Conditions: Mucosal Leishmaniasis Cutaneous Leishmaniasis
Keywords: leishmaniasis cutaneous disease mucosal disease miltefosine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
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.

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.

Arms:
arm 1: 2.5 mg/kg/day for 28 days

Interventions: intervention 1: Miltefosine
Intervention descriptions: intervention 1: 2.5 mg/kg/day for 28 days

Protocol document:
Prot_SAP_000.pdf: 
Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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Version 1, March 6, 2010 
TREATMENT OF MUCOCUTANEOUS LEISHMANIASIS  
WITH MILTEFOSINE 
 
Protocol No.  PLB-MILT-201 
 
 
Principal Investigator: 
 
Jonathan D. Berman, M.D., Ph.D. 
 
 
 
 
 
Sr. Vice President for Clinical Affairs 
Fast-Track Drugs and Biologics, LLC 
5 Paramus Court 
North Potomac MD 20878 
301-922-2097 
jberman@fasttrackresearch.com 
 
Associate Investigator: 
 
Janet H. Ransom, Ph.D.  
 
 
 
 
 
Fast-Track Drugs and Biologics, LLC 
5 Paramus Court 
North Potomac, Maryland 20878 
Tel: (301) 762-5787 
 
 
 
 
 
jransom@fasttrackresearch.com 
 
Consultant:  
 
 
Jaime Soto, M.D. 
 
 
 
 
 
Prodderma 
 
 
 
 
 
Calle Ayacucho 416, Of. 104 
 
 
 
 
 
Santa Cruz, Bolivia 
 
 
 
 
 
(011) 59 13 402 4000 
 
 
 
 
 
jaime.soto@prodderma.com  
 
 
 
Sponsor: 
 
 
 
Paladin Labs Inc. (USA) 
 
Sponsor’s Contact:  
 
Robert K. Vinson, Ph.D.  
Paladin Labs Inc.  
100 Blvd. Alexis Nihon, Suite 600 
St-Laurent, Québec H4M 2P2 
Tel: (514) 669-5323     
rvinson@paladinlabs.com 
  
Data Management Center:  
Fast-Track Drugs and Biologics, LLC 
5 Paramus Court 
North Potomac, Maryland 20878 
Tel: (301) 762-5787 
Fax: (301) 762-5730 
 
 
 
 
 
kkell@fasttrackresearch.com 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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Version 1, March 6, 2010 
 
TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................. 5 
2 
STUDY SCHEDULE ............................................................................................................. 6 
3 
ABSTRACT ............................................................................................................................ 7 
4 
INTRODUCTION AND RATIONALE ............................................................................... 10 
4.1 
Mucocutaneous Leishmaniasis (Murray et al., 2005) ................................................... 10 
4.1.1 
Clinical Spectrum.................................................................................................. 10 
4.1.2 
Diagnosis............................................................................................................... 10 
4.1.3 
Treatment with Classical Agents .......................................................................... 10 
4.2 
Miltefosine .................................................................................................................... 11 
4.2.1 
Dosage and Administration................................................................................... 11 
4.2.2 
Contraindications .................................................................................................. 11 
4.2.3 
Warnings and Precautions..................................................................................... 12 
4.2.4 
Adverse Reactions ................................................................................................ 12 
4.2.5 
Drug Interactions .................................................................................................. 12 
4.2.6 
Use in Specific Populations .................................................................................. 12 
4.2.7 
Clinical and Non-clinical Pharmacology .............................................................. 13 
4.2.8 
Clinical Studies in Mucocutaneous Leishmaniasis ............................................... 14 
4.2.9 
References ............................................................................................................. 20 
5 
STUDY OBJECTIVES ......................................................................................................... 21 
5.1 
Primary .......................................................................................................................... 21 
5.2 
Secondary ...................................................................................................................... 21 
6 
STUDY DESIGN.................................................................................................................. 21 
7 
STUDY SUBJECTS ............................................................................................................. 21 
7.1.1 
Estimated Number of Subjects.............................................................................. 21 
7.1.2 
Inclusion Criteria .................................................................................................. 21 
7.1.3 
Exclusion Criteria ................................................................................................. 21 
8 
INVESTIGATIONAL PRODUCT ....................................................................................... 22 
8.1 
Description .................................................................................................................... 22 
8.2 
Labeling ........................................................................................................................ 22 
8.2.1 
Storage .................................................................................................................. 23 
8.2.2 
Drug Accountability.............................................................................................. 23 
8.3 
Start of Treatment ......................................................................................................... 23 
8.4 
Administration of Investigational Product (Miltefosine) .............................................. 23 
8.5 
Allocation of Study Treatment to Subject and Compliance ......................................... 24 
8.6 
Treatment Modifications and Study Discontinuation ................................................... 24 
8.7 
Concomitant Therapy.................................................................................................... 24 
8.8 
Rescue Treatment.......................................................................................................... 24 
9 
STUDY PROCEDURES ...................................................................................................... 25 
9.1 
Subject Recruitment ...................................................................................................... 26 
9.2 
Screening Procedures .................................................................................................... 26 
9.3 
Assessment During Miltefosine Treatment .................................................................. 27 
9.3.1 
Study Day 1........................................................................................................... 27 
9.3.2 
Study Days 7 and 14 ............................................................................................. 27 


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9.3.3 
Study Day 28......................................................................................................... 27 
9.3.4 
Study Week 6 ........................................................................................................ 28 
9.3.5 
Study Month 3....................................................................................................... 28 
9.3.6 
Study Month 7....................................................................................................... 28 
9.3.7 
Study Month 13..................................................................................................... 28 
10 
EFFICACY ....................................................................................................................... 30 
10.1 
Efficacy Assessments of CL Subjects........................................................................... 30 
10.1.1 
Assessment Methods ............................................................................................. 30 
10.1.2 
Definitions of Clinical Response .......................................................................... 30 
10.1.3 
Definition of Lesion Responses ............................................................................ 30 
10.1.4 
Definition of Subject Responses ........................................................................... 31 
10.2 
Efficacy Assessment of ML Subjects ........................................................................... 31 
10.2.1 
Assessment Methods ............................................................................................. 31 
10.2.2 
Clinical Parameter and Definition of Clinical Responses..................................... 31 
10.2.3 
Definition of Subject Responses ........................................................................... 31 
10.3 
Withdrawal from Protocol for Lack of Efficacy ........................................................... 32 
11 
SAFETY/ADVERSE EVENTS........................................................................................ 33 
11.1 
Assessment Methods ..................................................................................................... 33 
11.1.1 
Symptoms ............................................................................................................. 33 
11.1.2 
Signs ...................................................................................................................... 33 
11.1.3 
Laboratory Assessments ....................................................................................... 33 
11.1.4 
Pregnancy Test ...................................................................................................... 33 
11.1.5 
Electrocardiogram (ECG) ..................................................................................... 33 
11.2 
AE Definition ................................................................................................................ 34 
11.3 
Severity Definitions ...................................................................................................... 34 
11.4 
Assessment of Causality ............................................................................................... 35 
11.5 
AE Actions and Outcomes ............................................................................................ 35 
11.6 
Monitoring and Reporting of Adverse Events .............................................................. 35 
11.7 
Serious Adverse Event (SAE) ....................................................................................... 36 
11.8 
SAE Reporting Requirements ....................................................................................... 36 
12 
ANALYTICAL PLAN ..................................................................................................... 37 
12.1 
Sample Size ................................................................................................................... 37 
12.2 
Analytical Populations .................................................................................................. 37 
12.3 
General Analytical Procedures ..................................................................................... 37 
12.4 
Analysis of Baseline Data ............................................................................................. 37 
12.5 
Analysis of Treatment Compliance Data ...................................................................... 37 
12.6 
Analysis of Efficacy Outcomes of CL Subjects ........................................................... 37 
12.6.1 
Lesion Area Measurements................................................................................... 37 
12.6.2 
Lesion and Subject Cure Rate ............................................................................... 37 
12.6.3 
Handling of Missing Data ..................................................................................... 38 
12.7 
Analysis of Efficacy Outcomes of ML Subjects........................................................... 38 
12.7.1 
Lesion assessments ............................................................................................... 38 
12.7.2 
Subject Cure Rate ................................................................................................. 38 
12.7.3 
Handling of Missing Data ..................................................................................... 38 
12.8 
Analysis of Safety Data ................................................................................................ 38 
13 
ADMINISTRATIVE AND REGULATORY STANDARDS.......................................... 39 


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13.1 
Ethical Review of Protocol ........................................................................................... 39 
13.2 
Informed Consent.......................................................................................................... 39 
13.3 
Responsibility for Subject Care .................................................................................... 39 
13.4 
Treatment Cost .............................................................................................................. 39 
13.5 
Protocol Exemption Committee .................................................................................... 39 
14 
STUDY DOCUMENTATION/DATA MANAGEMENT ............................................... 39 
14.1 
Subject Identification (ID) Code ................................................................................... 39 
14.2 
Data Collection and Monitoring ................................................................................... 39 
14.3 
Data Editing and Control .............................................................................................. 40 
14.4 
Data Analysis ................................................................................................................ 40 
14.5 
Publication .................................................................................................................... 40 
14.6 
Subject Confidentiality ................................................................................................. 41 
15 
ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL.................................... 41 
15.1 
Principal Investigator .................................................................................................... 41 
15.2 
Associate Investigator ................................................................................................... 41 
15.3 
Treating Physicians ....................................................................................................... 41 
15.4 
Data Management Center ............................................................................................. 42 
16 
STATEMENT OF AGREEMENT ................................................................................... 42 
17 
SIGNATURES .................................................................................................................. 42 
 
 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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1 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
AE 
adverse event 
ALT  alanine transaminase 
BUN  blood urea nitrogen 
CL 
cutaneous leishmaniasis 
CRF 
case report form 
CTC 
Common Terminology Criteria 
DCL diffuse cutaneous leishmaniasis 
DNA deoxyribonucleic acid 
ENT 
ear-nose-throat 
ECG electrocardiogram 
FDA food and drug administration 
IND 
investigational drug application 
IRB 
institutional review board 
mITT Modified Intention-to-treat 
ML 
mucosal leishmaniasis 
MSS mucosal severity score 
PCR 
polymerase chain reaction 
PE 
physical examination 
PI 
Principal Investigator 
SAE 
serious adverse event 
 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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2 
STUDY SCHEDULE 
 
Time and Event Schedule 
Study Phase 
Screeninga 
Treatment  
Follow-up 
Study 
Day/Week/Month  
Day 
-14 to -1 
Day 1 
Day 7  
3 days 
Day 14 
3 days 
Day 28 
Week 6 
Month 3 
Month 7 
Month 13h 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical Historyb, c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationd 
X 
X 
 
 
X 
X 
X 
X 
X 
Leishmanial History 
and Examc 
X 
 
 
 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
Blood Chemistries 
Xe 
 
 
Xf 
Xf 
Xg 
Xg 
Xg 
Xg 
ECG 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
X 
X 
X 
 
X 
X 
 
Eligibility Checklist 
X 
 
 
 
 
 
 
 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment  
 
Daily 
 
 
 
 
aScreening includes the 14-day period for conducting screening procedures prior to the first administration of investigation product on 
Day 1. 
bIncludes medication history 
cIf subject does not appear at the scheduled Week 6, Month 3, Month 7, or Month 13 visits, these data may be obtained from the 
subject by telephone, and will be noted as obtained in that manner. 
dIncludes vital signs  
eScreening laboratories 
fAlanine transaminase (ALT) and creatinine on Day 28 and also on nominal day 14 
gIf abnormal on previous examination 
hML subjects only 
 


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3 
ABSTRACT 
The purpose of this Treatment Protocol is to make miltefosine immediately available for 
mucocutaneous leishmaniasis subjects presenting in the United States. Submission of an 
application for New Drug Approval is in process. Enrollment in this protocol makes it possible 
for subjects and their physicians to utilize miltefosine prior to approval.  
 
