the termination of the treatment
Notes	Study funding sources: this study was supported and funded by the Vice Chancellor for Research, Kerman University of Medical Sciences. The founder had no financial or proprietary interest in any material or method used in this study and had no role in study design, data collection and analysis, or preparation of the manuscript. Possible conflicts of interest: no conflict of interest
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised allocation was performed by blocked randomisation method with block size of 2
Allocation concealment (selection bias)	Low risk	Randomised allocation was performed by blocked randomisation method and was prepared by the analyst of the research team who had no clinical involvement in the trial.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was impossible
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Assessing the outcomes and data analyst were blinded to group assignment. The photographs were reviewed by the dermatologist of the research team who was blinded to study groups. The photographs did not contain any indicator that could help differentiate the group of the lesion.
Incomplete outcome data (attrition bias) All outcomes	High risk	The numbers of withdrawals were high in both groups: 31.25% (10/32) in TC group and 18.75 % (6/32) in the ILMA group. Participants were removed from the study arms because of their poor adherence to the trial protocol and lost to follow‐up. No intention‐to‐treat analysis was done.
Selective reporting (reporting bias)	Low risk	The study published reported our outcomes
Other bias	Low risk	Other items assessed correctly reported

Methods	Study design: prospective randomised controlled trial Setting/location: dermatology clinic in Saadi Hospital, an academic center in Fars Province, Iran Study period: December 2008 to March 2010 (15 months) Sample size calculation: not described
Participants	Type of Leishmania: L major Inclusion criteria: participants that presented with skin lesions suspicious of CL, not receiving any previous treatment, positive for leishmaniasis with direct smears Exclusion criteria: pregnant and nursing women; children < 12 years old; lesions on the face; disease for more than 3 months; more than 5 active lesions; participants with any serious systemic disease or previous history of sensitivity to MA, allopurinol, or azithromycin; any difficulty in laboratory results before initial treatment (CBC diff, LFT, BUN, Cr); those who refused to sign the written informed consent form N randomised: 86 participants Withdrawals: 14 participants (6 in azithromycin + allopurinol group and 8 IMMA group) one lost follow‐up because of adverse effect N assessed: 71 participants (36 azithromycin + allopurinol group and 35 IMMA group) Mean age (SD; range): 38.2 years (12.6); range 16‐64. Azithromycin + allopurinol group: 39.7 years (12.6); IMMA: 36.8 years (12.8) Sex: 28 females and 53 males (azithromycin + allopurinol group: 13 females and 23 males; IMMA group: 15 females and 20 males Baseline data: most participants in azithromycin + allopurinol group had more than 3 lesions (72.3%) and in the IMMA group most participants also had more than 3 lesions (65.8%)
Interventions	Type of interventions: Group 1: azithromycin capsules (Tehran Chemie Pharmaceutical Company, Tehran, Iran) at a daily dose of 10 mg/kg (maximum dose of 500 mg) + allopurinol tablets (Hakim Pharmaceutical Company, Tehran, Iran) at a daily dose of 10 mg/kg (maximum doses 800 mg) Group 2: IMMA (Aventis Laboratories, France) at a dose of 20 mg/kg of antimony Duration of intervention: group 1, 2 months; group 2, 20 days. Co‐interventions: in case of any secondary bacterial infection, participants were with oral cephalexin for 10 days after which the antileishmanial was administered
Outcomes	Cure rate, assessed as follows: Complete response: complete re‐epithelialisation and relief of induration Partial response: more than 50% re‐epithelialisation and decrease of induration and size of lesion No response: < 50% decrease of induration and size of lesion or worsening of lesion was considered as no response Adverse effects Time points reported: 2 months after completing treatment
Notes	Study funding sources: funded by deputy of research, Shiraz University of Medical Sciences Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A total of 71 participants who met the inclusion criteria in the trial were randomly divided into two treatment groups according to simple even and odd number allocation"
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Fourteen of 86 patients dropped out due to poor compliance (six patients in the combination therapy and eight in the Glucantime group). The number and reason for their withdrawal were almost the same in both treatment groups. One patient also developed GI complications and headache while taking the combination therapy of azithromycin and allopurinol; therefore, overall 71 subjects completed the study." Comment: no ITT analyses were performed. However, withdrawals accounted for <20% and were homogeneous among the treatment groups.
