Treatment of Leishmaniasis With Impavido® (Miltefosine): Higher-Weight Patient Registry
Conditions: Leishmaniasis
Sponsor: Knight Therapeutics (USA) Inc

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
1 
 
 
Treatment of Leishmaniasis with Impavido® (Miltefosine):  
Higher-Weight Patient Registry 
 
Protocol No.  IMP 2127-4 
 
 
 
Principal Investigator: 
 
Janet H. Ransom, Ph.D.  
 
 
 
 
 
President 
 
 
 
 
 
Fast-Track Drugs and Biologics, LLC 
5 Paramus Court 
North Potomac, Maryland 20878 
Tel: (301) 762-5787 
 
 
 
 
 
jransom@fasttrackresearch.com 
 
 
 
Subinvestigators: 
 
 
Jonathan D. Berman, M.D., Ph.D. 
 
 
 
 
 
Vice President for Clinical Affairs 
301-922-2097 
jberman@fasttrackresearch.com  
 
Katarina Ujhazy, M.D. 
Sr. Scientist 
301-762-2609 
kujhazy@fasttrackresearch.com 
Fast-Track Drugs and Biologics, LLC 
5 Paramus Court 
North Potomac MD 20878 
 
Sponsor: 
 
 
 
Knight Therapeutics (USA) Inc. 
 
Sponsor’s Contact:  
 
Tanya Radhakrishna  
 
 
 
 
 
Director, New Products 
 
 
 
 
 
Knight Therapeutics (USA) Inc.  
 
 
 
 
 
376 Victoria Ave, Suite 220 
 
 
 
 
 
Westmount QC H3Z 1C3 
 
 
 
 
 
Tel : 514-484-4483 
 
 
 
 
 
Cell : 514-884-8050  
 
 
 
 
 
tradhakrishna@gud-knight.com 
 
Impavido Higher-Weight Patient  
Registry Coordinating 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. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
2 
 
 
 
TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................. 4 
2 
STUDY SCHEDULE OF ASSESSMENTS .......................................................................... 4 
3 
SYNOPSIS .............................................................................................................................. 5 
4 
INTRODUCTION AND RATIONALE ................................................................................. 7 
4.1 
Leishmaniasis ................................................................................................................... 7 
4.2 
Miltefosine ....................................................................................................................... 8 
4.2.1 
Structural Formula .................................................................................................... 8 
4.2.2 
Worldwide Registration ............................................................................................ 8 
4.2.3 
US Registration and Indications [Impavido PL, 2014] ............................................. 8 
4.2.4 
Recommended Dosage [Impavido NDA, 2014] ....................................................... 8 
4.2.5 
Higher-Weight-Patient Considerations ..................................................................... 9 
5 
STUDY OBJECTIVES ......................................................................................................... 11 
6 
STUDY DESIGN.................................................................................................................. 11 
7 
STUDY SUBJECTS ............................................................................................................. 11 
7.1 
Estimated Number of Subjects ....................................................................................... 11 
7.2 
Inclusion Criteria ............................................................................................................ 11 
8 
DRUG PRODUCT................................................................................................................ 11 
8.1 
Storage and Administration ............................................................................................ 11 
8.2 
Concomitant Therapy ..................................................................................................... 11 
9 
PROCEDURES..................................................................................................................... 12 
9.1 
Subject Recruitment ....................................................................................................... 12 
9.2 
Subject Consent .............................................................................................................. 12 
9.3 
Screening Procedures ..................................................................................................... 12 
9.4 
Outcomes ........................................................................................................................ 13 
10 DATA TO BE OBTAINED.................................................................................................. 13 
10.1 
Screening .................................................................................................................... 13 
10.2 
Treatment Data ........................................................................................................... 13 
11 ANALYTICAL PLAN ......................................................................................................... 14 
11.1 
Sample Size ................................................................................................................ 14 
11.2 
Analytical Populations ................................................................................................ 14 
11.3 
General Analytical Procedures ................................................................................... 14 
11.4 
Analysis of Baseline Data ........................................................................................... 14 
11.5 
Analysis of Treatment Compliance Data .................................................................... 14 
11.6 
Analysis of Outcomes ................................................................................................. 14 
12 ADMINISTRATIVE AND REGULATORY STANDARDS.............................................. 14 
12.1 
Ethical Review of Protocol ......................................................................................... 14 
12.2 
Informed Consent ....................................................................................................... 14 
12.3 
Responsibility for Subject Care .................................................................................. 14 
12.4 
Treatment Cost ........................................................................................................... 15 
13 STUDY DOCUMENTATION/DATA MANAGEMENT ................................................... 15 
13.1 
Subject Identification (ID) Code ................................................................................ 15 
13.2 
Data Collection and Monitoring ................................................................................. 15 
13.3 
Data Editing and Control ............................................................................................ 15 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
3 
 