If entrance criteria are met, subjects with mucosal or cutaneous leishmaniasis will receive 
miltefosine at a targeted dose of 2.5 mg/kg/day for 28 days. During the 28-day treatment period, 
the subject will return to the treatment facility at least three times for evaluations and recording 
of any AEs. Blood samples for the evaluation of transaminase and creatinine levels will be drawn 
at the midpoint and at the end of therapy.  
 
Subjects will return to the treatment facility to be examined clinically at Study Week 6 (i.e., 2 
weeks after the end of therapy), Month 3 (2 months after therapy), and Month 7 (6 months after 
treatment) for mucosal leishmaniasis (ML) and cutaneous leishmaniasis (CL) subjects. ML 
subjects will also be evaluated at Month 13 (12 months after treatment).  
 
OBJECTIVES 
Primary: Record the efficacy of miltefosine, approximately 2.5 mg/kg/day for 28 days, in the 
treatment of mucocutaneous leishmaniasis presenting in the United States. 
 
Secondary: Record the tolerance of miltefosine, approximately 2.5 mg/kg/day for 28 days, in the 
treatment of mucocutaneous leishmaniasis presenting in the United States. 
 
STUDY DESIGN 
Open-label, single group, multicenter study. 
 
POPULATION 
1. Male or female at least 18 years of age. 
2. Weight at least 30 kg. 
3. Provided informed consent 
4. ML or CL already demonstrated in at least one lesion by at least one of the following 
methods:  
a. positive culture of lesion material for promastigotes,  
b. microscopic identification of amastigotes in stained lesion tissue,  or 
c. PCR of lesion material.  
5. No antileishmanial therapy in the previous 4 weeks. 
6. Subject capable of understanding and complying with the protocol. 
7. If female and of child-bearing potential, 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. 
8. If female, not breast feeding. 
9. No clinically significant medical disorder. Specifically: 
a. Platelet count >100 x 109/L 
b. Leukocyte count >3 x 109/L 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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c. Hemoglobin >10 g/dL 
d. ALT <2 times upper limit of normal range 
e. Bilirubin <1.5 times upper limit of normal range 
f. Serum creatinine  <1.5 times upper limit of normal range 
g. Major surgery within last 2 weeks 
h. Any non-compensated or uncontrolled condition 
10. No known Sjogren-Larssen syndrome  
 
INVESTIGATIONAL PRODUCT 
Drug name:  Miltefosine (50 mg capsules). 
Dosing regimen:  Approximately 2.5 mg/kg/day (maximum: 150 mg per day) for 28 days.  
Dose:  The daily dosage for subjects of body weight 30-45 kg is 100 mg miltefosine (2 capsules 
Impavido 50 mg). Subjects with a body weight higher than 45 kg receive 150 mg miltefosine 
daily (3 capsules Impavido 50 mg). The dose is administered orally, with meals. 
 
STUDY PROCEDURES 
Subjects with ML or CL from which Leishmania have already been identified are potentially 
eligible to be treated with miltefosine via this protocol. Treating Physicians with potentially 
eligible subjects will contact the protocol Principal Investigator (PI), and receive the case report 
forms (CRF) from the PI. The Treating Physician will complete the screening CRF pages for 
demographics, medical history, leishmaniasis history, clinical laboratory results that are 
available, and identification of Leishmania in the lesion, and send the completed CRF pages to 
the PI. If after PI review, the subject is potentially eligible for the protocol, the PI will send 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 will have already been approved by 
a “central” Institutional Review Board (IRB), if there is an additional need to have the Treating 
Physician’s local IRB approve the protocol, the Treating Physician will obtain the approval, and 
obtain informed consent from the subject. The rest of the laboratory tests must be accomplished 
so that all screening laboratory tests are completed prior to enrolling a potential subject. If in the 
physician’s opinion the subject appears eligible for enrollment, the Treating Physician will send 
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 will be sent from the drug repository to the Treating Physician for that subject’s use. 
 
Treatment will be daily for 28 consecutive days. During treatment at weeks 1, 2, and 4, the 
subject will return to the treatment facility to be assessed for adverse events and to receive 
additional supply of medication if needed. Compliance with drug administration will be assessed 
by subject interview and pill count. Blood for transaminase and creatinine values will be drawn 
at the midpoint and at the end of therapy.  
 
Subjects will return to the treatment facility to be examined clinically at Study Week 6, Study 
Months 3 and 7 months for ML and CL subjects, and also at Study Month 13 for ML subjects.  
 
 


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SAMPLE SIZE AND STUDY DURATION:   
10-20 subjects per year for 1-5 years. 
 
 
OUTCOME PARAMETERS: 
Efficacy: Clinical response of lesions  
Safety:    AEs 
 
ANALYSIS:   
Efficacy: The percent of subjects who have clinical cure of all lesions will be calculated. 
Safety: The occurrence and severity of AEs will be described. 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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4 
INTRODUCTION AND RATIONALE  
4.1 
Mucocutaneous Leishmaniasis (Murray et al., 2005) 
4.1.1 Clinical Spectrum 
Sandflies inoculate the skin with flagellated Leishmania promastigotes, which invade or are 
phagocytosed by local and immediately recruited host cells. Within phagolysosomes of resident 
macrophages, surviving promastigotes transform and replicate as amastigotes, which infect 
additional macrophages either locally or in distant tissues after dissemination. 
 
Multiple Leishmania species produce CL, primarily L. major, L. tropica, and L. (L.) aethiopica 
(Old world cutaneous leishmaniasis); L. infantum and L. chagasi (Mediterranean and Caspian sea 
regions); and L. mexicana, L. (L.) amazonenesis, L. braziliensis, L. (V.) panamensis, L. (V.) 
peruviana, and L. (V.) guyanensis (New World CL).  
 
A papule typically begins at the sandfly bite, enlarges to a nodule, and ulcerates over 1–3 
months. Flat plaques or hyperkeratotic or wart-like lesions also develop in Old World disease. 
Subjects, including travelers and military personnel, first seek attention because of one to two, or 
sometimes several (up to dozens) non-healing skin lesions on nocturnally exposed skin. In Old 
World CL, most lesions are papules, nodules, or nodule-ulcers, whereas ulcerative lesions are 
most common in New World CL.  Disseminated lesions and localised lymphadenopathy 
preceding skin ulcers occur in Brazil. L. tropica infection disseminates in that new papules can 
appear around a healed lesion (leishmaniasis recidivans). 
 
Mucosal dissemination of New World species (L. braziliensis, L. panamensis, L. guyanensis) 
occurs in 1–10% of infections, developing 1–5 years after cutaneous leishmaniasis has healed, 
but sometimes coincident with active skin lesions; about 90% of subjects have a preceding 
cutaneous scar. ML typically begins with erythema and ulceration at the nares, proceeding to 
nasal septum perforation and destructive inflammatory lesions. The latter can obstruct the 
pharynx or larynx and produce remarkable disfigurement. Mucosal disease is occasionally 
reported outside of Latin America, and can be acquired by travelers.  
4.1.2 Diagnosis 
Diagnosis is routinely made microscopically by identification of amastigotes in biopsies, 
scrapings, or impression smears. Combination of microscopy and culture increases diagnostic 
sensitivity to more than 85%, and culture (or DNA analysis) allows species identification. 
Detection of parasite DNA in lesion material by polymerase chain reaction (PCR), although 
generally only performed in research settings, is usually most sensitive in the diagnosis of both 
cutaneous and mucosal leishmaniasis. 
4.1.3 Treatment with Classical Agents 
Cutaneous disease heals by re-epithelialization with scarring. Most Old World lesions self-cure 
within 2–4 months (L. major) or 6–15 months (L. tropica). In New World CL, self-healing after 
3 months is rapid in L. mexicana (~75%), but slow in L. braziliensis (about 10%) and L. 
panamensis infections (about 35%). 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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Version 1, March 6, 2010 
 
CL is treated to accelerate cure, reduce scarring especially at cosmetic sites, and to attempt to 
prevent dissemination (eg, mucosal disease) or relapse. Treatment is especially likely to be given 
for persistent lesions (>6 months) or lesions that are located over joints, multiple (5–10 or more), 
or large (4–5 cm or more). Classic treatment with parenteral antimony would probably be 
successful in CL in all regions; however, up to 20 daily injections of this moderately toxic drug 
approximates the morbidity of self-healing disease itself.  
 
ML can produce potentially life-threatening inflammatory disease and must be treated. The 
standard regimen, 28 days of parenteral antimony, induces cure in around 75% of cases of mild 
disease (nares only), but advanced disease responds less well. Amphotericin B can be used as 
rescue therapy.  
4.2 
Miltefosine 
Miltefosine (hexadecylphosphocholine ) is a phosphatidylcholine analogue. The structural 
formula of miltefosine is:  
 
  
The drug was registered in India in 2002 and in Germany in 2004 to treat visceral leishmaniasis.  
Miltefosine was registered in Columbia in 2005 to treat visceral and cutaneous leishmaniasis, 
and post 2005 to treat CL and ML in Bolivia and in many other countries in the Americas. As the 
only recognized oral agent for leishmaniasis, the years since 2005 have been spent in further 
studies of visceral leishmaniasis and other forms of leishmaniasis. 
4.2.1 Dosage and Administration 
Miltefosine is provided as capsules for oral administration, containing 50 mg of drug substance 
per capsule. 
 
List of excipients: Collodial anhydrous silica, microcrystalline cellulose, lactose monohydrate, 
talc, magnesium stearate, gelatin, titanium dioxide, ferric oxide, purified water. 
 
Recommended dosage: Approximately 2.5 mg/kg/day orally for 28 days. The daily dosage for 
subjects of body weight 30-45 kg is 100 mg miltefosine (2 capsules Impavido 50 mg). Subjects 
with a body weight greater than 45 kg receive 150 mg miltefosine daily (3 capsules Impavido 50 
mg).  
 