Selective reporting (reporting bias)	Low risk	Our primary outcomes (cure and adverse effects) were described in Methods and reported in Results
Other bias	Unclear risk	There was not enough information in the publication to assess if there were other biases present.

Methods	Study design: double‐blind, randomised controlled study Setting/location: Isfahan, Iran Study period: January 2009 to February 2010 (13 months) Sample size calculation: not described
Participants	Type of Leishmania: not described Inclusion criteria: met the histological criteria for presence of parasite, age > 5 years, acute leishmanial lesions smaller than 5 cm², fewer than 5 lesions, more than 3 months of disease duration Exclusion criteria: pregnancy, women of childbearing age, history of administration of immune suppressive drugs in the last 6 months or anti‐leishmanial drugs in the last month N randomised: 60 participants, 30 in each group Withdrawals: 0 N assessed: 60, 30 in each group Mean (SD) age: 25.29 years (4.01). Achillea millefolium 5%: 25.8 years (3.7); vehicle: 24.6 years (4.2). Sex: 15 (25%) female; 45 (75%) male. A millefolium: 7 (23.3%) female, 23 (76.6%) male; vehicle: 8 (26.6%) female, 22 (73.3%) male) Baseline data: Mean number of lesions (SD): A millefolium: 1.56 (0.8); vehicle: 1.52 (0) Type of lesions (%): A millefolium: papule 8/44 (18.1), ulcer 16/44 (36.3), plaque 10/44 (22.7), nodule 10/44 (22.7). vehicle: papule: 9/38 (23.6), ulcer: 16/38 (42.1), plaque: 11/38 (28.9), nodule: 12/38 (31.5) Mean duration of lesions (SD): A millefolium: 3 months (0.5); vehicle: 2.7 months (0.7)
Interventions	Type of interventions: Group 1: topical gel of 5% A millefolium (yarrow (containing 5% polyphenol) Group 2: vehicle gel. The vehicle gel was prepared using the same material except for the plant extract and chlorophyll was used as colorings agent. Both gels were identical in terms of the colour and consistency Duration of intervention: 4 weeks Co‐interventions: all participants received 4 weekly an injections of MA (Glucantime, Paris, France) at a dose of 20 mg/kg
Outcomes	Definition: complete or partial cure of lesions Time points reported: week 12 (visits months ‐ 3)
Notes	Study funding sources: none reported Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "During this double‐blind randomised study, 60 patients were randomised into two treatment groups by using random allocation computer software."
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "During this double‐blind randomised study ..." Quote: "Both gels were identical in terms of the colour and consistency."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up were reported, therefore ITT analyses performed
Selective reporting (reporting bias)	Unclear risk	Insufficient information to judge
Other bias	High risk	Sample size calculation and reporting of Leishmania spp involved was not correctly reported

Methods	Study design: randomised parallel clinical trial Setting/location: Skin Diseases and Leishmaniasis Research Center (SDLRC), Isfahan, Iran Study period: not described Sample size calculation: not described
Participants	Type of Leishmania: not described Inclusion criteria: 6‐60 years old, with positive results of leishmaniasis smear test Exclusion criteria: size of lesion > 3 cm, > 5 lesions, lesion duration > 12 weeks, lesion located on the eyelid or < 2 cm away from the eye, pregnant or lactating N randomised: 165, 55 in each of 3 treatment groups Withdrawals: 7; 3 (5.5%), participants were in the concentrated boiled extract group and 2 (3.6%) participants in the other groups withdrew from the study due to the allergic reaction to the medications N assessed: 158. Concentrated boiled extract of Cassia fistula: 52; hydroalcoholic extract of C fistula: 53; ILMA: 53 Mean (SD) age: boiled extract of C fistula: 20.6 years (12.4); hydroalcoholic extract of C fistula: 19.8 years (11.5); ILMA: 22.9 years (13.6) Sex (n,(%)): boiled extract of C fistula: male: 35 (63.6), female: 20 (36.4); hydroalcoholic extract of C fistula: male: 29 (52.7), female: 26 (47.3); ILMA: male: 25 (45.5), female: 30 (54.5) Baseline data: Location of lesions (n(%)): Concentrated boiled extract of C fistula: foot 9 (16.4), hand 25 (45.5), trunk 5 (9.1), head and neck 8 (14.5), hand and foot 8 (14.5). Hydroalcoholic extract of C fistula: foot 11 (20), hand 23 (41.8), trunk 6 (11), head and neck 10 (18.2), hand and foot 5 (9.1). ILMA: foot 8 (14.5), hand 24 (43.6), trunk 5 (9.1), head and neck 11 (20), hand and foot 7 (12.7) Mean number of lesions (SD): Concentrated boiled extract of C fistula: 1.8 (1.13) Hydroalcoholic extract of Cassia fistula: 1.72 (0.98) ILMA: 2.03 (1.07) Kind of lesions (n(%)): Concentrated boiled extract of C fistula: nodule 23 (41.8), papule 17 (30.9), papule and nodule 15 (27.3) Hydroalcoholic extract of C fistula: nodule 30 (54.5), papule 11 (20), papule and nodule 14 (25.5) ILMA: nodule 39 (70.9), papule 5 (9.1), papule and nodule 11 (20)
Interventions	Type of interventions: Group 1: concentrated boiled extract of C fistula. 500 g of C fistula was powdered and then mixed with water with ratio of 1:3, then boiled for 30 minutes and concentrated by distillation in vacuum condition. Group 2: hydroalcoholic extract of Cassia fistula on the lesions. 500 g of C fistula was powdered and mixed with 70% ethanol with ratio of 1:3, then placed in a percolator. After 48 hours, extraction was performed. The extract was then concentrated using distillation in vacuum condition. Group 3: ILMA. 0.5‐2 mL twice a week Duration of intervention: until complete resolution of the lesion (complete epithelialisation) or for a maximum duration of 4 weeks. Follow‐up: 3 months after completing the project, they were examined every month to assess the recurrence of the lesions
Outcomes	Clinical and parasitological cure: lesions were considered completely cured (improvement), if the participants achieved both clinical and parasitological resolutions (negative results of direct smear). Participants were considered resistant to the treatment, if no clinical changes were observed in the lesion or it was worsened. Time to healing: comparison of complete cure time of the cutaneous Leishmaniasis lesions between 3 groups Adverse effects: allergic reaction to the medications Time points reported: week 1, 2, 3, 4, 16, complete cure
Notes	Study funding sources: the study was self‐funded Possible conflicts of interest: there was no conflict of interest
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The participants were randomly allocated to 3 groups using table of random numbers.
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	Different administration of treatments: 2 groups: apply the extract‐soaked gauze; third group: ILMA
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers and reasons (allergic reaction to the medications) of withdrawals were similar and small in 2 of the groups 3.5% (3/28) in concentrated boiled group vs 3.6% (2/28) in the other groups.
Selective reporting (reporting bias)	Low risk	The study published reports our primary outcomes: cured and adverse effects
Other bias	High risk	Sample size calculation and reporting of Leishmania spp involved was not correctly reported

Methods	Study design: randomised, assessor‐blind, controlled clinical trial Setting/location: Kashan, Tehran, Iran Study period: September 2008 to April 2010 (19 months) Sample size calculation: 56 lesions per treatment group were needed to have 80% power to detect a significant difference in the expected cure rate of 60% in the ILMA alone group and the desired cure rate of 85% in the ILMA and either silver or non‐silver dressing‐treated group at week 10 with a type I error level of 0.05. Compensating for a 20% loss‐to‐follow‐up, recruiting 68 (round up to 70) lesions per treatment group looked reasonable.
