Phase 3, Clinical Trials of Drug Against Cutaneous Leishmaniasis

Leishmaniasis caused by at least 20 different species of Leishmania and transmitted by the bite of infected sand flies. Leishmaniasis is endemic in 88 countries, mostly developing ones. Leishmaniasis with an incidence rate of 1.5-2 million mostly cutaneous form, and 350 million population at risk is a major health problem in some endemic countries such as Iran which is endemic to cutaneous leishmaniasis (CL), both anthroponotic CL (ACL) caused by L. tropica and Zoonotic CL (ZCL) caused by L. major 1, 2. Pentavalent antimonials (sodium stibogluconate and meglumine antimoniate) have been used as standard treatment of leishmaniasis for about 80 years. Pentavalent antimonials are only parentrally available, which is painful, toxic, not affordable in most endemic areas and moreover is not always effective even sometimes with several courses of treatment, recently resistance of Leishmania to antimonials is reported. Other modalities such as physical, immunological, topical and systemic therapies are used with controversial results 3,4.

Miltefosine, is a phosphocholine analogue that affects cell-signaling pathways and membrane synthesis 5.

Almost all strains of mice are resistant to L. major and L. mexicana infection, in ressitant strain L. major infection induces a transient self healing lesion similar to human CL accompanies with a Th1 response but susceptible BALB/c mice infected with L. major induces a Th2 type immune response and the infection develop to a systemic form of disease similar to human Kala azar and eventually every mouse is succumed to the disease. Miltefosine has recently been shown to be effective in the treatment of visceral leishmaniasis (VL) caused by L. donovani and New World CL caused by L. vianna panamensis in Colombia 6-8. The results of an open-label, multicenteric, phase II trial of different doses of oral miltefosine (4 or 6 weeks) on patients with VL caused by L. donovani in India showed a cure rate of 95% (all 120 patients showed an initial parasitologic cure and relapsed was seen in only 6 patients) 6. In another randomized, open trial in India, VL patients received miltefosine orally (approximately 2.5 mg/kg daily for 28 days), or amphotericin B (1 mg/kg, every other day for 30 days) at the end of the treatment, parasitological cure rate was 100% and only 6% of the patients received miltefosien showed relapse by 6 months 7. Phase I-II of an open dose escalating trial of miltefosine against American CL in Colombia showed that oral miltefosine is safe and the cure rate was 66 and 94% for different doses 8. In a placebo-controlled trial of miltefosine in Colombia and Guatemala, American CL caused by L. v. panamensis was treated with miltfosine (2.5 mg/kg per day orally for 28 days), at the end of the teatment period, the per-protocol cure rates for miltefosine group was 91% and for placebo group was 38% 9.

The molecular mechanisms that contribute to the antileishmanial activity of miltefosine are not clearly understood but apparently the effect is not on immune response and macrophages since immunodefient mice such as SCID mice and other deficient mice are still susceptible to miltefosine action 10-12. It is shown that miltefosine induces nuclear DNA condensation and apoptosis-like death in L. donovani 12-14.

The controversy obsereved in the reports of the efficacy of different modalities for CL is mainly due to not considering the self healing nature of the disease in the design of the study. Factors such as variations in the susceptibility of different Leishmania species to the various drugs and differences in the criteria used to evaluate the efficacy of the drugs are important. Although no reliable report is available on the efficacy of glucantime in the treatment of ACL caused by L. tropica but surely the efficacy is very poor, and resistant of L. tropica to glucantime exist (manuscript submitted). Only with well designed, randomized clinical trial can precisely evaluate the efficacy of any therapeutic modalities in CL. In this study the efficacy of oral treatment of miltefosine 2.5 mg per Kg body weight for 4 weeks will be compared with standard treatment of intramuscular injections of 60 mg/kg/day glucantime for 2 weeks in ACL parasitologically proven patients. At 8 weeks after the initiation of the treatment any patient in the group who received miltefosine and has not responded to the treatment will be treated with the standard intramuscular injections of 60 mg/kg/day glucantime for 2 weeks. The clinical trial will be carried out according to GCP (Good Clinical Practice) guide lines.