The capsules should be taken with meals. Subjects taking 2 capsules per day should take one 
capsule with the morning meal and with the evening meal. Subjects taking 3 capsules per day 
should take one capsule with the morning meal, the noon meal, and the evening meal.  
 
4.2.2 Contraindications  
 Hypersensitivity to the active substance or any of the excipients 
 Pre-existing severe damage of liver or kidney function 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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 Sjögren-Larsson-Syndrome 
 Pregnancy and women of childbearing potential who do not use reliable contraception 
during and up to 3-6 months after treatment 
4.2.3 Warnings and Precautions 
Impavido is contraindicated in pregnancy. Women of childbearing potential have to use effective 
contraception during and up to 3-6 months after treatment. Vomiting/diarrhea are very 
common/common side effects of therapy with Impavido and can compromise the efficacy of oral 
contraception. The subject must be informed by her physician of these symptoms and if 
necessary, suitable alternative methods of contraception must be used. 
 
Subjects with ALT (liver function), serum creatinine, and blood urea nitrogen (BUN) (renal 
function) 1.25 times above the normal range were generally excluded from the clinical studies. 
Thus, data from subjects with abnormalities of liver and kidney function are not available. 
 
Treatment with Impavido may lead to an increase in serum creatinine. Kidney function must be 
evaluated in biweekly intervals. In subjects with clinically significant abnormality in kidney 
function, monitoring should be continued until normalization. 
 
Gastrointestinal symptoms such as nausea, vomiting, diarrhea, and a feeling of motion sickness 
are possible side effects of therapy with Impavido. The subjects must be instructed that in case of 
prolonged persistence of vomiting and diarrhea a sufficient fluid intake must be ensured, to avoid 
dehydration and consequently the risk of an impaired renal function.  
4.2.4 Adverse Reactions 
 
Organ system 
Very Common 
>10% of subjects 
Common 
1-10% of pts 
Gastrointestinal 
Nausea 
Vomiting Grade 1-2* 
Motion sickness 
Diarrhea Grade 1* 
Headache 
Renal 
Creatinine elevation 
Grade 1* 
 
*Grade = National Cancer Institute Common Terminology Criteria (CTC) grade 
4.2.5 Drug Interactions 
In vitro investigations have shown that interactions are unlikely with medications that are 
metabolized by cytochrome P450 or glucuronised or otherwise conjugated. However, the 
possibility of interactions with commonly used medicinal products cannot entirely be excluded. 
4.2.6 Use in Specific Populations 
Pregnancy: There are not adequate data on the use of miltefosine in pregnant women. Studies in 
animals have shown reproductive toxicity. Impavido is contraindicated in pregnancy. Women of 
childbearing potential have to use effective contraception during and up to 3-6 months after 
treatment. Vomiting/diarrhea are very common/common side effects of therapy with Impavido 
and can compromise the efficacy of oral contraception. The subject must be informed by her 


Protocol No.PLB-MILT-201:  Treatment of Mucocutaneous Leishmaniasis with Miltefosine 
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physician of these symptoms and if necessary, suitable alternative methods of contraception must 
be used. The subject has to be advised to immediately contact her physician for pregnancy 
testing as soon as there is any suspicion of pregnancy. If the test is positive, the physician and 
subject must discuss the risks associated with this pregnancy. 
 
Nursing mothers: It is not known whether miltefosine is excreted in the milk. Impavido must not 
be used during lactation; otherwise breast feeding must be stopped. 
 
Geriatric use: Few subjects of age 65 yrs or greater have been included in investigations. 
 
Renal impairment: Subjects with kidney function tests (serum creatinine, BUN) 1.25 times 
above the normal range were generally excluded from the clinical studies. Thus, data from 
subjects with mild/moderate/severe abnormalities of kidney function are not available. 
 
Hepatic impairment: Subjects with liver function tests (AST) 1.25 times above the normal range 
were generally excluded from the clinical studies. Thus, data from subjects with 
mild/moderate/severe abnormalities of hepatic function are not available. 
4.2.7 Clinical and Non-clinical Pharmacology 
4.2.7.1 Pharmacodynamic Properties 
Miltefosine has a marked direct antileishmanial activity in vitro and in animal models. However, 
the relevance of specific values (ED50, ED90) to clinical efficacy is unknown. The specific 
mode of action of miltefosine in leishmaniasis is unknown. Among other possible mechanisms, 
miltefosine can inhibit the metabolism of phospholipids in cell membranes of parasites. 
 
Nonclinical Pharmacokinetic Studies 
Distribution studies in rats, using radioactively labeled miltefosine, showed highest uptake of 
radioactivity in kidney, liver and spleen. Slow elimination of radioactivity from tissues (half 
lives 8-16 days) is partially explained by metabolism of miltefosine and incorporation of the 
labeled choline fragment into physiological lipids. 
 
No oxidative metabolism by 15 different cytochrome P450 isozymes was observed in vitro. No 
CYP3A induction by miltefosine was found in vivo, in rats. Thus, no interaction has to be 
expected between miltefosine and drugs, like contraceptive hormones, that are metabolized by 
CYP3A. A slow metabolic breakdown could be shown in human hepatocytes, resulting in the 
release of choline by phospholipase D like cleavage of the miltefosine molecule. The fatty 
alcohol containing fragment of miltefosine can enter the metabolism of fatty acids after being 
oxidized to palmitic acid. This oxidation is blocked in subjects with Sjögren-Larrson syndrome, 
which is caused by a genetic defect in fatty aldehyde dehydrogenase activity. Preclinical and 
clinical studies suggest that only a very minor part of the administered dose will be excreted as 
the unchanged drug substance. Instead, choline and choline-containing metabolites are the most 
likely excretion products. 
 
 
 
 


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Pharmacokinetic studies in subjects with cutaneous leishmaniasis (Dorlo et al., 2008) 
Subjects were administered miltefosine at an average dosage of 1.8 mg/kg/day. Pharmacokinetic 
analysis in this CL subject population resulted in calculation of two half lives: a first half-life of 
7.0 days and a terminal half-life of 31 days. 
 
Nonclinical Toxicology 
Toxicological studies with miltefosine have been performed in mice, rats, dogs and rabbits. 
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar 
to clinical exposure levels and with possible relevance to clinical use are described in the section 
below. 
 
Acute and Chronic Toxicity 
The oral administration of miltefosine in rats was associated with regressive and/or progressive 
lesions especially affecting the eyes (retinal degeneration), kidneys (acute resp. chronic 
nephropathy) and organs with rapidly dividing cell tissues (atrophy/hyperplasia), as well as 
reproductive organs (atrophy). These alterations were observed after 8 weeks treatment at doses 
of 10 mg/kg/day which led to plasma drug levels of about 52 μg/ml. Juvenile rats were more 
sensitive than adult rats to the miltefosine induced effects, especially on eyes and kidneys. 
 
Reproductive Toxicity 
Testicular atrophy and impaired fertility were observed in rats following daily oral doses of 8.25 
mg/kg. These findings were reversible within a recovery period of 10 weeks. Reproductive 
toxicity studies in rats during the early embryonic development (up to day 7 of pregnancy) 
indicate an embryotoxic, fetotoxic and teratogenic risk following miltefosine dosages of 1.2 
mg/kg/day and higher. Embryo- and fetotoxic findings were also observed in rabbits after oral 
administration of miltefosine during the phase of organogenesis (2.4 mg/kg/day and higher). 
 
Mutagenicity/Carcinogenicity 
Miltefosine tested negative in 6 of 7 of mutagenicity tests (AMES-Salmonella test, DNA-
amplification test, chromosomal aberration test in vitro, UDS-test in vivo/in vitro, oral mouse-
micronucleus test in vivo). The V 79 mammalian cell HPRT gene mutation test showed an 
increase in mutant frequency without dose dependency. In view of all mutagenicity test results, 
the single positive finding in the V 79 HPRT test is considered to be not of toxicological 
relevance with respect to a mutagenic risk to humans. The results of the mutagenicity tests ruled 
out a genotoxicity-mediated carcinogenic potential of miltefosine. Carcinogenicity studies were 
not performed.  
4.2.8 Clinical Studies in Mucocutaneous Leishmaniasis  
In a dose-ranging study against L. panamensis in Colombia, high rates of cure were seen in 
subjects treated with 2.5 mg/kg/day dose for 3-4 weeks, the same regimen previously used for 
visceral leishmaniasis. The regimen of 2.5 mg/kg/day x 28 days was then evaluated in a placebo-
controlled study in both Colombia against L. panamensis and Guatemala against L. 
braziliensis/L. mexicana. Success in this placebo-controlled study led to continent-wide and 
world-wide use of miltefosine for all forms of leishmaniasis.  
 


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Further studies in the New World have been reported for Bolivian CL and Bolivian ML due to L. 
braziliensis and against Venezuelan diffuse cutaneous leishmaniasis due to L. amazonensis. 
4.2.8.1 Dose-finding Study in L. panamensis Region in Colombia (Soto et al., 2001) 
The cure rate for evaluable subjects in group 1 (50 mg miltefosine/day) was 9/14 (64%). The 
cure rate in group 2 (100 mg miltefosine/day) was 12/18 (67%). The cure rate in subjects given 
150 mg miltefosine/day [2.5 mg/kg/day for these subjects of average weight of 67 kg] was 14/14 
(100%) for subjects treated for 20 days in group 3 and 16/18 (89%) for subjects treated for 28 
days in group 4. Because a larger total dose of drug should be more effective in the general 
population, the dose of approximately 2.5 mg/kg/day for 28 days was adopted based on this 
study. 
4.2.8.2 Placebo Controlled Study in L. panamensis Region in Colombia and in L. 
braziliensis/L. mexicana Region in Guatemala (Soto et al., 2004) 
The objective of this study was to demonstrate that miltefosine, 2.5 mg/kg/day for 28 days, was 
superior to placebo in cutaneous leishmaniasis in male or female subjects >12 yrs when assessed 
6 months after end of treatment. The per protocol cure rate against L. panamensis in Colombia 
was 91% (Table 1 below), in conformity to the results from groups 3 and 4 of the dose-ranging 
study #3092, and statistically higher than the cure rate for placebo (38%).  
 