Participants	Type of Leishmania: L major Inclusion criteria: parasitologically confirmed cases of CL based on positive smear and/or culture; otherwise healthy subjects on the basis of medical history; age of 12‐60 years; willingness to participate in the study and signing the informed consent form (by the participant or his/her parent/guardian in cases younger than 18 years). Exclusion criteria: pregnant or lactating women; duration of lesion more than 3 months; number of lesions more than 5; ulcer size greater than 5 cm in largest diameter; history of receiving full course standard treatment (antimonials); history of allergy to MA or silver; serious systemic illnesses (as judged by the physician); participation in any drug trials in the last 60 days; indication for systemic treatment with MA; presence of secondary bacterial infection of the lesion according to clinical appearance N randomised: 83 participants (158 lesions) ILMA: 26 participants (45 lesions); ILMA + non‐silver dressing: 26 participants (53 lesions); ILMA + silver dressing: 31 participants (60 lesions) Withdrawals: 10 participants (18 lesions) N assessed: 73 (140 lesions) Mean (SD) age: 28.81 years (14.45). ILMA: 32.88 years (12.92); ILMA + non‐silver dressing: 30.31 years (15.41); ILMA + silver dressing: 24.13 years (13.97) Sex: male 39; ILMA: male 8; ILMA + non‐silver dressing: male 11; ILMA + silver dressing: male 20 Baseline data: Mean duration of lesions (SD): 7.951 weeks (2.67); ILMA: 8.31 weeks (2.86); ILMA + non‐silver dressing: 8.46 weeks (2.15); ILMA + silver dressing: 7.23 weeks (2.82) Mean number of lesions (SD): 1.90 (1.21); ILMA: 1.77 (1.34); ILMA + non‐silver dressing: 2.00 (1.47); ILMA + silver dressing: 1.94 (1.12) Induration area median (IQR): 169 mm² (79‐433); ILMA: 270 mm² (120‐557); ILMA + non‐silver dressing: 156 mm² (67‐490); ILMA + silver dressing: 141 mm² (48‐346). Ulceration area median (IQR): 6 mm² (1‐25); ILMA: 8 mm² (2‐37); ILMA + non‐silver dressing: 6 mm² (0‐15); ILMA + silver dressing: 6 mm² (0‐24)
Interventions	Type of interventions: Group 1: eligible participants were randomly allocated into 2 groups and treated for 6 weeks with either: Weekly injections of ILMA combined with application of a non‐silver dressing (AtraumanH, Hartmann, CMC Consumer Medical Care GmbH, Germany) on the lesions, or Weekly injections of ILMA combined with application of a silver containing dressing (AtraumanH Ag, Hartmann, CMC Consumer Medical Care GmbH, Germany) on the lesions. Group 2: weekly injections of ILMA (GlucantimeH; Rhodia Laboratories, Rhone‐Poulenc, France) alone Duration of intervention: 6 weeks
Outcomes	Clinical cure (complete healing defined as more than 75% reduction, clinical improvement defined as 50%–75% reduction, and no response to treatment defined as less than 50% reduction in the size of the lesion compared with baseline) Relapse: defined as a reappearance of lesions at the site or periphery of previously healed lesions or an increase in the size of lesions after initial improvement was assessed 5 months after the termination of treatment Adverse effects: itching and burning, exudation, oedema, and dermatitis Time points reported: oucomes were assessed at the end of the treatment period (end of week 6), then at 4 weeks and 5 months after the last treatment session
Notes	Study funding sources: the budget of the research project has been provided by the Vice‐Chancellery of Research of Tehran University of Medical Sciences. Possible conflicts of interest: the authors have declared that no competing interests exist.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A random sequence generated by using the online software Random Sequence Generator, which is available at URL: www.random.org [22]. It was done by an investigator with no clinical involvement in the trial. R. Talaee was responsible for enrolment of the patients."