 
13.4 
Data Analysis .............................................................................................................. 15 
13.5 
Publication .................................................................................................................. 15 
13.6 
Subject Confidentiality ............................................................................................... 15 
14 ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL........................................ 15 
14.1 
Principal Investigator .................................................................................................. 15 
14.2 
Suvinvestigators.......................................................................................................... 16 
14.3 
Higher-Weight Patient Registry Coordinating Center ................................................ 16 
15 STATEMENT OF AGREEMENT ....................................................................................... 17 
16 REFERENCES ..................................................................................................................... 18 
 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
4 
 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AST 
Aspartate aminotransferase 
CL 
cutaneous leishmaniasis 
FDA 
Food and Drug Administration 
HX 
History 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
kDNA 
kinetoplast minicircle deoxyribonucleic acid 
ML 
mucosal leishmaniasis 
L. 
Leishmania 
MRHD  
maximum recommended human dose 
NDA 
New drug application 
PI 
Principal Investigator 
PL 
Product Label 
PMR 
Post Marketing Requirement 
US 
United States 
VL 
visceral leishmaniasis 
WHO 
World Health Organization 
 
 
2 
STUDY SCHEDULE OF ASSESSMENTS 
Parameter 
                                  Study Time Period 
 
 
 
Screening 
End of Treatment 
Period 
1 Month Post 
Treatment 
3 Months Post 
Treatment 
6 Months 
Post 
Treatment 
Consent 
 X 
 
 
 
 
Demographics 
(gender/age/weight/race) 
X 
 
 
 
 
Leishmaniasis Hx 
X 
 
 
 
 
Concomitant Diseases 
X 
X 
 
 
 
Miltefosine treatment 
(a) 
X 
 
 
 
Clinical Laboratory Tests  
X (b,c) 
X( b,c) 
X (c) 
X (c) 
X (c) 
Concomitant Medications 
X 
X 
 
 
 
Adverse Events 
X 
X 
 
 
 
Efficacy 
 
X 
X 
X 
X 
(a): Patients may contact the Registry after having been administered at least one dose of miltefosine 
(b): AST and creatinine at screening and end of treatment; white blood cells (WBC), hemoglobin, and platelet count 
for patients with VL at all time 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
5 
 
 
3 
SYNOPSIS 
Impavido® (miltefosine) was approved in the United States (US) in March 2014 for the 
treatment of visceral, cutaneous, and mucosal leishmaniasis due to specified Leishmania species. 
Impavido is the first drug approved in the US for cutaneous or mucosal leishmaniasis, and is the 
only oral drug worldwide that is generally effective for the leishmaniases. 
 
Since oral miltefosine is administered at 2 capsules for day to patients of 30-44 kg and 3 capsules 
per day to patients > 44 kg, in each weight bracket, higher weight patients will receive less drug 
on a mg/kg basis than lighter patients. For example, patients who weigh 45 kg and receive 3 
capsules per day will receive 3.3 mg/kg/day whereas patients who weigh 90 kg and receive 3 
capsules will receive 2.0 mg/kg/day. 
 
Whether higher-weight US patients will have efficacy rates that are lower on an absolute basis is 
unknown.  
 
Objective: The purpose of this observational study is to fulfill PMR 2127-4: implement a 
higher-weight-patient registry for the time period Mar 2015-Mar 2020. 
 
Study Design: This study is a prospective observational study in which patients undergoing 
treatment for leishmaniasis with Impavido in the US and who weigh > 75 kg can volunteer to 
provide information about their clinical response to treatment up to 6 months after the start of 
treatment. 
 