Table 1.  Efficacy of Miltefosine Used to Treat CL in Colombian and Guatemalan Subjects 
 
Variable 
Colombian site 
Guatemalan site 
Miltefosine 
recipients    
(n = 49) 
Placebo 
recipients  
(n = 24) 
Miltefosine 
recipients    
(n = 40) 
Placebo 
recipients  
(n = 20) 
No. of subjects cured 
40 
9 
20 
4 
No. of subjects with treatment failure 
 
 
 
 
    All 
4 
15 
18 
15 
    Parasite-positive lesions 
0 
15 
12 
12 
    Size of lesion doubled 
2 
5a 
4b 
2 
    Relapse 
2 
0 
4 
1 
No. of unassessable subjects 
 
 
 
 
    All 
5 
0 
2 
1 
    Lost after therapy 
2 
0 
1 
1 
    Lost after 2 weeks 
2 
0 
1 
0 
    Lost after 3 months 
1 
0 
0 
0 
Cure rate, n/N (%) 
 
 
 
 
    Intent-to-treat 
40/49 (82) 
9/24 (38) 
20/40 (50) 
4/20 (20) 
    Per-protocol 
  
40/44 (91) 
9/24 (38) 
20/38 (53) 
4/19 (21) 
a All 5 of these subjects also had parasite-positive lesions. 
b Two of these 4 subjects also had parasite-positive lesions. 
Table adapted from Soto et al., 2004. 
 


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The cure rate was comparable to that historically achieved for pentavalent antimony in 
Colombia. Although the per protocol cure rate in Guatemala (53%) was statistically higher than 
placebo cure rate (21%), the cure rate against L. braziliensis in this locale was less than that 
historically achieved for pentavalent antimony in Guatemala (>90%). 
 
Because this study was placebo-controlled, the rate of subjective and laboratory AEs specifically 
due to miltefosine can be determined. The percent of subjects with noteworthy subjective AEs, 
and with abnormal laboratory findings, is shown in Table 2 below:  
  
Table 2.  Subject Demographics and Efficacy results (Soto et al., 2008) 
 
Variable 
No. (%) of subjects 
Miltefosine 
recipients     
(n = 89) 
Placebo      
(n = 44) 
Treatment-emergent AEs 
 
 
    Nausea 
32 (36) 
4 (9)a 
    Motion sickness 
26 (29) 
10 (23) 
    Headache 
24 (27) 
9 (20) 
    Vomiting 
 
 
        ≥ 1 
28 (31) 
2 (5)a 
        1-2 
22 (25) 
1 (2) 
        3-4 
3 (3) 
1 (2) 
        >4 
3 (3) 
0 (0) 
    Diarrhea 
 
 
        ≥1 
5 (6) 
1 (2) 
        1-2 
4 (4) 
1 (2) 
        >2 
1 (1) 
0 (0) 
Laboratory parameters 
 
 
    Creatinine level 
 
 
        Increased 
29 (33) 
4 (9)b 
        CTC grade 1c 
28 (31) 
4 (9) 
        CTC grade 2d 
1 (1) 
0 (0) 
Elevated alanine aminotransferase level 
7 (8) 
8 (18) 
Elevated alanine aminotransferase level 
9 (10) 
5 (11) 
ap<0.001 
bp=0.003 
cless than 1.5 times the upper limit of normal 
dless than 1.5 and 3.0 times the upper limit of normal 
 
This placebo-controlled study of 89 miltefosine subjects shows that in humans who are without 
systemic disease, nausea and vomiting but not diarrhea occur significantly more frequently than 
in placebo subjects, and elevation of serum creatinine but not ALT occurs significantly more 
frequently than in placebo subjects. Most of the miltefosine-specific AEs were of mild severity: 
80% of the episodes of vomiting were CTC grade 1; 97% of the creatinine elevations were CTC 
grade 1.  


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4.2.8.3 Comparison of Miltefosine to Pentavalent Antimony in L. braziliensis Region in 
Bolivia (Soto et al., 2008) 
The subjects were randomized to treatment with miltefosine (2.5 mg/kg/d for 28 days) or to a 
standard course of intramuscular pentavalent antimony (Glucantime: 20 mg/kg/d for 20 days) in 
2:1 allocation.  
 
AEs were as expected for the two drugs. The primary AE for the miltefosine group was 
gastrointestinal symptoms, which were experienced by 27 of 44 subjects (61%) for a median of 3 
days (range, 1–10 days). For the glucantime group, 13 of 18 subjects (72%) reported arthralgias 
and/or local pain at the injection site for a median of 7 days (range, 5–14 days). Efficacy data is 
presented in the Table 3 below. 
 
Table 3.  Subject Demographics and Efficacy Results (Soto et al., 2008) 
 
  
  
Miltefosine 
recipients 
Glucantine 
subjects 
Presenting characteristics 
 
 
    Number of subjects 
44 
18 
    Age of subjects [years; median   (range)] 
27 (12-57) 
23 (12-51) 
    Male/Female 
36/8 
15/3 
    Weight of subjects [kg; median (range)] 
59 (39-78) 
59 (38-80) 
    Number of ulcers 
64 
30 
      Number per subject [median (range)] 
1 (1-3) 
1 (1-3) 
      Area (mm2) [median (range)] 
181 (10-3,172) 
150 (4-900) 
Results 
 
 
    End treatment 
 
 
      No. of subjects healed/failed/lost 
15/0/0 
9/0/1 
      Percent of subjects healed/evaluable 
15/44=34% 
9/17=53% 
    1 month after treatment 
 
 
      No. of subjects healed/failed/lost 
31/0/0 
16/0/2 
      Percent of subjects healed/evaluable 
31/44=70% 
16/16=100% 
    3 months after treatment 
 
 
      No. of subjects healed/failed/lost 
39/4/1 
15/1/2 
      Percent of subjects healed/evaluable 
39/43=91% 
15/16=94% 
    6 months after treatment 
 
 
      No. of subjects healed/failed/lost 
36/5/3 
15/1/2 
      Percent of subjects healed/evaluable 
36/41=88% 
15/16=94% 
*P=0.01 (Fisher exact test). 
 P=0.67 (Fisher exact test). 
 


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The final cure rate for miltefosine (88%) was insignificantly less than the value for pentavalent 
antimony (94%), although antimony was more rapidly curative since the cure rate at 1 month 
after therapy was higher for antimony (100%) than for miltefosine (70%). This comparator-
controlled study vs. L. braziliensis in Bolivia shows that the relative lack of efficacy of 
miltefosine for L. braziliensis in Guatemala may be an outlier. 
4.2.8.4 Single-arm Study on Diffuse Cutaneous Leishmaniasis (DCL) in Venezuela (Zerpa 
et al., 2007) 
DCL is essentially untreatable because of an inappropriate immunological response by the host 
to parasite antigens. Sixteen subjects with DCL refractory to multiple previous treatments were 
treated with miltefosine, 2.0–2.5 mg/kg daily, for long periods of time (75–218 days).  
 
AEs were very mild. Side-effects were observed in four subjects; two complained of nausea and 
vomiting and reduced the dose without consultation, with improvement in symptoms. One 
subject presented with dizziness on the second day of treatment. On day 20 one subject presented 
with urticaria, that improved with systemic antihistamines. None presented with alteration of 
laboratory parameters during the study. 
 
Subjects showed dramatic clinical improvement and reduction in the parasite burden by day 15 
after the initiation of treatment, which continued while treatment was maintained. By day 45, 15 
subjects showed 80–90% clinical improvement. Nevertheless, suspension of treatment was 
followed by the development of new lesions between 30 and 120 days later in all but one subject.  
This study shows that miltefosine treatment can be tolerated for months beyond the normally 
recommended period of 4 weeks. 
4.2.8.5 Mucosal Leishmaniasis (Soto et al., 2007)  
The initial study design was a randomized equivalency study of oral miltefosine (50 subjects) 
versus standard therapy with pentavalent antimony (25 subjects).  Due to changes in regional 
standard of care to amphotericin B (45 mg/kg as 1mg/kg doses for 45 consecutive days), and due 
to initial positive response rates in the miltefosine group, subjects refused to be treated with 
antimony or to be randomized to the amphotericin B arm of the study. Therefore, the final study 
design became an evaluation of one cohort of 78 subjects who received miltefosine (2.5 
mg/kg/day for 28 days). An almost contemporary group of 19 subjects who received 
amphotericin B (45 mg/kg) as miltefosine treatment was getting organized was evaluated as a 
post hoc comparison group. 
 
Miltefosine was well tolerated. Nausea, vomiting, and diarrhea were each reported by 8–17 
subjects. Most episodes were CTC grade 1; one episode was grade 3. Most episodes lasted 1–2 
days and a few lasted 3–4 days. Mean values of liver function tests and kidney function tests did 
not change; a few subjects had values that were slightly above the upper limit of normal after 
treatment. 
 
Of the 78 subjects who received miltefosine, 72 were evaluable. Fourteen of 19 subjects in the 
amphotericin B group were evaluable. Fifty-one (71%) of the 72 evaluable miltefosine subjects 
were “cured” by the definition of >90% diminution in the mucosal severity score with 12 months 
of follow up. Almost all (49 [96%]) of these subjects demonstrated complete resolution of their 


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clinical signs. The cure rate for the 36 subjects who had “mild” disease (i.e., affecting only the 
nasal skin and nasal mucosa) was 83%. The cure rate for the 36 subjects who had more extensive 
disease (involving the palate, pharynx, and larynx) was 58%.  
 
The cure rate for the amphotericin B group (45 mg/kg over 90 days) was 7 (50%) of 14. 
Since the historic cure rate for treatment of ML in neighboring Peru varies between 10% and 
75%, this study suggests that miltefosine is approximately as effective as standard treatment with 
antimony, and with amphotericin B, for Andean mucosal disease. Before-and-after photographs 
of one subject from this study with involvement of the external nares (Figure 1), illustrates the 
clinical improvement in skin and mucosa consequent to successful miltefosine therapy. 
 
4.2.8.6 Clinical Summary  
The cure rate for CL treated with miltefosine (2.5 mg/kg/day for 28 days) is superior to placebo 
and, except in one region, comparable to standard therapy with antimony. This regimen of 
miltefosine also gives cure rates for ML comparable to historic values for antimony, and 
provides remarkable clinical improvement for DCL subjects. 
  
 
Subjects with CL or ML are systemically normal. For these hosts, laboratory abnormalities due 
to miltefosine treatment consist of the common occurrence of low grade elevations in serum 
creatinine, and the uncommon occurrence of higher-grade elevations, both of which are 
reversible. The symptoms of nausea, vomiting, and perhaps motion sickness/headache are also 
common. 
  
Miltefosine has a favorable therapeutic index for CL and ML, with the additional advantage of 
being orally administrable. No other accepted antileishmanial agent, whether an investigational 
agent in the United States or registered agent elsewhere, is orally administrable.  


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4.2.9 References 
 
Investigator's Brochure. Edition 15 January 2009. Paladin Labs Inc. 
 
Dorlo, T. P., P. P. van Thiel, et al. (2008). Pharmacokinetics of miltefosine in Old World 
cutaneous leishmaniasis patients. Antimicrob Agents Chemother 52(8): 2855-60. 
 
Murray, H. W., J. D. Berman, et al. (2005). Advances in leishmaniasis. Lancet 366(9496): 1561-
77. 
 