Allocation concealment (selection bias)	Low risk	Quote: "The method for randomisation concealment was to use sequentially numbered, opaque, sealed envelopes (SNOSE). The envelopes were kept in a safe box, which was only accessible to A. Khatami who was responsible for assigning the patients to the interventions."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An assessor who was blinded to the type of treatment visited the patients at weekly intervals during the treatment period and 1‐ month and 5 months after the last treatment session"
Incomplete outcome data (attrition bias) All outcomes	Low risk	An intent‐to‐treat analysis was performed at 2 time points (end of the treatment period (day 42) and one month later (day 72)). The numbers of and the reasons for withdrawals were not significantly different between the 3 groups: 11% ILMA group; 19% ILMA + non‐silver and 6.45% ILMA + silver
Selective reporting (reporting bias)	Low risk	Comment: all relevant outcomes were reported
Other bias	Low risk	Other items assessed correctly reported

Methods	Study design: randomised, prospective Setting/location: dermatology department of Qaem University Hospital, Mashhad, Iran Study period: from October 2004 through November 2005 (13 months) Sample size calculation: not described
Participants	Type of Leishmania: not reported (although they reported that CLL is endemic and L tropica and, less commonly, L major are the most prevalent species) Inclusion criteria: aged > 2 years with CL of < 6‐months' duration; no treatment of the current infection during the last 3 months; and no history of a renal or liver disease Exclusion criteria: pregnant women; history of intolerance or allergy to Glucantime or macrolides; simultaneous use of antacids containing Al and Mg, theophyline, phenytoin, barbiturates, carbamazepine, and cyclosporin N randomised: 49: azithromycin: 22 (35 lesions), IMMA: 27 (58 lesions). Withdrawals: 2 (azithromycin group) N assessed: 47 participants; 20 (29 lesions) in the azithomicin group and 27 (58 lesions) in the IMMA group. Mean (SD) age: range 4‐70 years; azithromycin: 21.77 years (17.13) and IMMA: 22.78 years (13.17) Sex (male/female): 24/25; azithromycin: 8/14; IMMA: 16/11 Baseline data: Mean number of lesions (SD): azithromycin: 1.86 (1.52) and IMMA: 2.15 (1.38) Mean duration of lesions (SD): azithromycin: 4.28 months (1.39) and IMMA: 3.22 months (2.03) Type of lesions: Papule and plaque: azithromycin: 27 (77.1%); IMMA: 49 (84.5%) Nodular: azithromycin: 6 (17.1%); IMMA: 7 (12.1%) Ulcerative: azithromycin: 2 (5.8%); IMMA: 2 (2.8%)
Interventions	Type of interventions: Group 1: "daily oral dose of 500 mg of azithromycin for 5 days/month in adults and 10 mg/kg in children; treatment cycles were repeated monthly when no favourable response was achieved, up to a maximum duration of 4 months" Group 2: 60 mg/kg IMMA for 20 days Duration of intervention: up to 4 months (azithromicin) and 20 days (IMMA) Co‐interventions: participants showing no favourable response after 4 months of azithromycin therapy would receive IMMA at the same dose as the other group, at the end of the study.
Outcomes	Clinical cure: clinical response was determined on the basis of the lesions' size, border, induration, and infiltration of papulonodular lesions; ulcerative lesions were evaluated on the basis of the ulcer depth, diameter, crusting, and the extent of re‐epithelialisation Complete or significant improvement: decrease in the induration size > 75% or full re‐epithelialisation of the le‐scions and a negative direct skin smear (absence of parasites in the lesion) No improvement: decrease in induration size < 30% Partial improvement: any changes between above criteria Recurrence Adverse effects Time points reported: participants in the azithromycin group were evaluated monthly up to a maximum of 4 months, but participants in the IMMA group were evaluated both at the end of the treatment period (day 20) and 45 days later. Recurrence was reported after the 16‐week follow‐up period.
Notes	Study funding sources: not reported Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The 49 patients who met our inclusion criteria were randomly divided into two groups." Comment: insufficient detail was reported about the method used to generate the allocation sequence.
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not stated
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	48 of 50 participants randomised completed the study. 2/20 participants of the azithromycin group withdrew because of adverse effects. Applications of study drugs were conducted according to the protocol
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	High risk	Sample size calculation and reporting of Leishmania spp involved was not correctly reported

Methods	Study design: randomised double‐blind clinical trial Setting/location: Skin Clinic of Anuradhapura Teaching Hospital, Sri Lanka Study period: January 2012 to February 2013 (14 months) Sample size calculation: approximately 473 participants per group were required to enable the detection of a treatment difference of 5% with a lowest cure rate of one group of 90%
Participants	Type of Leishmania: L donovani Inclusion criteria: the study recruited participants with suspected CL who consented to participation. Exclusion criteria: pregnant or lactating women, subjects with a history of cardiac, renal, or hepatic disease N participants randomised (lesions): 444 (643). 10% HSCS: 192 (297); 15% HSCS: 82 (101); ILSSG: 170 (245) Withdrawals (lesions): 17 (20) lost to follow‐up. 10% HSCS: 8 (7); 15% HSCS: 3 (3); ILSSG: 6 (10) N assessed (lesions): 427 (623); 10% HSCS: 79 (98); 15% HSCS: 184 (290); ILSSG: 164 (235) Age: mean 32.7 years (range 14 months to 88 years). Most (60.8%) were aged 16–45 years Sex (male/female): 286/158 Baseline data: the average delay in presentation was 8 months (range: 4 weeks to 5 years). 91% of lesions were located on exposed areas of the body. Most (69.8%) participants had a single lesion.