Population: Leishmaniasis patients treated with Impavido who weigh more than 75 kg. 
 
Drug Product:  
Drug name:  Impavido (50 mg capsules). 
Dosing regimen:  as per the Impavido Product Label 
 
Study Procedures: Patients who weigh more than 75 kg will become aware of the Impavido 
Higher-Weight Patient Registry via the Impavido website. By calling 1-866-588-5405, the 
patient will be connected to the Impavido Higher-Weight Patient Registry Coordinating Center. 
A trained staff member will acquaint the patient with the goals and procedures of the study. If the 
patient tentatively agrees to participate in the study over the telephone, the patient will be mailed 
information forms, the Consent/Assent Forms, and the Consent for the patient’s physician to 
release medical information. Receipt of the two signed Consent and/or Assent Forms by the 
Coordinating Center will signify patient consent. The Coordinating Center will contact the 
patient’s physician at the end of treatment, and at 1, 3, and 6 months after completing treatment, 
to collect data on efficacy and adverse effects (only during treatment). 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
6 
 
 
Sample Size and Study Duration: Estimated 3-10 patients per year for 5 years. 
 
Outcome Parameters:  
Efficacy 
Adverse effects 
 
Analysis:  Baseline data, compliance to prescribed treatment, and outcomes will be reported for 
individual patients and for all patients.  

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
7 
 
 
4 
INTRODUCTION AND RATIONALE  
4.1 
Leishmaniasis  
Infection of the macrophages of the skin, mucosal membranes, and visceral reticuloendothelial 
system with Leishmania gives rise to the major forms of leishmaniasis: cutaneous, mucosal, and 
visceral disease.  
 
According to the World Health Organization (WHO), Leishmania infection is endemic in 98 
countries or territories with a yearly incidence of 0.5 million cases of visceral leishmaniasis (VL) 
and l.5 million cases of cutaneous leishmaniasis (CL) (WHO 2010). 
 
VL (Kala-azar) -- infection of the liver, spleen, and bone marrow-- presents with fever, 
hepatosplenomegaly, and pancytopenia. The majority of VL occurs in the Indian subcontinent. 
Approximately 30% of the world’s cases occur in Africa especially Sudan, Ethiopia, and Kenya; 
there is also a focus of disease in Brazil. The main species causing VL are Leishmania ( L). 
donovani in India and Africa, L. infantum in Europe and the Mediterranean, and L. infantum 
chagasi in the New World. 
 
In VL, Sudden onset of fever with rigor and chills herald the onset of illness, which may subside 
to recur again. Splenomegaly soon follows and may become remarkable. Hepatomegaly and 
lymphadenopathy are other clinical features, though the latter is rare. Anemia is universal and 
may be quite severe leading to weakness, fatigue and heart failure. Thrombocytopenia and 
subsequent bleeding episodes such as epistaxis, intestinal bleeding, and retinal hemorrhages are 
not uncommon. Concurrent illnesses including pneumonia, herpes zoster, tuberculosis, amebic 
or bacillary dysentery, boils, and scabies are common. VL and coinfection with HIV or other 
immunocompromising diseases is increasingly a serious health threat.  
 
CL generally presents as a papule that enlarges to a nodule and if it ulcerates, does so over 1 to 3 
months. CL lesions are often located at exposed areas of the skin (face, arms, legs), either as 
single or as multiple lesions. Lesions can develop in anybody who intrudes into an endemic 
region and gets bitten by an infected sand fly. In recent years, industrialized nations have become 
more aware to the problem due to increasing numbers of imported cases either by military 
personnel or travelers. In the New World from the Texas-Mexico border down through South 
America to the level of the Tropic of Capricorn, ulcerative lesions are most common. In the Old 
World (the Mediterranean, North and Sahelian Africa, the Middle East, the Indian subcontinent, 
and Central Asia), most lesions are papules, nodules, or nodule-ulcers. The primary species 
causing CL are diverse: L. mexicana, L. amazonensis, L. viannia (v) panamensis, L. (v) 
braziliensis, L. (v) peruviana, and L. (v) guyanensis in the New World and L. major, L. tropica, 
L. aethiopica, and L. infantum in the Old World. 
 
