The purpose of this Treatment Investigational New Drug application was to make miltefosine available for mucocutaneous leishmaniasis patients presenting in the United States.

If entrance criteria were met, subjects with mucosal or cutaneous leishmaniasis received miltefosine at a targeted dose of 2.5 mg/kg/day for 28 days. During treatment at weeks 1, 2, and 4, the patient returned to the treatment facility to be assessed for adverse events. Blood for transaminase and creatinine values were drawn at the midpoint and at the end of therapy.

Patients returned to the treatment facility to be examined clinically at 6 weeks (ie, 2 weeks after the end of therapy), 3 months (2 months after therapy), and 7 months (6 months after treatment) for mucosal leishmaniasis and cutaneous leishmaniasis patients, and also at 13 months (12 months after treatment) for mucosal leishmaniasis patients.

Subjects with mucosal leishmaniasis or cutaneous leishmaniasis from which Leishmania have already been identified were potentially eligible to be treated with miltefosine via this protocol. Treating Physicians with potentially eligible subjects contacted the protocol Principal Investigator (PI), and received the case report forms (CRF) from the PI. The Treating Physician completed the screening CRF pages for demographics, medical history, leishmaniasis history, clinical laboratory results that were available, and identification of Leishmania in the lesion, and sent the completed CRF pages to the PI. If after PI review, the subject was potentially eligible for the protocol, the PI sent the protocol, the miltefosine package insert, the informed consent form, and a blank copy of FDA form 1572 to the Treating Physician. Although this protocol would have already been approved by a "central" Institutional Review Board (IRB), if there was an additional need to have the Treating Physician's local IRB approve the protocol, the Treating Physician would obtain the approval, and obtain informed consent from the subject. The rest of the laboratory tests were accomplished so that all screening laboratory tests were completed prior to enrolling a potential subject. If in the physician's opinion the subject appeared eligible for enrollment, the Treating Physician sent to the PI the local IRB signature page (if needed), protocol signature page, informed consent signed by both the subject and the Treating Physician, the rest of the completed CRF pages for screening, and the form 1572 completed with the Treating Physician's information plus the Treating Physician's curriculum vitae. After the PI's review of these forms, the investigational product was sent from the drug repository to the Treating Physician for that subject's use.

Treatment was daily for 28 consecutive days. During treatment at weeks 1, 2, and 4, the subject returned to the treatment facility to be assessed for adverse events and to receive additional supply of medication if needed. Compliance with drug administration was assessed by subject interview and pill count. Blood for transaminase and creatinine values were drawn at the midpoint and at the end of therapy.

Subjects returned to the treatment facility to be examined clinically at Study Week 6, Study Months 3 and 7 months for mucosal leishmaniasis and cutaneous leishmaniasis subjects, and also at Study Month 13 for mucosal leishmaniasis subjects.

Inclusion Criteria:

1. Is the subject a male or female at least 18 years of age?
2. Does the subject weigh at least 30 kg?
3. Does the subject have a diagnosis of mucosal leishmaniasis or cutaneous leishmaniasis in at least one lesion by at least one of the following methods: 1) positive culture for promastigotes of lesion material, 2) microscopic identification of amastigotes in stained lesion tissue, 3) Polymerase chain reaction of lesion material?
4. In the opinion of the investigator, is the subject capable of understanding and complying with the protocol?
5. If female and of child-bearing potential, did the subject have a negative pregnancy test during screening and agree to use an acceptable method of birth control during the treatment phase and for 6 months after treatment is completed?
6. Has the patient signed informed consent?

Exclusion Criteria:

1. Is the subject a female who is breast-feeding?

2. Does the subject have a clinically significant medical disorder?

   • Thrombocyte count <100 x 10e9/L
   • Leukocyte count <3 x 10e9/L
   • Haemoglobin <10 g/100 mL
   • Aspartate transaminiase (ASAT), alanine transaminase (ALAT) >2 times upper limit of normal range
   • Bilirubin >1.5 times upper limit of normal range
   • Serum creatinine >1.5 times upper limit of normal range
   • Major surgery within last 2 weeks
   • Any non-compensated or uncontrolled condition

3. In the last 4 weeks up to the present, has the subject received other treatment for leishmaniasis, including any medication with pentavalent antimony; amphotericin B, paromomycin, or imidazoles?

Up to 7 months for CL; Up to 13 months for ML