Interventions	Type of interventions: Group 1: 10% HSCS, prepared by dissolving 18.2 g of medical sodium chloride in 200 mL of 0.9% sodium chloride (normal saline) solutions Group 2: 15% HSCS, prepared by dissolving 28.2 g of medical sodium chloride in 200 mL of 0.9% sodium chloride (normal saline) solutions Group 3: ILSSG Duration of intervention: participants were seen weekly for the first 3 injections, fortnightly for the 4th and 5th injections, and then monthly until a cure was achieved.
Outcomes	Clinical and parasitological cure: responses were graded as slight (10% improvement from the initial status of the lesion), mild (20%–30% improvement), moderate (50% improvement), marked (80%–90% improvement), or as total if the lesion had cleared and parasites were not detected in the affected area by smear or culture. Both marked improvements and total clearance were considered to represent a cure. Reported at the end of treatment. Duration of treatment: in weeks, mean (range) Time required to achieve the cure of the lesion: mean and median times taken for cure for the different treatments groups. Every 5 weeks until achieve 30 weeks. Injections per lesion, mean (range): number of injections for cure per lesion Relapse: L recidivans Adverse effects: local side effects: at the site of the lesion caused by the injections: pain during injections, postinflammatory hyperpigmentation, scarring, postinflammatory depigmentation, ulceration and necrosis, L recidivans. Systemic side effects: no systemic or significant local side effects with either SSG or 10% HSCS. Time points reported: participants were followed up every 3 months after cure for more than 6 months to assess recurrences and evidence of visceralisation
Notes	Study funding sources: none reported Possible conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The treatment options were documented separately and packed in opaque envelopes numbered consecutively according to the randomisation schedule at a ratio of 2: 2: 1
Allocation concealment (selection bias)	Low risk	The allocation sequence was concealed from the researcher who enrolled and assessed the participants by the use of sequentially numbered, opaque, sealed, and stapled envelopes that were impermeable even to intense light.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The participants and the investigator (who assessed the participants for their clinical response) were blind to the type of therapy allocated.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	At each visit, the participant was examined by the primary investigator, who was blinded to the therapy.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers of withdrawals were similar and small in the 3 groups: 4.1% (8/192) in group 1, 3.6% (3/82) in group 2, and 3.5% (6/170) in group 3.
Selective reporting (reporting bias)	Low risk	The study published reports our primary outcome and adverse effects.
Other bias	Low risk	Other items assessed correctly reported

Methods	Study design: single‐centre, 3‐armed, open label, randomised, controlled, phase IIb trial Setting/location: Leishmania and Malaria Centre (LMC) of the Provincial Balkh Civil Hospital Mazar‐e‐Sharif (Afghanistan) Study period: November 2010 to March 2011 (15 months) Sample size calculation: the sample size calculation was based on the per protocol (PP) analysis, defined as all participants evaluable with respect to the primary endpoint
Participants	Type of Leishmania: in 44/69 participants analysed, 28 (64%) lesions were infected with L tropica and 16 (36%) with L major Inclusion criteria: CL lesions with Leishmania‐positive Giemsa smears without prior CL treatment Exclusion criteria: age < 12 years; more than one skin lesion (to exclude intra‐individual variations in this phase IIb analysis); lesion age > 3 months; lesions located on eye lids, lips or nose; drug addiction; coinfection with Mycobacterium tuberculosis, HIV, or diabetes N randomised: 87 participants: group 1, 24 (27.5%), group 2, 32 (36.8%), and group 3, 31 (35.6%) Withdrawals: lost after registration: group 2, 3; group 3, 3. Not followed up for the full treatment period: SSG, 1; group 2, 6; group 3, 3. Mixed treatment: group 3, 2 N assessed: 81 (93.10%). group 1: 24; group 2: 29; group 3: 28 Mean age: 29 years (95% CI 25–33) Sex (male/female): 32 (46%)/37 (54%) Baseline data: comparable in all 3 regimens