Mucosal disease (ML) in the New World may result from dissemination of cutaneous organisms 
(particularly Leishmania species of the subgenus Vianna: L. (v).braziliensis, L.(v). guyanensis 
and L.(v) panamensis) to the nares, nasal septum, palate, pharynx, and larynx. Mucosal disease 
causes a progressive destruction of the mucosa, the cartilage and bones of nose and pharynx, 
leading to a severe mutilation of the face. ML can be lethal by aspiration pneumonia or other 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
8 
 
 
complications. Classic ML occurs months to years after healing of CL, but ML can also occur 
virtually simultaneously with CL.  Recently, it was shown that asymptomatic infection of the 
mucosal membranes is common for CL patients infected with members of the L. viannia 
subgenus. Two patients with ML and 26 patients with CL due to L. v. panamensis, L.v. 
guyanensis, and L.v. braziliensis had Leishmania kinetoplast minicircle deoxyribonucleic acid 
(kDNA) examined in mucosal tissues. kDNA was amplified from swab samples of nasal mucosa 
from 14 (58%) of 24 patients, tonsils from 13 (46%) of 28 patients, and conjunctiva from 6 
(25%) of 24 patients. Although the reason that initially asymptomatic infection converts to 
clinical disease is unknown, cutaneous infection with any of these 3 species has to be regarded as 
leading to mucosal infection and potentially to mucosal disease with its possibly fatal outcome. 
4.2 
Miltefosine 
4.2.1 Structural Formula 
Miltefosine (hexadecylphosphocholine ) is a phosphatidylcholine analogue. The structural 
formula of miltefosine is:  
 
  
4.2.2 Worldwide Registration 
The drug was registered in India in 2002 and in Germany in 2004 to treat visceral leishmaniasis.  
Impavido was registered in Columbia in 2005 to treat visceral and cutaneous leishmaniasis, and 
post-2005 to treat CL (and by extension ML) in many other countries in the Americas.  
4.2.3 US Registration and Indications [Impavido PL, 2014] 
On 19 Mar 2014, miltefosine (trade name Impavido®) was approved in the US for treatment of 
visceral, cutaneous, and mucosal leishmaniasis due to specific species of Leishmania (Impavido 
PL, 2014). 
 
 Visceral leishmaniasis (VL) due to Leishmania donovani  
 Cutaneous leishmaniasis (CL) due to Leishmania braziliensis, Leishmania 
guyanensis, and Leishmania panamensis  
 Mucosal leishmaniasis (ML) due to Leishmania braziliensis  
4.2.4 Recommended Dosage [Impavido NDA, 2014]  
Each IMPAVIDO capsule for oral use contains 50 mg miltefosine. 
 
Administer with food to ameliorate gastrointestinal adverse reactions. 
30 to 44 kg: one 50 mg capsule twice daily for 28 consecutive days. 
45 kg or greater: one 50 mg capsule three times daily for 28 consecutive days. 
 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
9 
 
 
4.2.5 Higher-Weight-Patient Considerations  
Since oral miltefosine is administered at 2 capsules for day to patients of 30-44 kg and 3 capsules 
per day to patients > 44 kg, in each weight bracket, higher patients will receive less drug on a 
mg/kg basis than lighter patients. For example, patients who weigh 45 kg and receive 3 capsules 
per day will receive 3.3 mg/kg/day whereas patients who weigh 90 kg and receive 3 capsules 
will receive 2.0 mg/kg/day. 
 
In developmental studies for both VL and CL, there appeared to be a trend towards less efficacy 
with a lower mg/kg/day dose. 
 