Soto, J., J. Toledo, et al. (2001). Treatment of American cutaneous leishmaniasis with 
miltefosine, an oral agent. Clin Infect Dis 33(7): E57-61. 
 
Soto, J., B. A. Arana, et al. (2004). Miltefosine for new world cutaneous leishmaniasis. Clin 
Infect Dis 38(9): 1266-72. 
 
Soto, J., J. Toledo, et al. (2007). Treatment of Bolivian mucosal leishmaniasis with miltefosine. 
Clin Infect Dis 44(3): 350-6. 
 
Soto, J., J. Rea, et al. (2008). Efficacy of miltefosine for Bolivian cutaneous leishmaniasis. Am J 
Trop Med Hyg 78(2): 210-1. 
 
Zerpa, O., M. Ulrich, et al. (2007). Diffuse cutaneous leishmaniasis responds to miltefosine but 
then relapses. Br J Dermatol 156(6): 1328-35. 
 
 


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5 
STUDY OBJECTIVES 
5.1 
Primary 
Record the efficacy of miltefosine, 2.5 mg/kg/day for 28 days, in the treatment of 
mucocutaneous leishmaniasis presenting in the United States. 
5.2 
Secondary 
Record the tolerance of miltefosine, approximately 2.5 mg/kg/day for 28 days, in the treatment 
of mucocutaneous leishmaniasis presenting in the United States. 
6 
STUDY DESIGN 
Open-label, single group, multicenter study 
7 
STUDY SUBJECTS 
7.1.1 Estimated Number of Subjects 
10-20 per year for 1-5 years 
7.1.2  Inclusion Criteria 
To be eligible for the study, the following must be answered “YES” or not applicable as 
appropriate for the study subject: 
 
1. Is the subject a male or female at least 18 years of age? 
2. Does the subject weight at least 30 kg? 
3. Does the subject have a diagnosis of ML or CL in at least one lesion by at least one of the 
following methods:  
a. positive culture of lesion material for promastigotes,  
b. microscopic identification of amastigotes in stained lesion tissue, or 
c. PCR 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 subject signed informed consent? 
7.1.3 Exclusion Criteria  
To be eligible for the study, the following must be answered “NO” or not applicable as 
appropriate for the study subject: 
  
1. Is the subject a female who is breast-feeding? 
2. Does the subject have a clinically significant medical disorder? 
a. Platelet count <100 x 109/L 
b. Leukocyte count <3 x 109/L 
c. Hemoglobin <10 g/dL 


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d. ALT, >2 times upper limit of normal range 
e. Bilirubin >1.5 times upper limit of normal range 
f. Serum creatinine  >1.5 times upper limit of normal range 
g. Major surgery within last 2 weeks 
h. 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?  
8 
INVESTIGATIONAL PRODUCT 
8.1 
Description  
Miltefosine is formulated as capsules of 50 mg strength. The ingredients are as follows:  
 
 
Active Principle:  
50 mg miltefosine 
Inactive ingredients:  Lactose D10, avicel PH 101, talkum, aerosil V200, magnesium   
stearate 
 
The investigator or authorized person assigns the box to an eligible subject by writing the 
subject’s study number and alpha code on the label on the box, i.e. capsules in a box are for use 
in a single subject only; residual capsules may not be used for another subject. The trial 
medication may not be used after the retest or expiry date which is specified in the certificate of 
analysis.  
8.2 
Labeling 
Each box of miltefosine contains 56 capsules: 8 packs of blisters, with each blister pack 
containing 7 capsules. Each box has a preprinted label with a space for the subject’s ID number, 
alpha code, dosing instructions, 24/7 emergency telephone number, storage conditions, 
precautions, and lot# and expiry date, as follows: 
 


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Each blister pack is preprinted with “Impavido 50 mg capsules” as well as other identifying 
information. 
8.2.1 Storage 
Medication should be kept out of the reach of children and away from direct sun light, and at 
temperatures not above 40C (104F).  
8.2.2 Drug Accountability 
The Treating Physician has to account for all used and unused trial supplies and has to complete 
a Medication Accountability Form. Residual supplies will be destroyed by the Treating 
Physician as directed. The completed Medication Accountability Form will be returned to the 
Data-Management Center. The trial medication must not be used outside this protocol.  
8.3 
Start of Treatment 
Treatment should be started within 2 weeks after the completion of screening assessments. 
Otherwise compliance with eligibility criteria has to be reassessed. 
8.4 
Administration of Investigational Product (Miltefosine)  
Route:  Oral administration 
 
Dose:   The daily dosage for subjects of body weight 30-45 kg is 100 mg miltefosine (2 capsules 
Impavido 50 mg). Subjects with a body weight higher than 45 kg receive 150 mg miltefosine 
daily (3 capsules Impavido 50 mg).  
 
The capsules should be taken with meals. Subjects taking 2 capsules per day should take one 
capsule with the morning meal and with the evening meal. Subjects taking 3 capsules per day 
should take one capsule with the morning meal, the noon meal, and the evening meal.  
 
Clinical Study # PLB-MILT-201           Sponsor: Paladin Labs (USA) Inc. 
 
ID #    _____________________         Alpha code ___________________ 
 
 
Take 1 capsule ____ times a day with meals 
 
If medical emergency, call your doctor at (         ) ________________ 
 
Store in original container at room temperature 
 
CAUTION: INVESTIGATIONAL NEW DRUG LIMITED BY FEDERAL 
LAW TO INVESTIGATIONAL USE. 
 
Caution: Keep out of the reach of children 
 
Lot #   8J7717                                    Expiry Date: 10 July 2012 
 
Manufactured by: Haupt Pharma Amareg GmbH, Regensburg, Germany 


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Duration of treatment:  28 days. 
8.5 
Allocation of Study Treatment to Subject and Compliance 
For subjects who will receive 2 capsules per day, the subject will receive a box of medication (56 
capsules) at the initiation of therapy which is sufficient for the total treatment period of 28 days. 
For subjects who will receive 3 capsules per day, the subject will receive a box of medication (56 
capsules) at the beginning of therapy that is enough for 18 days of treatment, and will return to 
the treatment facility after 2 weeks to receive the final 2 week’s supply of medication.  
Compliance with drug administration will be assessed by subject interview and pill count. 
8.6 
Treatment Modifications and Study Discontinuation 
Dose reduction due to AEs: A subject who does not tolerate the planned dosage will go off-
treatment. No dose reduction is planned.  
 
Discontinuation of study treatment and withdrawal from protocol for other reasons:  A subject 
may withdraw from the study at any time and for any reason without penalty, if he or she wishes 
to do so.  The Treating Physician may withdraw a subject if continuing participation is believed 
to be harmful to the subject’s well-being or in the event of protocol violations, non-compliance, 
positive pregnancy test during active treatment, serious intercurrent illness, or apparent failure of 
efficacy. The sponsor, PI, and IRB have the right to discontinue the investigation at any time. 
 
In the event that the subject withdraws from the study before the completion of the 28 days of 
treatment, s/he will be asked to come to the clinic for a final assessment including AEs, lesion 
measurements, vital signs, blood creatinine, and concomitant medication use.  
 
If the subject withdraws during the follow-up period, s/he will be contacted, if possible, and 
requested to come to the clinic for lesion measurements. 
 
If possible, positive pregnancy should be followed to the end of the pregnancy.  
8.7 
Concomitant Therapy  
All concomitant medications and any therapies (prescribed and non-prescribed) must be recorded 
on the CRF. Any change during the study should be documented as well. Symptomatic treatment 
of side effects and treatment of concomitant diseases not associated with leishmaniasis is 
permitted. Treatment with other agents known or likely to be active against Leishmania 
(pentavalent antimony, amphotericin B, paromomycin, imidazoles, local heat or cold therapy) is 
not permitted. 
8.8 
Rescue Treatment   
Anti-leishmaniasis drugs must not be administered while the subject is on protocol. If the subject 
is removed from the protocol for any reason (decision that the subject has failed treatment, 
inability of the subject to comply with the protocol conditions, or desire of the subject, physician, 
Sponsor, or IRB), the subject may be treated with another antileishmanial agent off-protocol at 
the discretion of the treating physician. 
 


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9 
STUDY PROCEDURES 
 
Time and Event Schedule 
Study Phase 
Screeninga 
Treatment  
Follow-up 
Study 
Day/Week/Month  
Day 
-14 to -1 
Day 1 
Day 7  
3 days 
Day 14 
3 days 
Day 28 
Week 6 
Month 3 
Month 7 
Month 13h 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical Historyb, c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationd 
X 
X 
 
 
X 
X 
X 
X 
X 
Leishmanial History 
and Examc 
X 
 
 
 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
Blood Chemistries 
Xe 
 
 
Xf 
Xf 
Xg 
Xg 
Xg 
Xg 
ECG 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
X 
X 
X 
 
X 
X 
 
Eligibility Checklist 
X 
 
 
 
 
 
 
 
 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment  
 
Daily 
 
 
 
 
aScreening includes the 14-day period for conducting screening procedures prior to the first administration of investigation product on 
Day 1. 
bIncludes medication history 
cIf subject does not appear at the scheduled Week 6, Month 3, Month 7, or Month 13 visits, these data may be obtained from the 
subject by telephone, and will be noted as obtained in that manner. 
dIncludes vital signs  
eScreening laboratories 
fAlanine transaminase (ALT) and creatinine on Day 28 and also on nominal day 14 
gIf abnormal on previous examination 
hML subjects only 
 


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9.1 
Subject Recruitment 
The medical community will be alerted to the availability of miltefosine via this Treatment IND 
via informal communications and listing on ClinicalTrials.gov. 
 
Subjects with mucosal or cutaneous lesions from which Leishmania have already been identified 
are potentially eligible to be treated with miltefosine via this protocol. Treating Physicians with 
potentially eligible subjects will contact the protocol PI, and receive the CRFs from the PI. The 
Treating Physician will complete the screening CRF pages for demographics, medical history, 
leishmaniasis history, clinical laboratory results that are available, and identification of 
Leishmania in the lesion, and send (mail or fax) these CRF pages to the PI. If after PI review, the 
subject is potentially eligible for the protocol, the PI will send the protocol, the miltefosine 
package insert, the informed consent form, and the FDA form 1572 to the Treating Physician. 
Although this protocol will have already been approved by a “central” IRB, if there is an 
additional need to have the Treating Physician’s local IRB approve the protocol, the Treating 
Physician will obtain the approval, and obtain informed consent from the subject. The rest of the 
laboratory tests must be accomplished so that all screening laboratory tests are completed prior to 
enrolling a potential subject. If in the physician’s opinion the subject appears eligible for 
enrollment, the Treating Physician will send the local IRB signature page (if needed), protocol 
signature page, informed consent signed by both the subject and the Treating Physician, the rest 
completed CRF pages for screening data to the PI, and the form 1572 completed with the 
Treating Physician’s information plus his/her curriculum vitae. After the PI’s review of these 
documents, the investigational product will be sent from the drug repository to the Treating 
Physician for that subject’s use. 
 