Interventions	Type of interventions: Group 1: intradermal injections of 0.6 mL SSG according to a protocol used by Zeglin 2009 Group 2: aseptic MWT with 0.045% DAC N‐055 following a single initial superficial wound debridement with HF‐EC, which was performed under local anaesthesia after wound cleansing and disinfection with gauzes soaked in physiological saline solution containing 320 ppm chlorine dioxide (pH 5.5 acidified 0.09% DAC N‐055) for 15 min Group 3: MWT with 0.045% DAC N‐055 alone Duration of intervention: for all groups: daily treatments (with the exception of Fridays) during the first week, followed by topical treatments at the centre twice a week until the end of week 4 and thereafter once a week until wound closure In group 1, the SSG treatment was discontinued after week 4. In groups 2 and 3, participants dressed their lesion themselves after week 4 with the topical NaClO₂‐basic‐crème between their visits at the centre until lesion closure
Outcomes	Primary outcome was the ratio of closed versus open wounds at day 75 (D75) in the PP analysis for each regimen Speed of healing: not reported in Methods Adverse effects: not reported in Methods 6 visits were scheduled in the first week, 2 visits per week from weeks 2 to 4, and 1 visit per week thereafter until complete wound closure. Follow‐up visits were required once a month until day 180 after treatment start
Notes	The funders had no role in study design, data collection, data analysis, and interpretation, decision to publish, or preparation of the manuscript. KWS and HCS are members of the Board and CB is a member of the non‐profit NGO Waisenmedizin PACEM e.V. promoting access to essential medicine
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Each patient was randomly assigned to one of the 3 regimens by the random allocation generator in the computer‐based Leishmedoc system."
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	High risk	Study was described as open and no blinding was done
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "the present trial could not be conducted as either a double or a single blinded trial due to the physical nature of the applied interventions"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The intention‐to‐treat analysis (ITT) is solely added as additional information. Patients that could not be evaluated were patients that were lost immediately after registration before treatment started. 81 out of 87 patients (93.1%) were suitable for the ITT and 69 (79.3%) for the PP analysis"
Selective reporting (reporting bias)	Low risk	Clinicaltrials.gov ID: NCT00996463. Registered: 15 October 2009
Other bias	Low risk	Other items assessed correctly reported

Study	Reason for exclusion
Alavi‐Naini 2012	Review
Banihashemi 2015	Inclusion criteria of the patients: patients with lupoid leishmaniasis, chronic recurrent leishmaniasis, that typically follows an acute form of cutaneus leishmaniasis
Bumb 2010	Not an RCT. "Selected patients were categorised into two groups (groups A and B) of 110 persons each. Alternate patients were included in group A and B, respectively"
Dogra 1986	They stated that participants were randomly selected for the study, but not randomly assigned to the treatment groups.
Dogra 1994	They stated that participants were randomly selected for the study, but not randomly assigned to the treatment groups.
Dorlo 2012	Review
El On 1992	Cross‐over study
Frankenburg 1993	It measured immunity parameters but did not show any clinical results.
Kim 2009	This was a meta‐analysis.
Moosavi 2005	The method of generation of randomisation was inappropriate. The author was contacted and stated that after enrolling the participants, they did consecutively allocate ILMA for odd number participants and used topical paromomycin for even number participants.
Nilforoushzadeh 2010	They stated that participants were randomly selected for the study, but not randomly assigned to the treatment groups.
Nilforoushzadeh 2011	Included immunocompromised and chronically ill patients
Siavash 2013	Only studied electrocardiogram and biochemical adverse effects of meglumine antimoniate
Singh 1995	They stated that participants in both groups were randomly selected. However, they did not have an initial population eligible for the study that was randomly divided in the 2 treatment groups. But rather one group of people that were randomly selected for one group and another group of participants that were also randomly selected to form part of the other group. Besides, the duration of treatments was not the same and the follow‐up was also different for both treatment groups.
Trau 1987	No clear data is available for multiple lesions. Only lesions from participants with multiple lesions were randomised. The lesions from participants with single lesions a cross‐over study was performed.