For VL, the cure rate in patients receiving < 2 mg/kg/day (86%) was less than the cure rate in 
higher mg/kg/day patients (Table 1). 
Table 1: 
Cure Rate by Dose Level in VL Studies in India (mg/kg/day)  
(Daily)Dose 
per kg body 
weight 
Final parasitological cure, ITT populationa 
All 
No 
Yes 
Missing/ not assessable 
n 
% 
n 
% 
n 
% 
n 
<2 mg  
12 
12.8 
81 
86.2 
1 
1.1 
94 
2.0-2.4 mg 
12 
6.3 
174 
92.1 
3 
1.6 
191 
2.5-2.9 mg 
3 
1.3 
213 
95.5 
7 
3.1 
223 
3.0-3.9 mg 
2 
2.2 
89 
96.7 
1 
1.1 
92 
≥4 mg 
3 
4.3 
66 
95.7 
0 
0 
69 
All 
32 
4.8 
623 
93.4 
12 
1.8 
667 
 
For CL, there was a trend towards a lower cure rate in patients receiving a lower mg/kg/day dose 
(Table 2). 
Table 2: 
Final Cure Rates with respect to Miltefosine Dose: Integrated Analysis of CL 
Studies 3168, Soto, Z020a, Z020b 
Dose Group 
(mg/kg/day) 
N 
Failed 
N (%) 
Cured 
N (%) 
1.7-2.2 
38 
12 (27.9) 
26 (60.5) 
2.3-2.8 
128 
24 (17.8) 
104 (77.0) 
2.9-3.3 
27 
6 (22.2) 
21 (77.8) 
 
Whether higher-weight US patients will have cure rates that are low on an absolute basis is 
unknown.  
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
10 
 
 
 
4.3 
Post Marketing Requirement [Impavido NDA, 2014] 
 
4.2.1 FDA Post-Marketing Requirement # 2127-4:  
“Conduct a descriptive study regarding efficacy outcome and adverse reactions in patients with 
leishmaniasis who weigh more than 75kg.” 
 
Final Protocol Submission: March 2015 
Interim Report Submission: March 2016 
Interim Report Submission: March 2017 
Interim Report Submission: March 2018 
Interim Report Submission: March 2019 
Study Completion: March 2020 
Final Report Submission: March 2021” 
 
4.3.2 
Previous Advice from the FDA Concerning this Requirement  
 
 “Conduct a descriptive study regarding efficacy outcome and adverse reactions in patients 
with leishmaniasis who weigh more than 75kg. This study should cover the period of five years 
following drug approval. Patient demographics (including age, weight, sex, race, prior medications, 
geographic area where Leishmania infection was acquired and immune status), total daily dosage of 
Impavido and mg/kg dosage received, treatment duration and site of infection should be described. 
Efficacy outcome and adverse reactions should be described. Yearly reports summarizing this data 
should be submitted.” (information request of 24 Jan 2014) 
 
4.4 
Rationale for Protocol 
In an operational sense, the purpose of this protocol is to fulfill post-marketing requirement 
2127-4 in accord with the specifics of the information request of 24 Jan 2014. 
 
In a scientific sense, the purpose of this protocol is to provide as much data as possible on the 
possible relationship of lower mg/kg daily doses of miltefosine and efficacy. 
 
For these purposes, a Higher-weight Patient Registry will be instituted and maintained from 
March, 2015 to March, 2020. 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
11 
 
 
5 
STUDY OBJECTIVES 
Implement a higher-weight-patient registry for Impavido in the US for the time period March, 
2015 to March 2020. 
6 
STUDY DESIGN 
This study is a prospective observational study in which patients undergoing treatment for 
leishmaniasis with Impavido in the US and who weigh > 75 kg can volunteer to provide 
information about their clinical response to treatment up to 6 months after the start of treatment. 
7 
STUDY SUBJECTS 
7.1 
Estimated Number of Subjects 
Estimated 3-10 per year. 
7.2 
Inclusion Criteria 
To be eligible for the study, the following must be answered “YES”: 
 
 
1. 
Did the subject give consent to collect data from her or her physician? 
2. 
Was the subject treated for leishmaniasis with miltefosine? 
3. 
Does the subject weigh more than 75 kg? 
8 
DRUG PRODUCT 
Impavido (capsules of 50 mg strength) obtained through purchase in the US. 
8.1 
Storage and Administration 
Appropriate storage and administration of Impavido in accord with the Product Label is the 
responsibility of the patient.  
 
Storage and administration data will be recorded on appropriate pages of the data form. 
8.2 
Concomitant Therapy  
All concomitant medications will be recorded on the data form. 
 