Note that because the tests needed to satisfy the entrance criteria of medical history, 
leishmaniasis history, and identification of Leishmania in the lesion are standard of care for this 
disease, the tests can be performed prior to signing the consent form for this protocol. This 
procedural order [evaluate certain entrance criteria, then achieve local IRB approval if needed 
and signing of consent, then evaluate the rest of the entrance criteria] is chosen so that subjects 
do not undergo excess procedures and expectations  if the subject ultimately is unlikely to be 
able to enroll in the protocol. 
9.2 
Screening Procedures 
Subjects will have the following procedures performed during a two week period prior to the  
initiation of investigational product: 
1. Consent form completed and signed. 
2. Demographics form completed. 
3. Medical history form completed and record medications used in the past 2 weeks. 
4. Physical examination form completed including vital signs, height, and weight. 
5. Leishmaniasis history and physical form completed. 
a. Record history of leishmaniasis including; 
(1) CL:   estimated date that the lesion(s) first appeared, evolution of symptoms, 
treatments to date 
(2) ML:  estimated date that the symptoms first appeared, evolution of symptoms, 
treatments to date 


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            b.  CL subject examination: For each cutaneous lesion, record the size of the lesion 
ulceration (length/width), characteristics of the lesion (ulcerated versus non-
ulcerated), and anatomical location. Examination of nasal skin, nasal mucosa, palate, 
and pharynx must be performed by the Treating Physician. 
c.  ML subject examination: Examination of mucosal membranes. Each of 5 possible 
sites (nasal skin, nasal mucosa, palate, pharynx, and larynx) will be evaluated for 4 
possible signs of disease (erythema, edema, infiltration, and erosion) by an ear, nose, 
and throat (ENT) specialist. 
6. Pregnancy test from completed for women of child-bearing potential. 
7. Hematology form completed to include white blood cells (WBC), neutrophil count, 
hemoglobin, hematocrit, and platelet count. 
8. Chemistry form completed including glucose, sodium, potassium, creatinine, ALT, and 
bilirubin in the serum. 
9.3 
Assessment During Miltefosine Treatment 
9.3.1 Study Day 1 
Study Day 1 visit is conducted on the first day of miltefosine therapy and includes: 
1. Medical History - record changes in medical history or medications since screening visit 
2. Physical Examination form - perform brief physical exam including vital signs 
3. Pregnancy test form - perform a pregnancy test in women of child bearing potential, 
unless the screening pregnancy test was performed within the previous 24 hours. 
4. Complete the eligibility checklist to ascertain if the subject still meets all of the eligibility 
criteria, then the subject will receive the first dose of medicine. 
5. Record any AEs 
9.3.2 Study Days 7 and 14 
Two visits are scheduled to occur between Study Day 2 through Study Day 27 and should 
preferably occur at the end of Study Week 1 and Study Week 2 with in a three-day window 
either side of Day 7 and Day 14. At these two visits the following assessments are performed: 
1. Medical History - The subject will return to clinic for evaluation; record any AEs 
2. Treatment form – complete log 
3. If more medication than that which was dispensed on day 1 is needed, further medication 
will be dispensed on the nominal day 14 visit 
4. Chemistry – record values of ALT and creatinine in the serum (Day 14 visit only) 
5. Record any AEs 
9.3.3 Study Day 28 
Study Day 28 visit is conducted the last day of miltefosine therapy and includes: 
1. Medical History - record changes in medical history or medications 
2. Physical examination – record vital signs 
3. Interval History of leishmaniasis: 
a. CL - lesion reactions 
b. ML - evolution of symptoms 
4. CL subjects: Re-examination of each CL lesion and re-recording the size of the lesion 
ulceration (length/width), other notable characteristics of the lesion 


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5. ML subjects: Re-examination of mucosal membranes 
6. Pregnancy test in women of child-bearing potential 
7. Chemistry – record values of ALT and creatinine in the serum 
8. Record any AEs 
9.3.4 Study Week 6 
Two weeks after the Study Day 28 visit record the following: 
1. Medical History - record changes in medical history or medications since 28-day visit 
2. Physical examination - perform brief physical exam if appropriate, and vital signs 
3. Interval History of leishmaniasis since last visit to include: 
a. ML - re-examination of mucosal membranes. Evolution of symptoms 
b. CL subjects - re-examination of each CL lesion and record the size of the lesion 
ulceration (length/width), other notable characteristics of the lesion  
4. ALT and creatinine: Repeat if abnormal on last examination 
5. Record any AEs 
9.3.5 Study Month 3 
Study Month 3 visit is conducted 2 months after the end of miltefosine therapy and includes: 
1. Medical History - record changes in medical history or medications since 6-week visit 
2. Physical Examination - perform brief physical exam if appropriate, and vital signs 
3. Interval History of leishmaniasis since last visit to include: 
a. ML - re-examination of mucosal membranes. Evolution of symptoms. 
b. CL subjects - re-examination of each CL lesion and record the size of the lesion 
ulceration (length/width), other notable characteristics of the lesion  
4. Pregnancy test in women of child bearing potential 
5. ALT and creatinine: Repeat if abnormal on last examination 
6. Record any AEs 
9.3.6 Study Month 7 
Study Month 7 visit is conducted 6 months after the end of miltefosine therapy. Final follow up 
visit for CL subjects and includes: 
1. Medical History - record changes in medical history or medications since 3-month visit 
2. Physical Examination - perform brief physical exam if appropriate, and vital signs 
3. Interval History of leishmaniasis since last visit to include: 
a. ML - re-examination of mucosal membranes. Evolution of  symptoms  
b. CL subjects - re-examination of each CL lesion and record the size of the lesion 
ulceration (length/width), other notable characteristics of the lesion  
4. Pregnancy test in women of child bearing potential 
5. ALT and creatinine: Repeat if abnormal on last examination 
6. Record any AEs 
9.3.7 Study Month 13 
Study Month 13 visit is conducted 12 months after the end of miltefosine therapy. Final follow 
up visit for ML subjects and includes: 
1. Medical History - record changes in medical history or medications since 7-month visit 
2. Physical Examination - perform brief physical exam if appropriate, and vital signs 


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3. Interval History of leishmaniasis since last visit to include: 
a. ML - re-examination of mucosal membranes. Evolution of symptoms.  
b. CL subjects - re-examination of each CL lesion and record the size of the lesion 
ulceration (length/width), other notable characteristics of the lesion  
4. ALT and creatinine: Repeat if abnormal on last examination 
5. Record any AEs 
 
NOTE: if the subject does not return to clinic for the post-treatment visits, medical history and 
interval history of leishmaniasis may be obtained by telephone. Further, the subject’s 
examination of a CL lesion may be obtained by telephone. Telephonic data will be noted as such 
on the CRF. 
 
 


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10 EFFICACY 
NOTE: Responses in subjects with CL and ML will be presented separately. 
10.1 Efficacy Assessments of CL Subjects 
10.1.1 Assessment Methods 
10.1.1.1 Parasitological Diagnosis of Leishmaniasis 
Prior to entrance into this protocol, lesion(s) will have been scraped, aspirated, or biopsied; and 
the specimens will have been smeared onto microscope slides for examination with DifQuik or 
Giemsa staining, placed in culture medium to visualize motile promastigotes, or subjected to 
PCR analysis for Leishmania-specific nucleic acid.  
 
NOTE: The Treating Physician may choose to perform these parasite diagnostic procedures on 
lesions that are not-healed post therapy or on a new lesion to see if the lesion contains 
Leishmania. These procedures are at the Treating Physician’s discretion and not formally part of 
this protocol. 
10.1.1.2 Examination of Cutaneous Lesions  
Ulcerated CL lesions will be measured in mm for the longest diameter and perpendicular width 
of ulceration. Non-ulcerated lesions will be measured for length and width of the raised area of 
the lesion. Lesion area = Length x Width. Lymph nodes in the drainage path of the cutaneous 
lesion will be noted and measured. 
10.1.1.3 Examination of Mucosa 
For CL subjects, the Treating Physician will examine the nasal and oral mucosa of each subject. 
10.1.2 Definitions of Lesion Response  
Healed:  
100% reduction in lesion area [lesion size = 0x0 mm2] 
Improved:  
50% - 99% reduction in lesion area 
No change: 
49% enlargement to 49% reduction in lesion area 
Worse: 
>50% enlargement of lesion area at or after the end of therapy. 
Relapsed: 
Substantial enlargement of lesion after initial improvement or healing. 
 
10.1.3 Definition of Clinical Responses 
Lesion Cure:  Lesion is healed at the Month 7 visit. 
Lesion Failure: Each lesion will be considered a failure if it does not meet the criteria for cure 
(missing data will be considered failures). The intended response to therapy is a progressive 
diminution in lesion size and no relapse. Lesion failure therefore is defined as clinically worse at 
the end of therapy or thereafter, OR does not improve at the Week 6 or Month 3 visit, OR is not 
healed at the Month 7 visit, OR relapses.  
 
NOTE: Parasitological responses can assist the clinician in evaluating the clinical response of the 
lesion. If the Treating Physician has parasitologically re-investigated a slowly responding lesion 


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at time-points greater than 2 weeks after the end of therapy, and parasites are still present by 
microscopy or culture, the physician may interpret the data as indicating therapeutic failure. Note 
that the presence of parasites prior to 2 weeks after the end of therapy should not be interpreted. 
Note that because PCR is more sensitive than microscopy or culture on which the clinical 
experience in the literature is based, PCR positivity post therapy cannot easily be interpreted.  
10.1.4 Definition of Subject Cure 
Subject Cure:  All lesions cured by the end of follow up at Month 7 visit.  
Subject Failure:  Not all lesions clinically cured, or a new lesion due to Leishmania. 
 
Primary endpoint(s):  The co-primary endpoints are the subject cure rate for the modified 
intention-to-treat (mITT) and evaluable populations.  
10.2 Efficacy Assessment of ML Subjects 
10.2.1 Assessment Methods 
For subjects with suspected ML, an ENT specialist will examine the nasal and oral mucosa. Each 
of 5 possible sites (nasal skin, nasal mucosa, palate, pharynx, and larynx) will be evaluated for 4 
possible signs of disease (erythema, edema, infiltration, and erosion) and graded on a 0-3 scale: 0 
= no disease, 1 = mild disease, 2 = moderate disease, 3 = severe disease. If possible, the ENT 
specialist who first examined the subject will re-evaluate the oral-nasal mucosa at each follow-up 
visit for the subject 
10.2.2 Clinical Parameter and Definition of Clinical Responses 
Clinical response will be measured will be a composite score, the mucosal severity score (MSS). 
The MSS is the sum of the severity scores for each clinical sign at each clinical site of disease. 
The Maximum MSS is 60: grade 3 severity for each of 4 possible signs at each of the 5 possible 
sites. 
 
