Miltefosine to Treat Mucocutaneous Leishmaniasis

Treatment of Mucocutaneous Leishmaniasis With Miltefosine

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.

Study Overview

• Status: Completed
• Conditions: Cutaneous Leishmaniasis; Mucosal Leishmaniasis
• Intervention / Treatment: Drug: Miltefosine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • NIH
    • Bethesda, Maryland, United States, 20852
      • For this treatment IND, each Physician entered patients at his/her own facility. Below data is for protocol central contact:

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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?

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Miltefosine; 2.5 mg/kg/day for 28 days	Drug: Miltefosine; 2.5 mg/kg/day for 28 days; Other Names: Impavido

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinical Cure of Lesions	Percent of participants with clinical cure of all lesions. Ulcerated CL lesions were measured for the longest diameter and perpendicular width of ulceration; non-ulcerated lesions were measured for length and width of the raised area. A healed lesion was 100% reduction in lesion area (0x0); a cured lesion was a lesion healed at the Month 7 visit. For subjects with ML, an Ear, Nose, and Throat specialist examined the nasal and oral mucosa. Each site (nasal skin, nasal mucosa, palate, pharynx, larynx) was evaluated for signs of disease (erythema, edema, infiltration, erosion) and graded on a scale: 0=no disease, 1=mild disease, 2=moderate disease, 3=severe disease. Max score was 60 = poor outcome. Clinical response measured as a composite score, the mucosal severity score, which was the sum of the severity scores for each clinical sign at each clinical site of disease. A healed lesion had a score of 0 in absolute value (0% of the entrance score), and clinical cure was lesion is healed.	Week 6, Month 3, Month 7, and Month 13
Number of Participants With Adverse Events	The number of participants with adverse events (AEs) by occurrence and severity. The Treating Physician monitored participants for the occurrence of AEs from the time the first investigational product was taken on Day 1 through the end of follow up at Month 7 for CL or Month 13 for ML. For the period between Study Day 1 and Study Week 6 (2 weeks after the end of therapy), all AEs regardless of seriousness or relationship to the investigational product were to be recorded on the case report form (CRF). For the period Week 6 to Month 7 for CL, or Month 13 for ML, only AEs requiring medical attention were recorded on the CRF.	Up to 7 months for CL; Up to 13 months for ML

Collaborators and Investigators

• Sponsor: Knight Therapeutics (USA) Inc
• Investigators: Principal Investigator: Jonathan Berman, MD, Fast Track Drugs and Biologics LLC

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: January 12, 2010
• First Submitted That Met QC Criteria: January 14, 2010
• First Posted (Estimate): January 18, 2010

Study Record Updates

• Last Update Posted (Actual): September 30, 2020
• Last Update Submitted That Met QC Criteria: September 8, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: miltefosine; leishmaniasis; cutaneous disease; mucosal disease
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Skin Diseases, Parasitic; Skin Diseases, Infectious; Euglenozoa Infections; Leishmaniasis; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Anti-Infective Agents; Antineoplastic Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Miltefosine
• Other Study ID Numbers: PBL-MILT-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No