 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
12 
 
 
9 
PROCEDURES 
Parameter 
                                  Study Time Period 
 
 
 
Screening 
End of Treatment 
Period 
1 Month Post 
Treatment 
3 Months Post 
Treatment 
6 Months 
Post 
Treatment 
Consent 
 X 
 
 
 
 
Demographics 
(gender/age/weight/race) 
X 
 
 
 
 
Leishmaniasis Hx 
X 
 
 
 
 
Concomitant Diseases 
X 
X 
 
 
 
Miltefosine treatment 
(a) 
X 
 
 
 
Clinical Laboratory Tests  
X (b,c) 
X( b,c) 
X (c) 
X (c) 
X (c) 
Concomitant Medications 
X 
X 
 
 
 
Adverse Events 
X 
X 
 
 
 
Efficacy 
 
X 
X 
X 
X 
(a): Patients may contact the Registry after having been administered at least one dose of miltefosine 
(b): AST and creatinine at screening and end of treatment;  
(c): White blood cells (WBC), hemoglobin, and platelet count for patients with VL at all time 
9.1 
Subject Recruitment 
Patients will be alerted to the Impavido Higher-weight-patient Registry availability via the 
Impavido website which will supply a toll free number (1-866-588-5405) to call.  
9.2 
Subject Consent/Assent 
When the subject or parent/legal guardian calls the toll free number (1-866-588-5405) of the 
Impavido Higher-Weight Patient Registry Coordinating Center, a trained staff member will 
summarize information on the goals, eligibility requirements, and procedures of the registry. 
This information will also be on the website. 
 
If on the telephone the patient or parent/legal guardian expresses a tentative desire to participate 
in the registry, the patient or parent/legal guardian will be mailed paper copies of the goals, 
eligibility requirements, and procedures of the registry, the Patient Information Sheet/Consent 
Form/Assent Form (“Consent Form/Assent Form”), and the Release of Medical Information by 
the Patient’s Physician (“Medical Information Form”). 
  
Consent and assent will be in effect when the patient (or, for adolescents aged 12-17 years, the 
patient plus the parent/guardian) signs the Consent/Assent Form and the Medical Information 
Form and mails them back to the Impavido Higher-Weight Patient Registry Coordinating Center. 
9.3 
Screening Procedures 
 
Physician will complete data form sections relevant to demographics, history of leishmaniasis, 
history of Impavido treatment (if any), pre-treatment clinical laboratory tests [aspartate 
aminotransferase (AST), creatinine, and if the patient has VL WBC, hemoglobin, and platelet 
count], concomitant diseases, concomitant medications. 
 
From this information, eligibility to participate in the Higher-Weight Patient Registry will be 
determined. 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
13 
 
 
9.4 
Outcomes  
The Impavido Higher-Weight Patient Registry Coordinating Center will contact the patient’s 
physician at the end of the treatment period, and at 1, 3, and 6 months after the end of therapy, 
and request that the relevant data forms be completed and submitted. 
10 
DATA TO BE OBTAINED  
10.1 
Screening 
Demographic Data 
Age  
Weight  
Sex  
Race  
Prior medications  
Geographic area where Leishmania infection was acquired  
Immune status [normal vs abnormal. If latter, specify disease] 
 
Leishmaniasis History 
Site of infection [mark body chart] 
Disease parameters  
VL : 
Spleen size  
 
 
Hemoglobin, platelets, white cell count 
ML: 
Symptoms, Physical status at site of infection 
CL :  Lesion characteristics at entrance: ulcer, nodule, plaque, scab 
Lesion size at entrance: Approximate size [length x width in inches, cm, or 
finger widths]  
Clinical Laboratory Tests 
AST, creatinine, and if the patient has VL WBC, hemoglobin, and platelet count  
 
Concomitant Diseases 
 
Concomitant Medications 
10.2 
Treatment Data 
 
Miltefosine Treatment Regimen 
Daily dose in mg, dose in mg/kg, duration of therapy 
 
Adverse events 
 
Symptoms: gastrointestinal, other 
Laboratory parameters (if available) 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
14 
 
 
10.3 
Efficacy Data at 1, 3, and 6 months  
 
VL : 
Spleen size 
 
Hemoglobin, platelets, white cell count 
ML: 
Symptoms, physical status at original site of infection 
CL :  Lesion characteristics: ulcer, nodule, plaque, scab 
Lesion size: Approximate size [length x width in inches, cm, or fingerwidths] 
11 
ANALYTICAL PLAN  
11.1 
Sample Size  
Since there is no hypothesis for this study, there is no formal sample size calculation.  
11.2 
Analytical Populations  
Data for all eligible subjects will be analyzed. An eligible subject is anyone who received at least 
one administration of Impavido for leishmaniasis.   
11.3 
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.  
11.4 
Analysis of Baseline Data  
By-subject and summaries of the baseline data will be provided.  
11.5 
Analysis of Treatment Compliance Data 
By subject and summaries of compliance with prescribed treatments will be provided, including 
total exposure (number of days, total dose in mg, daily dose in mg/kg) to Impavido.  
11.6 
Analysis of Outcomes 
By-subject and summaries of the outcome data will be provided.  
12 
ADMINISTRATIVE AND REGULATORY STANDARDS 
This protocol will be submitted to IND# 105,430. The Principal Investigator (PI) will sign a 
Form FDA 1572. 
12.1 
Ethical Review of Protocol    
The PI will obtain protocol approval from a central IRB before starting the study.  
12.2 
Informed Consent 
Subject consent will be obtained in accord with protocol section 9.2 
12.3 
Responsibility for Subject Care 
The patient’s physician is responsible for the care of his/her subject.  

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
15 
 
 
12.4 
Treatment Cost 
The patient is responsible for the cost of treatment including miltefosine. 
13 
STUDY DOCUMENTATION/DATA MANAGEMENT  
13.1 
Subject Identification (ID) Code  
Each subject will be assigned a subject ID code. The Subject ID code will be used on all data 
forms and reports of the data to the IRB and FDA. 
13.2 
Data Collection and Monitoring 
Data forms will be collected by mail from the patient and/or from the patient’s physician. Upon 
receipt at the Impavido Higher-Weight Registry Coordinating Center, data forms will be stored 
in a secure controlled access location. 
 
The patient and/or the patient’s physician will be responsible for the accuracy of the data. 
13.3 
Data Editing and Control 
Data received at the Impavido Higher-Weight Patient Registry Coordinating Center 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 patient and/or patient’s physician for a 
response. 
13.4 
Data Analysis 
An analysis of all data will be performed at the intervals specified by 2127-4. 
 
A final clinical study report will be prepared in accordance with International Committee on 
Harmonization E3 Structure and Content of Final Clinical Study Reports. 
13.5 
Publication 
The results of the full study may be published at the discretion of the sponsor. No personal 
identifying data will be available in any external communication or publication. 
13.6 
Subject Confidentiality 
To maintain subject confidentiality, all electronic records and data reports using the subject ID 
code. Data forms and other records containing the patient’s name, address, and telephone number 
will be stored in a secure location and only the protocol staff will have access to the records. 
14 
ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL 
14.1 
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 the Impavido Higher-Weight Patient Registry Coordinating 
Center to ensure protocol adherence, data integrity, and overall coordination of the study.  
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
16 
 
 
14.2 
Subinvestigators 
Subinvestigators 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 subinvestigator in the absence of the PI”. 
14.3 
Higher-Weight Patient Registry Coordinating Center  
The Impavido Higher-Weight Registry Coordinating Center maintains and staff’s personnel who 
respond to calls from patients and enrolled subjects. It also prepares and provides data forms; 
designs, develops, and validates the clinical trial database; performs data entry into the clinical 
trial database and performs database quality control and data analysis. 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
17 
 
 
 
15 
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.  
 
SIGNATURES 
 
 
 
 
 
 
 
________________________________ 
 
_______________________ 
Principal Investigator  
 
 
 
Date 
 
 
________________________________ 
 
_______________________ 
Sponsor 
 
 
 
 
 
Date 
 

Protocol No. IMP 2127-4 
 
Knight Therapeutics (USA) Inc. 
Impavido Higher-Weight Patient Registry 
 
NCT02429505 
 
Version 4, Date 30Dec2014 
18 
 
 
 
16 
REFERENCES 
 
Impavido NDA 2014. Product label. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204684s000lbl.pdf  
 
WHO 2010. Control of the Leishmaniases. WHO Technical Report Series # 949.