Healed:  
MSS that is 0 in absolute value [equals 0% of the entrance MSS score].  
Improved:  
MSS that is 1%-25% of the entrance MSS score. 
Non-substantial Change:  
MSS that is 26%-99% of the entrance MSS score. 
Worse:  
MSS >100% of the entrance MSS score.  
Relapse: 
 MSS substantially increases after initially improving or becoming 0. 
10.2.3 Definition of Subject Responses 
Subject cure:  Clinical cure is lesion is healed. 
Subject failure:  Leasion did not heal. NOTE: The intended response to therapy is a progressive 
diminution in signs and symptoms and no relapse. Subject failure is defined as clinically worse at 
the Week 6 visit or thereafter, OR does not improve at the Month 3 or month 7 visits, OR is not 
healed at the Month 13 visit, OR relapses.  
 
Primary endpoint(s):   The primary endpoints are the clinical cure rates for the mITT and 
evaluable population. 


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10.3 Withdrawal from Protocol for Lack of Efficacy 
The Treating Physician may choose to withdraw the subject from the protocol for lack of 
efficacy and to initiate rescue (alternative) therapy for ML or CL.  
 
For CL, the basis for lack of efficacy will generally be failure of at least one lesion: lesion has  
worsened at the end of therapy or thereafter, OR does not Improve at the Week 6 or Month 3 
visit, OR is not healed at the Month 7 visit, OR relapses, or a new lesion. 
 
For ML, the basis for lack of efficacy will generally be failure: clinically worse (by MSS score) 
at the Week 6 visit of or thereafter, OR does not improve at the Month 3 or Month 6 visit, OR is 
not healed at the Month 13 visit, OR relapses.  


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11 SAFETY/ADVERSE EVENTS 
11.1 Assessment Methods 
11.1.1 Symptoms  
Medical history: At screening, during treatment, and during follow up, subjects will be asked 
general questions about their well being and specific questions about gastrointestinal distress 
(nausea, vomiting, diarrhea). If a medically substantial problem is reported, it should be reported 
to the Treating Physician immediately.   
11.1.2 Signs 
At screening, a physical exam of the head, eyes, ears, cardiovascular system, lungs, abdomen 
(liver/spleen), extremities, skin, lymphatic system, neuropsychiatric mental status and 
sensory/motor status, musculoskeletal system and general appearance will be performed. Height 
and weight will be recorded. Vital signs (blood pressure, heart rate, temperature) will be 
recorded. During treatment and follow up, a targeted physical exam will be performed if 
prompted by the subject or the subject’s appearance. Vital signs will be recorded.  
11.1.3 Laboratory Assessments 
Venous blood will be collected during screening for measurement of hematology parameters to 
be reported [white blood cells (WBC), neutrophil count, hemoglobin, hematocrit, and platelet 
count] and chemistry parameters including glucose, sodium, potassium, creatinine, ALT, and 
bilirubin.  These baseline values will be used to determine if the subject has a concomitant 
medical condition. 
 
On nominal days 14 and 28, a blood sample will be collected for AST and creatinine only. On 
follow up visits at Month 3, Month 7, and Month 13, blood will again be collected for ALT and 
creatinine if on the previous sample the ALT value was above the upper limit of normal, or if the 
creatinine clearance was abnormal. Serum creatinine levels will be used to calculate creatinine 
clearance (CrCl) according to the Cockroft-Gault formula as follows: 
 
Males  
CrCl (mL/min) =   [140 – age (years) x body weight (kg)]   
      (72) x (serum creatinine [mg/dL]) 
 
Females 
CrCl (mL/min) =  0.85 x [140 – age (years) x body weight (kg)] 
(72) x (serum creatinine [mg/dL]) 
11.1.4 Pregnancy Test 
For females of child-bearing potential, an FDA-cleared serum or urine pregnancy test that 
measures human β-chorionic gonadotropin will be used during screening, at the end of treatment, 
and during follow up. 
11.1.5 Electrocardiogram (ECG) 
An ECG will be taken during screening to evaluate if the subject has a baseline medical 
condition. 


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11.2 AE Definition 
An AE is defined as any reaction, side effect, or untoward event that occurs during the course of 
the clinical trial, whether or not the event is considered investigational product-related or 
clinically significant. For this study, AEs will include events reported by the subject, as well as 
clinically significant abnormal findings on physical examination or laboratory evaluation.   
 
A new illness, symptom, sign, or clinically significant clinical laboratory abnormality is 
considered an AE. A worsening of a pre-existing condition or abnormality is also considered an 
AE. The appearance of scars at healed lesion sites will not be reported as an AE. Stable chronic 
conditions which are present prior to clinical trial entry and do not worsen are not considered 
AEs.  
11.3 Severity Definitions 
Subjective AEs will be graded according to the definitions provided below: 
 
Grade 1:   Mild symptoms invoking a minimum degree of discomfort that are easily tolerated. 
 
Grade 2:   Moderate symptoms that result in a reduction in normal daily activity, but is not 
totally incapacitating. This may or may not require medical intervention. 
 
Grade 3:   Severe symptoms that may be totally incapacitating or result in marked reduction in 
normal daily activity. Medical intervention is usually required. 
 
Grade 4:   Potentially life-threatening event that requires emergency intervention or 
hospitalization. 
 
 
Physical examination AEs and laboratory AEs will be graded according to the National Cancer 
Institute’s CTC for AEs. For the expected AEs of vomiting, diarrhea, ALT elevation, and 
creatinine elevation, the Common Terminology Criteria are: 
 
Analyte 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT elevated 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Creatinine 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
Vomiting 
1 episode per day 
2 to 5 episodes 
per day 
6 to 10 episodes per 
day 
more than 10 
episodes per day 
Diarrhea 
increase of 2 to 3 
stools per day 
increase of 4 to 6 
stools per day 
7 to 9 stools per day 10 or more stools 
per day 
 
The Common Terminology Criteria for unanticipated AEs will be accessed if needed.  
 


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11.4 Assessment of Causality 
The relatedness of an AE to the investigational product is the best estimate of the causal 
relationship between the investigational product and an AE at the time of reporting. Causality 
will be assessed by the Treating Physician and subsequently by the PI.  
 
Definitions are:  
 
 
Unrelated:   
There is no temporal relationship between the event and the administration 
of the investigational product or the event is clearly due to the subject’s 
medical condition, other therapies, or accident. 
 
Unlikely:  
There is evidence of exposure to the investigational product but there is 
another more likely cause of the event. 
 
Possibly Related:   
There is some temporal relationship between the event and the 
administration of the investigational product and the event is unlikely to 
be explained by the subject’s medical condition or other therapies. 
 
Probably Related:   
The temporal relationship between the event and the administration of the 
investigational product is compelling, and the subject’s medical condition 
and other therapies cannot explain the event. 
 
Definitely Related:   The event follows a reasonable temporal sequence from administration of 
the medication or follows a known or suspected response pattern to the 
medication. 
 
The categories of Definitely Related, Probably Related, and Possibly Related will be considered 
investigational product related with regards to summary statistics. 
11.5 AE Actions and Outcomes  
For each AE that is reported, the actions taken with respect to investigational product can be: 
1. none 
2. permanently discontinued  
 
Also, outcomes will be recorded as:  
1. resolved 
2. resolved with sequelae 
3. ongoing 
4. required treatment 
5. unknown 
11.6 Monitoring and Reporting of Adverse Events  
The Treating Physician will monitor subjects for the occurrence of AEs from time the first 
investigational product is 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 are to 


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be recorded on the CRF.  For the period Week 6 to Month 7 for CL, or Month 13 for ML, only 
AEs requiring medical attention are to be recorded on the CRF. 
 
Whenever possible, symptoms should be grouped as a single syndrome or diagnosis. The 
Treating Physician should specify the date of onset, maximum severity grade, his/her opinion as 
to association between the AE and the administration of the investigational product (causality), 
outcomes including corrective therapy given (if applicable). Clinically significant AEs ongoing 
at the last follow up visit will be followed to resolution or stabilized including the administration 
of any concomitant medications. 
11.7 Serious Adverse Event (SAE) 
Each AE or reaction will be classified by the Treating Physician as serious or non-serious. Based 
on the seriousness of the AE or reaction appropriate reporting procedures will be followed.  
An SAE is defined as: 
 
 results in death; 
 is life-threatening;  (NOTE: The term "life-threatening" in the definition of "serious" 
refers to an event in which the subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more 
severe.) 
 requires inpatient hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability/incapacity; or 
 is a congenital anomaly/birth defect. 
 
In addition, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug reaction, when based on appropriate 
medical judgment that may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the above definition. For this protocol, 
becoming pregnant between Study Day 1 and Month 7 is considered to be an SAE. 
11.8 SAE Reporting Requirements  
The Treating Physician must report all SAEs to the PI that are possibly, probably, or definitely 
related to study medication within 24-hours of learning of the SAE by email, telephone, or fax. 
 
Within a further 3 working days, the SAE CRF, along with any other appropriate supporting 
documentation, must be submitted by the Treating Physician to the PI. 
 
 
The Data Management Center will prepare a narrative or a MedWatch (FDA Form 3500A) if the 
SAE meets the criteria for expedited reporting for an SAE.  


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12  ANALYTICAL PLAN  
12.1 Sample Size  
As the study is not designed to compare the efficacy of the two treatments, there is no formal 
sample size calculation.  
12.2 Analytical Populations  
mITT Population:  The mITT population includes all subjects who received any administration 
of an investigational product.   
 
Evaluable Population:  The evaluable population will include all subjects who received daily 
doses of investigational product for at least 25 of the total of 28 days, had lesion measurements at 
the Month 7 for CL or the month 13 visit for ML, and who did not receive rescue medications to 
treat leishmaniasis at any time during the study. 
 
Efficacy outcomes will be presented separately for subjects with CL and ML. 
 
Safety Population:  The safety population includes all subjects who received any administration 
of investigational product. 
12.3 General Analytical Procedures 
Descriptive statistics will be used to present study data. Continuous variables will be presented 
as number of observations (n), mean, standard deviation (SD), median, minimum and maximum 
values. Categorical variables will be presented as counts and percentages.  
12.4 Analysis of Baseline Data  
By-subject and summaries of the baseline data will be provided for the mITT, and evaluable 
populations.  
12.5 Analysis of Treatment Compliance Data 
By subject and summaries of compliance with scheduled treatments will be provided, including 
total exposure (number of days and total dose) to investigational product.  
12.6 Analysis of Efficacy Outcomes of CL Subjects 
12.6.1 Lesion Area Measurements 
Summary statistics for each subject will include lesion area and change from baseline at each 
measurement time point. 
12.6.2 Lesion and Subject Cure Rate 
For each subject, the proportion of lesions at each measurement time point that have healed, 
improved, did not change, worsened, or relapsed will be calculated. Also for each subject, the 
proportion of all lesions that cured and all lesions that failed will be presented. The proportion of 
subjects who cure or fail will be calculated. This data will be presented for the mITT and 
evaluable populations. 


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12.6.3 Handling of Missing Data 
Missing lesion measurements will be ignored when presented as summary statistics of lesion 
areas and lesion responses as presented by numbers of lesions evaluated at each time point. 
Subjects who do not provide lesion response measurements at their final scheduled follow up 
will be considered lesion ane subject failures in the mITT analysis. 
 
Note that if a subject does not appear at the scheduled Study Week 6, Month 3, or Month 7 visits, 
the subject’s estimate of his/her lesion response may be obtained from the subject by telephone, 
and will be noted as obtained in that manner. Such data is not defined as missing. For such data, 
the Treating Physician and the PI will jointly decide if the subject’s estimate is likely to be 
reliable. In a single-group non-comparative study such as this one, errors in interpretation will 
only apply to miltefosine subjects and will not be corrected by being equally applied to a 
comparator group. Therefore, it is important for subject, physician, and Investigator to avoid two 
potential errors:  1) erroneously viewing a lesion as healed when in fact it is still present, 2) 
erroneously viewing a lesion as failed because a subject does not show up for clinic, when in fact 
the lesion has healed and the subject does not want to spend time coming to clinic. 
12.7 Analysis of Efficacy Outcomes of ML Subjects 
12.7.1 Lesion assessments 
Summary statistics for each subject will include the individual components of the MSS score and 
the total MSS score, and change from baseline in both parameters, at each measurement time 
point. 
12.7.2 Subject Cure Rate  
The proportion of subjects at each measurement time point with clinical cure, improvement, fail, 
and relapse will be calculated. Data will be presented for the mITT and evaluable populations. 
12.7.3 Handling of Missing Data 
Missing lesion measurements will be ignored when presented as summary statistics of lesion 
areas and lesion responses as presented by numbers of lesions evaluated at each time point. 
Subjects who do not provide lesion measurements at their final scheduled follow up will be 
considered clinical failures in the mITT analysis. 
 
Note that because the subject cannot accurately examine his/her oro-nasal membranes, subject 
reports of physical mucosal examination cannot be accepted. 
12.8 Analysis of Safety Data 
Symptoms (subjective AEs) will be coded using the most recent version of the Medical 
Dictionary of Regulatory Affairs (MedDRA) by assigning a preferred term and will be grouped 
by system, organ, and class (SOC) designation. Listings of each individual AE including start 
date, stop date, severity, relationship, duration, and outcome will be provided.  
 


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Laboratory data and physical signs (including vital signs) will be presented as summary statistics 
by Study Day including changes from baseline as well as in by-subject data listings. A summary 
and listing of analyte concentrations and vital signs for subjects with levels outside normal 
laboratory limits will also be presented. Clinically significant AEs, SAEs, discontinuation due to 
AEs, and other significant AEs will be individually listed and narrated. 
 
The above safety analysis will be provided for the mITT and Evaluable populations.  
13  ADMINISTRATIVE AND REGULATORY STANDARDS 
An IND will be obtained from the FDA. The PI will sign a Form FDA 1572. 
13.1 Ethical Review of Protocol    
The PI will obtain protocol approval from a central IRB before starting the study.  
13.2 Informed Consent 
Each subject’s Treating Physician will be responsible for obtaining informed consent from that 
subject prior to his/her participation. If that subject’s treatment will occur in a facility over which 
an IRB has responsibility and that IRB requires review of the protocol, the Treating Physician 
will obtain approval from that IRB prior to the subject’s participation in the protocol. 
13.3 Responsibility for Subject Care 
The Treating Physician is responsible for the care of his/her subject.  
13.4 Treatment Cost 
Miltefosine will be provided by the Sponsor at no cost; however, subject care is the 
responsibility of the Treating Physician and no payment for subject care can be made by the 
Sponsor. 
13.5 Protocol Exemption Committee 
The PI and the Sponsor’s Representative will constitute the protocol exemption committee. 
14  STUDY DOCUMENTATION/DATA MANAGEMENT  
The data management plan and a statistical analysis plan will be prepared by the data 
management center. 
14.1 Subject Identification (ID) Code  
Each subject will be assigned a subject ID code which will be provided with the screening CRF 
package. The subject ID code will consist of a three digit numeric code and a three digit 
alphabetical (alpha) code. The first digit of the numeric code will be a sequential number starting 
with 101. The alpha code will be a random sequence of three letters. The Subject ID code will be 
used on all CRFs, and laboratory data sheets.  
14.2 Data Collection and Monitoring 
Data will be collected at the study site in the subject’s medical records, which will be transcribed 
at the site on to the study CRFs provided by the data management center. CRFs are to be 
completed on an ongoing basis according to the instructions in the Study Procedures Manual.  


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The Treating Physician will be responsible for completing the CRFs, verifying the accuracy of 
the CRF data versus the source documentation, and sending the completed CRFs to the data 
management center.  
 
The Treating Physician will correspond with the PI at the following time points: 
 
 prior to obtaining informed consent to verify subject eligibility, 
 Study Day 28 or Week 6 follow-up visit, 
 Month 7 follow up for CL subjects, or Month 7 and 13 for ML subjects. 
 
Completed CRFs should be submitted to the data management center prior to the Treating 
Physician contacting the PI by telephone. The purpose of these communications between 
Treating Physician and PI is to assure optimum subject care and conveyance of study data.  
 
The Treating Physician and PI can also correspond with each other at any other time of their 
choosing. 
 
In spite of these interactions and advice that may be offered by the PI, clinical responsibility for 
subject care rests with the Treating Physician. 
14.3 Data Editing and Control 
Data received at Fast-Track will be reviewed prior to being entered into the main study database. 
If incomplete or inaccurate data are found, a data clarification request will be forwarded to the 
clinical site for a response. The site will resolve data inconsistencies and errors prior to returning 
data to Fast-Track. Errors must be corrected by drawing a single line through the incorrect entry 
and by writing the new value as close to the original as possible. The correction must then be 
initialed and dated. All corrections and changes to the data will be reviewed prior to being 
entered into the main study database 
14.4 Data Analysis 
A final analysis of all clinical trial data will be performed when all of the data for every subject 
has been collected, entered into the main study database, audited, and locked for analysis. A final 
clinical study report will be prepared in accordance with International Committee on 
Harmonization E3 Structure and Content of Final Clinical Study Reports. 
14.5 Publication 
The results of the full study may be published at the discretion of the sponsor. The Treating 
Physician may publish or  present the data of his/her patients provided that the 
publication/presentation does not disclose any of the Sponsor’s Proprietary Information.  The 
Treating Physician agrees to submit the draft of any proposed publication/presentation to 
Sponsor at least thirty (30) days prior to submission for publication/ presentation, and agrees, at 
the request of Sponsor, to withhold any such submission for an additional period, not to exceed 
ninety (90) days, to allow Sponsor to file patent applications or to take any other action designed 
to protect its patent rights. No personal data will be used in any external communication or 
publication. 


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14.6 Subject Confidentiality 
To maintain subject confidentiality, all records and CRFs specifically generated by this protocol 
will be identified using the subject ID code. Protocol generated records will be stored in a secure 
location and only the protocol staff will have access to the records. 
15 ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL 
15.1 Principal Investigator   
Signs the protocol agreement, below, and the Form FDA 1572.  The PI is responsible for passage 
of the protocol and any amendments through a “central” IRB before starting the study. The PI is 
responsible for interaction with Treatment Physicians to ensure protocol adherence and data 
integrity, and overall coordination of the study.  
 
The PI is also responsible for participating in safety evaluations of subjects during the conduct of 
the study. The PI will review all unanticipated problems involving risk to subjects or to others, 
SAEs, and all subjects’ deaths associated with the protocol, and provide an unbiased written 
report of the event. At a minimum, the PI should comment on the outcomes of the event or 
problem and, in the case of a SAE or death, comment on the relationship to participation in the 
study. The PI should also indicate whether he/she concurs with the details of the report provided 
by the Treating Physician. Reports for SAEs determined by either the Treating Physician or PI to 
be possibly, probably, or definitely related to participation and reports of events resulting in 
death should be promptly forwarded to the Sponsor and the “central” IRB.  
 
 
The PI is responsible for filing a final clinical study report with the Sponsor. 
15.2 Associate Investigator 
Associate investigators are responsible for performing the PI’s duties in his/her absence. In all 
sections of this protocol, “PI” is taken to mean “PI or Associate PI in the absence of the PI”. 
15.3 Treating Physicians 
This protocol involves the clinical use of an investigational agent. Treating Physicians are 
responsible for implementation of protocol with respect to his/her subject: briefing potential 
participants, obtaining proper informed consent, obtaining IRB approval if needed, determining 
study eligibility based on inclusion and exclusion criteria, accountability and proper storage of 
the investigational product, administering the product to the patients, reporting of any AEs or 
protocol deviations, entering and verifying CRF data, reporting study data to the Data 
Management Center via CRFs, and corresponding with the PI at scheduled time periods.  
 
 
 
The Treating Physician is considered an “investigator” in the regulatory sense, and has to supply 
a Form FDA 1572 and curriculum vitae to the PI so that these documents can be sent to the FDA.  
 


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15.4 Data Management Center  
Prepare and provide CRFs to clinical site; design, develop, and validate the clinical trial 
database; perform data entry into the clinical trial database; perform database quality control and 
data analysis. 
16 STATEMENT OF AGREEMENT 
The PI has carefully read this protocol and agrees to oversee the clinical study as described in a 
professional and competent manner in accordance with the generally accepted standards of Good 
Clinical Practice.  
 
The Treating Physician has carefully read this protocol and agrees to oversee the clinical 
treatment as described in a professional and competent manner in accordance with the policies of 
the medical institution where the Treating Physician conducts the clinical treatment and any 
applicable local, state, and agency laws and regulations. The Treating Physician understands that 
the IND has been submitted the protocol to FDA. The Treating Physician agrees to cooperate 
with and be available to regulatory authorities as needed regarding the conduct of this clinical 
study. 
 
The Treating Physician further attests that he/she has obtained informed consent from the subject 
to be treated under this protocol. 
17 SIGNATURES 
 
 
 
 
 
 
 
________________________________ 
 
_______________________ 
Principal Investigator  
 
 
 
Date 
Jonathan Berman, M.D., Ph.D. 
 
 
________________________________ 
 
_______________________ 
Sponsor 
 
 
 
 
 
Date 
Robert K. Vinson, Ph.D.       
 
 
________________________________ 
 
_______________________ 
Treating Physician 
 
 
 
 
Date 
Name: