A 36-Month, Multicenter, Open Label Phase 4 Study to Evaluate the Immunogenicity of Daily SC Metreleptin Treatment in Patients With Generalized Lipodystrophy
Phase: PHASE4
Conditions: Generalized Lipodystrophy
Sponsor: Aegerion Pharmaceuticals, Inc.

 
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A 36-Month, Multicenter, Open Label Phase 4 Study to 
Evaluate the Immunogenicity of Daily SC Metreleptin 
Treatment in Patients with Generalized Lipodystrophy 
 
Protocol AEGR-734-401 
 
Aegerion Pharmaceuticals Inc. 
One Main Street, Suite 800 
Cambridge, MA 02142 
USA 
 
 
 
 
 
 
 
Date of Original Protocol, Version 1.0:  03 December 2014 
Version 2.0:  10 November 2016 
Version 3.0: 17 August 2017 
Version 4.0: 08 February 2018 
 

 
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STUDY CONTACTS 
Study Sponsor: 
Aegerion Pharmaceuticals, Inc. 
One Main Street, Suite 800 
Cambridge, MA 02142 USA 
Telephone: +1 617-500-7867 
Fax: +1 617-945-7968 
Sponsor’s Medical Contact: 
Alison Long, MD PhD 
Vice President, Clinical 
Aegerion Pharmaceuticals, Inc. 
One Main Street, Suite 800 
Cambridge, MA 02142 
Telephone: (857) 242-5142 
Email: alison.long@aegerion.com 
Sponsor’s Study Contact: 
Matthew Chittick 
Clinical Project Manager 
Aegerion Pharmaceuticals, Inc. 
One Main Street, Suite 800 
Cambridge, MA 02142 
Telephone (857) 242- 5158 
matthew.chittick@aegerion.com 
Medical Monitor: TBD  
(CRO to be confirmed) 
 
 
Biostatistician: TBD  
(CRO to be confirmed) 
 
 
Central Laboratory: TBD  
(CRO to be confirmed) 
 
 

Aegerionc 
Pharmaceuticals 
A NOVELION THERAPI: T '-
COMPANY 
INVESTIGATOR AGREEMENT 
Metreleptin 
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Clinical Study Protocol 
I have read this protocol and agree that it contains all necessary details for carrying out 
the study as described. I will conduct this protocol as outlined herein, including all 
statements regarding confidentiality. I will make a reasonable effort to complete the 
study within the time designated. I will provide copies of the protocol and access to all 
information furnished by the sponsor to study personnel under my supervision. I will 
discuss this material with them to ensure that they are fully informed about the drug 
and the study. I understand that the study may be terminated or enrolment suspended 
at any time by the sponsor, with or without cause, or by me if it becomes necessary to 
protect the best interests of the study patients. I agree to conduct this study in full 
accordance with all applicable regulations, guidelines, and International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP). 
Principal Investigator 
Name 
Principal Investigator Signature 
Date 
SPONSOR AGREEMENT 
I have read the foregoing protocol and agree to conduct the study as described herein: 
Alison Long 
PhD 
Vice President, Clinical 
Aegerion Pharmaceuticals, Inc. 
Confidential 
<[ ft f3 g_\,( M j 2.D I 8'. 
Date 
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TABLE OF CONTENTS 
STUDY CONTACTS ......................................................................................................... 2 
INVESTIGATOR AGREEMENT...................................................................................... 3 
SPONSOR AGREEMENT ................................................................................................. 3 
LIST OF ABBREVIATIONS ............................................................................................. 9 
1. 
SYNOPSIS ............................................................................................................... 10 
2. 
INTRODUCTION ................................................................................................... 16 
2.1 
Background ........................................................................................................ 16 
2.2 
Rationale for Study Design, Doses and Control Groups .................................... 17 
2.3 
Benefit/Risk and Ethical Assessment ................................................................. 18 
3. 
STUDY OBJECTIVES ............................................................................................ 19 
3.1 
Primary Objective .............................................................................................. 19 
3.2 
Secondary Objectives ......................................................................................... 19 
3.3 
Safety Objectives ................................................................................................ 19 
3.4 
Exploratory Objectives ....................................................................................... 19 
4. 
INVESTIGATIONAL PLAN .................................................................................. 20 
4.1 
Study Design ...................................................................................................... 20 
4.2 
Number of Patients ............................................................................................. 20 
4.3 
Inclusion Criteria ................................................................................................ 21 
4.4 
Exclusion Criteria ............................................................................................... 21 
4.5 
Patient Enrollment and Randomization .............................................................. 22 
4.6 
Procedures for Handling Incorrectly Enrolled Patients ...................................... 23 
4.7 
Methods for Assigning Treatment Groups ......................................................... 23 
4.8 
Methods for Ensuring Blinding .......................................................................... 23 
4.9 
Methods for Unblinding ..................................................................................... 23 
4.10  Restrictions ......................................................................................................... 23 
4.11  Discontinuation of Metreleptin .......................................................................... 23 
4.11.1 
Procedures for Discontinuation of a Patient from Metreleptin ................... 24 
4.12  Criteria for Withdrawal from the Study ............................................................. 24 
4.12.1 
Screen Failures ............................................................................................ 24 
4.12.2 
Withdrawal of the Informed Consent ......................................................... 25 

 
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4.13  Discontinuation of the Study .............................................................................. 25 
5. 
STUDY PLAN AND TIMING OF PROCEDURES............................................... 25 
6. 
STUDY PROCEDURES ......................................................................................... 26 
6.1 
Schedule of Assessments ................................................................................... 26 
6.2 
Enrollment/Screening Period ............................................................................. 29 
6.2.1 
Screening..................................................................................................... 29 
6.2.2 
Baseline/Enrollment Visit  .......................................................................... 30 
6.3 
Treatment Period ................................................................................................ 30 
6.4 
Follow-up for Patients with In Vitro Neutralizing Activity ............................... 31 
7. 
STUDY ASSESSMENTS ....................................................................................... 32 
7.1 
Efficacy Assessments ......................................................................................... 32 
7.2 
Safety Assessments ............................................................................................ 32 
7.2.1 
Laboratory Safety Assessments .................................................................. 32 
7.2.2 
Physical Examination.................................................................................. 33 
7.2.3 
Vital Signs ................................................................................................... 34 
7.3 
Immunogenicity ................................................................................................. 34 
7.3.1 
Collection of Samples for Measurement of Antibodies to 
Metreleptin and Leptin and In Vitro Neutralizing Activity ...................................... 34 
7.3.2 
Determination of Antibodies to Metreleptin and Leptin ............................. 34 
7.3.3 
Determination of Metreleptin In Vitro Neutralizing Activity ..................... 35 
7.4 
Pharmacokinetics ............................................................................................... 35 
7.4.1 
Collection of Samples for Measurement of Leptin ..................................... 35 
7.4.2 
Determination of Leptin Concentration ...................................................... 36 
7.4.3 
Storage and Destruction of Pharmacokinetic Samples ............................... 36 
7.5 
Pharmacodynamics ............................................................................................. 36 
7.6 
Pharmacogenetics ............................................................................................... 36 
7.7 
Biomarker Analysis ............................................................................................ 36 
8. 
SAFETY REPORTING AND MEDICAL MANAGEMENT ................................ 36 
8.1 
Definition of Adverse Events ............................................................................. 37 
8.2 
Definitions of Serious Adverse Events .............................................................. 37 
8.3 
Recording of Adverse Events ............................................................................. 38 

 
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8.3.1 
Time Period for Collection of Adverse Events ........................................... 38 
8.3.2 
Follow-up of Unresolved Adverse Events .................................................. 38 
8.3.3 
Variables ..................................................................................................... 38 
8.3.4 
Causality Collection .................................................................................... 39 
8.3.5 
Adverse Events Based on Signs and Symptoms ......................................... 40 
8.3.6 
Adverse Events Based on Examinations and Tests .................................... 40 
8.3.7 
Hy’s Law ..................................................................................................... 40 
8.3.8 
Adverse Events of Special Interest ............................................................. 40 
8.4 
Reporting of Serious Adverse Events ................................................................ 41 
8.5 
Overdose ............................................................................................................. 41 
8.6 
Reporting Adverse Events .................................................................................. 42 
8.7 
Pregnancy ........................................................................................................... 43 
8.8 
Management of Metreleptin-related Toxicities .................................................. 43 
9. 
METRELEPTIN AND OTHER TREATMENTS ................................................... 44 
9.1 
Metreleptin ......................................................................................................... 44 
9.2 
Dose and Treatment Regimens .......................................................................... 44 
9.3 
Labeling .............................................................................................................. 44 
9.4 
Storage ................................................................................................................ 44 
9.5 
Compliance ......................................................................................................... 44 
9.6 
Accountability .................................................................................................... 45 
9.7 
Concomitant and Other Treatments ................................................................... 45 
9.7.1 
Other Concomitant Treatment .................................................................... 45 
10.  STATISTICAL ANALYSES .................................................................................. 45 
10.1  Statistical Considerations ................................................................................... 45 
10.2  Sample Size Estimate ......................................................................................... 45 
10.3  Definitions of Analysis Sets ............................................................................... 46 
10.4  Outcome Measures for Analyses ........................................................................ 47 
10.5  Methods for Statistical Analyses ........................................................................ 47 
11.  STUDY AND DATA MANAGEMENT ................................................................ 48 
11.1  Training of Study Site Personnel ....................................................................... 48 
11.2  Monitoring of the Study ..................................................................................... 49 

 
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11.2.1 
Source Data ................................................................................................. 49 
11.2.2 
Study Agreements ....................................................................................... 49 
11.2.3 
Archiving of Study Documents .................................................................. 50 
11.3  Study Timetable and End of Study .................................................................... 50 
11.4  Data Management  ............................................................................................. 50 
11.4.1 
Serious Adverse Event Reconciliation ........................................................ 50 
12.  ETHICAL AND REGULATORY REQUIREMENTS ........................................... 51 
12.1  Ethical Conduct of the Study ............................................................................. 51 
12.2  Patient Data Protection ....................................................................................... 51 
12.3  Ethics and Regulatory Review ........................................................................... 51 
12.4  Informed Consent ............................................................................................... 52 
12.5  Changes to the Protocol and Informed Consent Form ....................................... 52 
12.6  Audits and Inspections ....................................................................................... 53 
12.7  Registration of the Trial ..................................................................................... 53 
12.8  Disclosure ........................................................................................................... 53 
12.9  Data Quality Assurance ...................................................................................... 53 
12.10  Final Study Report ............................................................................................. 54 
12.11  Insurance ............................................................................................................ 54 
12.12  Publication Policy .............................................................................................. 54 
12.13  Study Records and Source Documents .............................................................. 55 
12.14  Confidentiality .................................................................................................... 56 
13.  LIST OF REFERENCES ......................................................................................... 57 
APPENDICES .................................................................................................................. 58 
LIST OF FIGURES 
Figure 1: 
Study Schematic ............................................................................................ 20 

 
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LIST OF TABLES 
Table 1: 
Schedule of Study Assessments ...................................................................... 27 
Table 2: 
Laboratory Safety Variables ........................................................................... 33 
Table 3: 
MYALEPT Recommended Dosage ................................................................ 44 
Table 4: 
Expected Number of Patients with Maximum Antibody Titer ....................... 46 
 

 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase
Anti-HuL 
Anti human leptin
AST 
Aspartate aminotransferase 
βhCG 
Beta human chorionic gonadotropin 
CSA 
Clinical Study Agreement
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice
HbA1c 
Glycated hemoglobin
HuL 
Human leptin
ICF 
Informed Consent Form
ICH 
International Conference on Harmonisation
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities
PK 
Pharmacokinetics
REMS 
Risk Evaluation and Mitigation Strategy
SAE 
Serious adverse event
ULN 
Upper limit of normal
US/USA 
United States (of America) 
USPI 
United States prescribing information 

 
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1. 
SYNOPSIS 
NAME OF 
SPONSOR/COMPANY: 
AEGERION PHARMACEUTICALS, INC. 
Name of Finished 
Product: 
MYALEPT 
Name of Active 
Ingredient: 
Metreleptin 
Study Number: 
Protocol AEGR-734-401 
Title of Study: 
A 36-Month, Multicenter, Open Label Phase 4 study to 
Evaluate the Immunogenicity of Daily SC Metreleptin 
Treatment in Patients with Generalized Lipodystrophy 
Number of 
Investigators and 
Study Centers: 
The study will be conducted at approximately 10 study centers 
in the United States (US). 
Development Phase: Phase 4 
Objectives: 
 
Primary Objective: 
Outcome Measure: 
Evaluate the immunogenicity 
associated with daily SC 
metreleptin treatment in 
patients with congenital or 
acquired generalized 
lipodystrophy. 
Anti-metreleptin, anti human 
leptin (anti-HuL) binding 
antibody titers over time.  
Category of in vitro neutralizing 
activity to metreleptin in a cell-
based assay and titer in a 
receptor-binding assay in 
metreleptin/leptin- antibody 
positive samples over time.   
 
 
Secondary Objective: 
Outcome Measure : 
Assess 2 methods of 
measuring in vitro 
neutralizing activity to 
metreleptin. 
Receptor-binding assay titer, cell-
based assay category. 
 
 

 
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Safety Objectives: 
Outcome Measure: 
Evaluate the safety and 
tolerability in relation to the 
development of or absence of 
anti-metreleptin or anti-huL 
antibodies, and/or in vitro 
neutralizing activity to 
metreleptin in patients with 
congenital or acquired 
generalized lipodystrophy.  
SAEs, adverse events leading to 
discontinuation, loss of response 
(as assessed by HbA1c and serum 
triglycerides), severe infections 
and/or sepsis, standard laboratory 
tests, and vital signs over time. 
Measure in vitro neutralizing 
activity in all patients with 
suspected loss of response 
(worsening of metabolic 
control) or endogenous leptin 
action (severe infections or 
sepsis) at time of adverse 
event report.     
Receptor-binding assay titer, cell-
based assay category. 
 
 
Exploratory Objective: 
Outcome Measure: 
Evaluate the efficacy 
achieved with daily SC 
metreleptin treatment in 
patients with congenital or 
acquired generalized 
lipodystrophy.  
Change from baseline in HbA1c 
and fasting triglycerides over 
time.  
Study Population 
Patients who have been prescribed metreleptin for treatment of 
these conditions will be enrolled in the study, prior to initiation 
of metreleptin treatment.  Pediatric patients will be included 
since patients with congenital generalized lipodystrophy 
present with this condition at birth and patients with acquired 
generalized lipodystrophy often present during early 
childhood. 
 
Assessment of antibodies is required; thus, only patients who 
have not been previously treatment with metreleptin will be 

 
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enrolled in order to document the development of antibodies 
over time.  
Methodology/Study 
Design: 
MYALEPT™ (metreleptin) has been approved as an adjunct to 
diet as replacement therapy to treat the complications of leptin 
deficiency in patients with congenital or acquired generalized 
lipodystrophy (MYALEPT Prescribing Information).  This 
study is a multicenter, open-label, Phase 4 trial to provide an 
assessment of the immunogenicity associated with metreleptin 
and of any major potential risks due to development of 
antibodies to metreleptin.  The study is being conducted to 
comply with the postmarketing requirement. 
 
Patients who have been prescribed metreleptin for 
lipodystrophy, who meet all enrollment criteria and sign 
informed consent for this study at Screening (Visit 1) will 
receive the first dose of metreleptin at Enrollment/Baseline 
(Visit 2) at the study site.  Patients will return to the study site 
for follow-up and collection of blood samples at regular 
intervals (at Months 1, 2, 4, 6, 9, 12, 18, 24, 30, and 36), for a 
total of 12 visits over 3 years (36 months).   
 
All patients with suspected loss of metreleptin efficacy 
(worsening of metabolic control) or endogenous leptin action 
(severe infections or sepsis) should be tested for in vitro 
neutralizing activity. 
Planned Number of 
Patients: 
Ten patients who have been prescribed metreleptin will be 
enrolled.   
Study Population/ 
Inclusion Criteria: 
For inclusion in the study, patients should fulfill the following 
criteria at the screening visit: 
1. Provision of informed consent prior to any study specific 
procedures.  If <18 years of age, has a parent or guardian 
able to read, understand, and sign the Informed Consent 
Form (ICF) and a Child Assent form, communicate with 
the Investigator, and understand and comply with protocol 
requirements.  Adolescent patients must also read and 
understand the Child Assent Form.  If the child is too 
young or unable to read, then the Child Assent form must 
be explained to the child.  
2. Female and/or male patients ≥1 years of age. 

 
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3. Physician-confirmed diagnosis of congenital or acquired 
generalized lipodystrophy and will begin treatment with 
MYALEPT for the first time.  
4. Negative pregnancy test (urine or serum) for female 
patients of childbearing potential. 
5. Female patients of childbearing potential must be 1 year 
postmenopausal, surgically sterile, or be willing to use an 
acceptable method of contraception (an acceptable method 
of contraception is defined as a barrier method in 
conjunction with a spermicide) for the duration of the 
study (from the time they sign consent).  In addition, oral 
contraceptives, approved contraceptive implant, long-term 
injectable contraception, intrauterine device, or tubal 
ligation are allowed.  Oral contraception alone is not 
acceptable; additional barrier methods in conjunction with 
spermicide must be used. 
6. Male patients must be surgically sterile or be willing to use 
an acceptable method of contraception (defined as barrier 
methods in conjunction with spermicides) for the duration 
of the study (from the time they sign consent). 
7. Patients who are blood donors should not donate blood 
during the study and for 3 months following their last dose 
of metreleptin. 
Exclusion Criteria:  
Patients should not enter the study if any of the following 
exclusion criteria are fulfilled: 
1. Involvement in the planning and/or conduct of the study 
(applies to both Aegerion staff and/or staff at the study 
site.) 
2. Previous treatment with metreleptin. 
3. Participation in another clinical study with an 
investigational product during the last 6 months. 
4. Patients with prior severe hypersensitivity reactions to 
metreleptin or to any of the product components. 
5. Known to have tested positive for human 
immunodeficiency virus, are immunocompromised, or are 
receiving immunomodulatory drugs.  
6. Known history of drug or alcohol abuse within 1 year of 
screening. 
7. Creatinine clearance <30 mL/min using institutional 
standards: 
e.g., calculated using Cockcroft-Gault formula for patients 

 
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≥18 years of age; 
calculated using Schwartz equation for patients <18 years 
of age.  
8. For women only - currently pregnant (confirmed with 
positive pregnancy test) or breast-feeding. 
9. Any condition where, in the opinion of the Investigator, 
participation in this study may pose a significant risk to the 
patient or could render the patient unable to successfully 
complete the study.  
Test Product, Dose, 
Dosage Form, Mode 
of Administration: 
Patients who have been prescribed metreleptin and are 
enrolled in the study will be administered metreleptin once 
daily by SC injection at doses consistent with the US 
prescribing information (see table below).  Based on clinical 
response (e.g., inadequate metabolic control) or other 
considerations (e.g., tolerability issues, or excessive weight 
loss, particularly in pediatric patients), the dose may be 
decreased or increased to the maximum dosage (see table 
below). 
Baseline 
weight 
Starting daily 
dose (injection 
volume) 
Dose adjustments 
(injection volume) 
Maximum 
daily dose 
(injection 
volume) 
≤40 kg 
(male and 
female 
patients) 
0.06 mg/kg 
(0.012 mL/kg) 
0.02 mg/kg 
(0.004 mL/kg) 
0.13 mg/kg 
(0.026 mL/kg) 
Male 
patients 
>40 kg 
2.5 mg (0.5 mL) 
1.25 mg (0.25 mL) 
to 2.5 mg (0.5 mL) 
10 mg (2 mL) 
Female 
patients 
>40 kg 
5 mg (1 mL) 
1.25 mg (0.25 mL) 
to 2.5 mg (0.5 mL) 
10 mg (2 mL) 
  
Duration of 
Treatment and 
Study Participation: 
Development of neutralizing antibodies to metreleptin and 
HuL has been observed with metreleptin treatment.  The time 
to the first sample in which Category D or E in vitro 
neutralizing activity was detected ranged from 20 weeks to 
156 weeks following initiation of metreleptin treatment.  In 
this study, immunogenicity will be assessed over 3 years 
(36 months) of continuous treatment to allow sufficient time to 
evaluate not only binding antibodies to metreleptin and HuL, 
but also potential in vitro neutralizing activity.  

 
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Statistical Methods: 
There will be no hypothesis testing.  All data will be 
summarized by descriptive statistics and/or listing.  The 
following will be used for all analyses: 
Patients treated with a dose of metreleptin will be included in 
the safety and tolerability and patients with a post dose sample 
will be assessed for immunogenicity 
Patients treated with a dose of metreleptin and with baseline 
and postdose efficacy data will be included in the efficacy 
analyses.  

 
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2. 
INTRODUCTION 
2.1 
Background 
Metreleptin is a recombinant analog of human leptin recently approved in the United 
States (US) as an adjunct to diet as replacement therapy to treat complications of leptin 
deficiency in patients with congenital or acquired generalized lipodystrophy.  Antibodies 
to metreleptin develop in the majority of patients who are treated with metreleptin.  Anti-
metreleptin antibodies with in vitro neutralizing activity have been identified in a small 
number of patients treated with metreleptin (MYALEPT Prescribing Information).  The 
consequences of these neutralizing antibodies are not well characterized, but may 
potentially include inhibition of endogenous leptin action and/or loss of metreleptin 
efficacy.  Severe infection and/or worsening metabolic control have also been reported.  
Because of potential risks associated with the development of anti-metreleptin antibodies 
that neutralize endogenous leptin, metreleptin is available only through a restricted 
program: the MYALEPT Risk Evaluation and Mitigation Strategy (REMS) Program. 
Assessment of binding (non-neutralizing) antibodies (based on immunoassay) as well as 
neutralizing activity to metreleptin (based on an in vitro cell-based assay) has been 
performed in 2 metreleptin development programs: obesity and lipodystrophy.  
Prospective assessment of antibody development was specified in the obesity 
development program and retrospective testing of available samples was conducted in the 
lipodystrophy program.  Anti-metreleptin antibodies have been detected in 70 to 95% of 
patients who received metreleptin in clinical studies across both programs.  Data from the 
obesity and lipodystrophy programs indicate that, in most patients, anti-metreleptin 
antibodies occur at a low level (titer), are detected within 4-8 weeks following initiation 
of treatment, reach a peak titer or plateau within 10 to 20 weeks, and tend to decrease 
over time despite chronic antigen presentation (due to continued metreleptin therapy), but 
generally do not disappear completely during therapy.  It should be noted that data from 
the lipodystrophy program generally confirm these findings, but the time course of 
antibody development and peak titer in lipodystrophy patients is less well-defined due to 
inconsistent sampling across patients in the clinical studies.  In both populations, a small 
number of patients developed very high anti-metreleptin antibody titers which, in some 
cases, was associated with in vitro metreleptin neutralizing activity. 

 
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To fill some of the void in understanding immunogenicity in patients with generalized 
lipodystrophy, assessment of the immunogenicity associated with metreleptin treatment 
in a relevant number of patients was included as a post-approval requirement in the US.  
The requirement included the following: 1) assessment of anti-metreleptin and anti-
human leptin (anti-HuL) binding antibodies when responses peak, 2) assessment of 
neutralizing antibodies in samples that are confirmed positive for binding antibodies to 
leptin, and 3) testing for in vitro neutralizing activity in patients with loss of effect 
(worsening metabolic control) or loss of endogenous leptin action (severe infections or 
sepsis), as well as an analysis of clinical events, over time, associated with binding 
antibodies or neutralizing antibodies.  This study is designed to provide data for these 
assessments. 
2.2 
Rationale for Study Design, Doses and Control Groups 
This study is being conducted to satisfy a postmarketing requirement to assess the 
immunogenicity associated with metreleptin treatment.  Because immunogenicity can 
only be evaluated in the context of drug treatment, the study is open-label and will 
characterize antibody and in vitro neutralizing activity over time and will compare safety 
and tolerability in patients with different antibody statuses (e.g., binding antibody titer, in 
vitro neutralizing activity category, in vitro neutralizing activity percent inhibition).  
Immunogenicity will be evaluated in the context of the prescribing information for 
MYALEPT; thus, the patient population and dosing will be per the US prescribing 
information (MYALEPT Prescribing Information). 
Anti-metreleptin and anti-HuL binding antibody titers over time will be evaluated in 
order to establish a time course of antibody development and to assess the development 
of antibodies that recognize the endogenous protein.  Because samples from a few 
patients treated with metreleptin have demonstrated in vitro neutralizing activity in an in 
vitro cell-based assay, in vitro neutralizing activity will also be assessed in all antibody 
positive samples.  To provide an orthogonal method to evaluate potential in vitro 
neutralizing activity, all antibody positive samples will also be assessed using a ligand-
binding assay. 
Safety and tolerability of metreleptin associated with the development of, or absence of, 
antibodies will be evaluated.  All adverse events (AEs) will be collected throughout the 
course of this study. Serious adverse events (SAEs), adverse events of special interest 

 
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(AESI) AEs leading to discontinuation, standard laboratory tests and vital signs will be 
collected over time and analyzed for any potential association with antibody status. See 
Section 8.2 for definitions of AEs and AESIs. 
The study duration is based on following patients treated with metreleptin for a period of 
3 years.  In previous studies, the time to the first sample in which Category D or E 
in vitro neutralizing activity was detected ranged from 20 weeks to 156 weeks following 
initiation of metreleptin treatment; therefore, in order to gain a relevant assessment of the 
time course for development of in vitro neutralizing activity as well as to allow sufficient 
time to capture cases of in vitro neutralizing activity, 3 years of exposure to metreleptin 
was selected. 
2.3 
Benefit/Risk and Ethical Assessment 
Native leptin is a hormone predominantly secreted by adipose tissue that informs the 
central nervous system of the status of energy stores in the body.  In patients with 
generalized lipodystrophy, leptin deficiency, resulting from the loss of adipose tissue, 
contributes to excess caloric intake, which exacerbates the metabolic abnormalities 
leading to comorbid conditions including severe insulin resistance, diabetes, and 
hypertriglyceridemia.  As reported in the USPI, MYALEPT is indicated as an adjunct to 
diet as replacement therapy to treat the complications of leptin deficiency in patients with 
congenital or acquired generalized lipodystrophy.  Treatment with MYALEPT resulted in 
robust mean/median reductions in HbA1c, fasting glucose, and triglycerides at 1 year.  
The magnitude of these reductions was greater in patients with higher HbA1c, fasting 
glucose, and triglycerides prior to treatment (MYALEPT Prescribing Information). 
T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy, 
both treated and not treated with MYALEPT.  The benefits and risks of treatment with 
MYALEPT in patients with significant hematologic abnormalities and/or acquired 
generalized lipodystrophy should be considered. 
Anti-metreleptin antibodies with in vitro neutralizing activity have been identified in 
patients treated with MYALEPT.  The consequences of these neutralizing antibodies are 
not well characterized but could include inhibition of endogenous leptin action and/or 
loss of MYALEPT efficacy.  Severe infection and/or worsening metabolic control have 
been reported. 

 
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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective 
Primary Objective: 
Outcome Measure: 
Evaluate the immunogenicity associated 
with daily SC metreleptin treatment in 
patients with congenital or acquired 
generalized lipodystrophy. 
Anti-metreleptin, anti-HuL binding antibody 
titers over time.  Category of in vitro neutralizing 
activity to metreleptin in a cell-based assay and 
titer in receptor-binding assay in 
metreleptin/leptin- antibody positive samples 
over time.   
3.2 
Secondary Objectives 
Secondary Objective: 
Outcome Measure: 
Assess 2 methods of measuring in vitro 
neutralizing activity to metreleptin. 
Receptor-binding assay titer, cell-based assay 
category. 
3.3 
Safety Objectives 
Safety Objectives: 
Outcome Measure: 
Evaluate the safety and tolerability in 
relation to the development of or absence 
of anti-metreleptin or anti-huL antibodies, 
and/or in vitro neutralizing activity to 
metreleptin in patients with congenital or 
acquired generalized lipodystrophy.  
Measure in vitro neutralizing activity in all 
patients with suspected loss of response 
(worsening of metabolic control) or 
endogenous leptin action (severe infections 
or sepsis) at time of adverse event report.    
SAEs, adverse events leading to discontinuation, 
loss of response (as assessed by HbA1c and 
serum triglycerides), severe infections and/or 
sepsis, standard laboratory tests, and vital signs 
over time.  
Receptor-binding assay titer, cell-based assay 
category. 
 
3.4 
Exploratory Objectives 
Exploratory Objective: 
Outcome Measure: 
Evaluate the efficacy achieved with daily 
SC metreleptin treatment in patients with 
congenital or acquired generalized 
lipodystrophy.  
Change from baseline in HbA1c and fasting 
triglycerides over time.  

 
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4. 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
The study flow diagram is presented in Figure 1.   
Patients who sign informed consent and meet all inclusion/exclusion criteria will be 
enrolled in the study.  Assessments will be made at the times specified in the Study Plan 
(Table 1).  Patients with in vitro neutralizing activity should enroll in the Immunogenicity 
Follow-up Program; refer to Section 7.3.3 for definitions of in vitro neutralizing activity 
categories. 
Figure 1: Study Schematic 
 
 
4.2 
Number of Patients 
Ten patients who have been prescribed MYALEPT will be enrolled. 

 
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4.3 
Inclusion Criteria 
For inclusion in the study, patients should fulfill the following criteria at the screening 
visit: 
1. Provision of informed consent prior to any study specific procedures.  If <18 
years of age, has a parent or guardian able to read, understand, and sign the 
Informed Consent Form (ICF) and a Child Assent form, communicate with the 
Investigator, and understand and comply with protocol requirements.  Adolescent 
patients must also read and understand the Child Assent Form.  If the child is too 
young or unable to read, then the Child Assent form must be explained to the 
child.  
2. Female and/or male patients ≥1 years of age. 
3. Physician-confirmed diagnosis of congenital or acquired generalized 
lipodystrophy and will begin treatment with MYALEPT for the first time. 
4. Negative pregnancy test (urine or serum) for female patients of childbearing 
potential. 
5. Female patients of childbearing potential must be 1 year postmenopausal, 
surgically sterile, or be willing to use an acceptable method of contraception (an 
acceptable method of contraception is defined as a barrier method in conjunction 
with a spermicide) for the duration of the study (from the time they sign consent).  
In addition, oral contraceptives, approved contraceptive implant, long-term 
injectable contraception, intrauterine device, or tubal ligation are allowed.  Oral 
contraception alone is not acceptable; additional barrier methods in conjunction 
with spermicide must be used. 
6. Male patients must be surgically sterile or be willing to use an acceptable method 
of contraception (defined as barrier methods in conjunction with spermicides) for 
the duration of the study (from the time they sign consent). 
7. Patients who are blood donors should not donate blood during the study and for 
3 months following their last dose of metreleptin. 
4.4 
Exclusion Criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Involvement in the planning and/or conduct of the study (applies to both Aegerion 
staff and/or staff at the study site.) 
2. Previous treatment with metreleptin. 

 
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3. Participation in another clinical study with an investigational product during the 
last 6 months. 
4. Patients with prior severe hypersensitivity reactions to metreleptin or to any of the 
product components. 
5. Known to have tested positive for human immunodeficiency virus, are 
immunocompromised, or are receiving immunomodulatory drugs.  
6. Known history of drug or alcohol abuse within 1 year of screening. 
7. Creatinine clearance <30 ml/min using institutional standard: 
e.g., calculated using Cockcroft-Gault formula for patients ≥18 years of age; 
calculated using Schwartz equation for patients <18 years of age.  
8. For women only - currently pregnant (confirmed with positive pregnancy test) or 
breast-feeding. 
9. Any condition where, in the opinion of the Investigator, participation in this study 
may pose a significant risk to the patient or could render the patient unable to 
successfully complete the study. 
For procedures for withdrawal of incorrectly enrolled patients, see Section 4.6. 
4.5 
Patient Enrollment and Randomization 
Patients will not be randomized in this study.  Patients who have been prescribed 
metreleptin will be screened for enrollment. 
Investigator(s) should keep a record (the patient screening log) of patients who entered 
screening. 
The Investigator(s) will: 
 Obtain certification under the REMS for MYALEPT to prescribe MYALEPT. 
 Confirm the patient meets the requirements for MYALEPT prescription, as per 
the USPI. 
 Obtain signed informed consent from the potential patient or his/her 
guardian/legal representative before any study-specific procedures are performed. 
 Assign potential patient a unique enrollment number.  
 Determine patient eligibility (see Sections 4.3 and 4.4). 
 Schedule Enrollment/Baseline visit to coincide with treatment initiation. 

 
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If a patient withdraws from participation in the study, then his/her enrollment code cannot 
be reused. 
4.6 
Procedures for Handling Incorrectly Enrolled Patients 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  If, however, the patient meets eligibility criteria at 
a later date they can be evaluated and enrolled on a case by case basis.  If patients are 
enrolled but subsequently found not to meet all the eligibility criteria, the Investigator 
should consult with the Aegerion medical monitor to determine if continued participation 
poses a risk to the patient. 
4.7 
Methods for Assigning Treatment Groups 
Patients will not be randomized; patients who meet all inclusion/exclusion criteria will be 
included in the study. 
4.8 
Methods for Ensuring Blinding 
This section is not applicable.  The study is open-label. 
4.9 
Methods for Unblinding  
This section is not applicable.  The study is open-label. 
4.10 
Restrictions 
Patients must abstain from donating blood/plasma from the time of informed consent to 
end of study.   
Patients should adhere to dietary instructions provided by their physicians (e.g., low-fat 
diet). 
4.11 
Discontinuation of Metreleptin 
Patients may be discontinued from metreleptin in the following situations: 
 Patient decision.  The patient is, at any time, free to discontinue treatment, 
without prejudice to further treatment. 
 Investigator decision due to an AE. 

 
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 Investigator decision due to severe noncompliance. 
Patients should be encouraged to continue in the study and attend all protocol-specified 
visits until the end of the 3-year study period, even if discontinued from metreleptin, to 
enable continued evaluation of immunogenicity. 
4.11.1 
Procedures for Discontinuation of a Patient from Metreleptin  
At any time, patients are free to discontinue metreleptin, without prejudice to further 
treatment.  When discontinuing metreleptin in patients with risk factors for pancreatitis 
(e.g., history of pancreatitis, severe hypertriglyceridemia), tapering of the dose over a 
1-week period is recommended.  During tapering, triglyceride levels should be monitored 
and initiation of or adjustment of the dose of lipid-lowering medications should be 
considered, as needed.  Signs and/or symptoms consistent with pancreatitis should 
prompt an appropriate clinical evaluation.  
A patient who decides to discontinue metreleptin will be asked about the reason(s) and to 
specify any AEs or SAEs leading to discontinuation.  If possible, patients should be seen 
and assessed by the Investigator(s).  Adverse events will be followed up (see Section 8).  
Patients should return for all protocol-specified visits to allow for continued assessments, 
even if metreleptin has been discontinued.  In addition to AESIs (refer to Section 8.3.8) 
and SAEs, samples for antibodies and in vitro neutralizing activity should be collected 
after discontinuation of metreleptin. 
Patients who discontinue metreleptin may restart treatment at any time during the 3-year 
study period. 
If a patient is withdrawn from the study, see Section 4.12. 
4.12 
Criteria for Withdrawal from the Study 
4.12.1 
Screen Failures  
Screening failures are patients who sign the ICF but do not fulfill the eligibility criteria 
for the study and therefore must not be enrolled.  Patients are allowed to be rescreened 
and enrolled into the study if they are found to be eligible at a later date.  Patients who 
fail the screening process should have the reason for study withdrawal recorded as 

 
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“patient does not meet the required inclusion/exclusion criteria.”  This reason for 
withdrawal from study is only valid for screen failures and not for enrolled patients. 
4.12.2 
Withdrawal of the Informed Consent 
Patients are free to withdraw from the study at any time (metreleptin and assessments), 
without prejudice to further treatment.  In this case, the Investigator should provide a 
statement, in writing, that the patient declines all further follow-up.  A patient who has 
withdrawn from the study is allowed to reenter the study and restart treatment any time 
during the 3-year study period, provided they still meet all inclusion criteria and none of 
the exclusion criteria. 
A patient who withdraws consent will always be asked about the reason(s) and to specify 
any AEs or SAEs leading to withdrawal.  The Investigator will follow up AEs/SAEs 
outside of the clinical study.  
If a patient withdraws from participation in the study, then his/her enrollment code cannot 
be reused.  Withdrawn patients will be replaced if time from enrollment to withdrawal is 
less than 6 months. 
4.13 
Discontinuation of the Study 
The study may be stopped if, in the judgment of Aegerion, trial patients are placed at 
undue risk because of clinically significant findings that: 
 meet individual stopping criteria or are otherwise considered significant  
 are assessed as causally related to study drug  
 are not considered to be consistent with continuation of the study 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the electronic case report form (eCRF).  
All reasons for discontinuation of treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to 
the protection of the patients’ interests. 
5. 
STUDY PLAN AND TIMING OF PROCEDURES  
The Study Plan is presented in Table 1. 

 
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All patients with suspected loss of metreleptin efficacy (worsening of metabolic control) 
or endogenous leptin action (severe infections or sepsis) should be tested for in vitro 
neutralizing activity. 
6. 
STUDY PROCEDURES 
6.1 
Schedule of Assessments 
Study procedures are summarized in Table 1.  Detailed descriptions of the efficacy, PK, 
and safety procedures to be conducted during this study are provided in the following 
sections. 

 
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Table 1: Schedule of Study Assessments 
VISIT NUMBER 
SCREENING 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FOR DETAILS, SEE 
PROTOCOL 
SECTION: 
MONTH 
-1 
0 
1 
2 
4 
6 
9 
12 
18 
24 
30 
36 
 
WINDOW (DAYS) 
-28 TO 0 
±0 
±7 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
±14 
 
PROCEDURE 
Informed Consent and 
Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination,  
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Vital Signs/ Weight/ 
Heighta 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum or Urine 
Pregnancy Testb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fasting Samples for 
Hematology & 
Clinical Chemistry 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
X 
 
HbA1c, Lipids, 
Fasting Glucose  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Samples for Antibody 
and Leptin 
Measurementsc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

 
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VISIT NUMBER 
SCREENING 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FOR DETAILS, SEE 
PROTOCOL 
SECTION: 
MONTH 
-1 
0 
1 
2 
4 
6 
9 
12 
18 
24 
30 
36 
 
WINDOW (DAYS) 
-28 TO 0 
±0 
±7 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
±14 
 
PROCEDURE 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Study Medication 
Administration First 
Dose 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events, 
including SAEs and 
AESI 
 
Continuous Monitoring 
 
 
Concomitant use of 
Lipid-Lowering, 
Antidiabetic and 
Immunomodulatory 
Agents 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a 
For all pediatric patients (≤18 years of age), a pubertal development assessment should also be conducted at Screening and Months 12, 24, and 36. 
b 
A serum or urine pregnancy test (βhCG) should be completed for all female patients of child-bearing potential, unless the patient has had a hysterectomy.  
c 
Samples for antibody measurement should be taken before administering metreleptin at each study visit in order to minimize high levels of metreleptin in the 
samples, which could interfere with antibody testing. 

 
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6.2 
Enrollment/Screening Period 
6.2.1 
Screening 
At screening, consenting patients will be assessed to ensure that they meet eligibility 
criteria.  Patients who do not meet these criteria must not be enrolled in the study.  
 The Informed Consent and HIPAA Authorization forms, will be signed prior to 
performing any protocol-required procedures.  The following will be conducted at the 
Screening Visit: 
 Inclusion and exclusion criteria will be verified. 
 Body weight and height will be measured as part of a complete physical exam. 
 The patient’s complete medical/surgical history will be recorded. 
 All prior medications (prescription medications within 3 months) and current 
medications will be reviewed; concomitant use of lipid-lowering and antidiabetic will 
be recorded in the eCRF. 
 Vital signs (sitting systolic and diastolic blood pressure and heart rate) will be 
measured. 
 Urine will be collected for urinalysis. 
 A serum or urine pregnancy test (hCG) will be conducted for all female patients of 
childbearing potential. 
 Fasting blood samples will be collected for the following assessments: 
 Chemistry and hematology. 
 HbA1c, lipids, and fasting glucose. 
When all the screening results are available, individuals will be notified by telephone of 
their eligibility status.  Those who qualify will be eligible to return to the clinical study 
site within 28 days after the Screening Visit to complete eligibility requirements for 
enrollment. 
Prior to the Enrollment Visit (Visit 2), the Investigator should obtain certification under 
the REMS for MYALEPT to enable prescribing of metreleptin.  Once the prescription for 
metreleptin is filled, the physician should have the first drug shipment sent to the 
physician’s office in preparation for the Enrollment Visit.  

 
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6.2.2 
Baseline/Enrollment Visit  
At the Enrollment Visit (Visit 2), to be conducted within 28 days of the Screening Visit, 
patients are to have fasted overnight (8 hours).  Patients should delay administering their 
morning dose of anti-diabetes therapy (if applicable) until enrollment procedures have 
been completed.  All procedures specified in the Study Plan (Table 1) should be 
conducted prior to first administration of metreleptin.  The following will be conducted at 
the Baseline/Enrollment visit: 
 Inclusion and exclusion criteria will be verified.  
 Blood samples for measurement of leptin and antibodies to metreleptin and human 
leptin will be collected to provide a measurement prior to initiation of metreleptin. 
 Fasting samples for hematology and clinical chemistry will be collected. 
 Samples for measurement of HbA1c, lipids and fasting glucose will be collected. 
 Vital signs and weight will be measured. 
 Concomitant use of lipid-lowering and anti-diabetic, will be reviewed. 
 The Investigator will instruct the patient on proper reconstitution of metreleptin and 
have the patient or caregiver administer the first dose of metreleptin by SC injection 
under observation. 
 Serious adverse events and AESI (refer to Section 8.3.8) will be reviewed. 
 Urine pregnancy tests (βhCG) will be conducted for all female patients of 
childbearing potential. 
6.3 
Treatment Period 
After the first dose of metreleptin is administered at Visit 2 (Month 0), patients will 
complete Visits 3 to 12 at Months 1, 2, 4, 6, 9, 12, 18, 24, 30, and 36.  Descriptions of the 
procedures for this period are included in the Study Plan (Table 1); all procedures should 
be conducted prior to administration of metreleptin on the day of the study visit.  The 
following will be conducted during the treatment period: 
 Blood samples for measurement of leptin and antibodies to metreleptin and human 
leptin will be collected. 
 Samples for measurement of HbA1c, lipids and fasting glucose will be collected. 
 Fasting samples for hematology and clinical chemistry will be collected (only at 
Visits 6, 8, 9, 10, and 12). 

 
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 Vital signs and weight will be measured. 
 A physical examination, including height, will be conducted at Visits 8, 10, and 12. 
 Concomitant use of lipid-lowering and antidiabetic, will be reviewed. 
 Urine will be collected for urinalysis (only at Visits 8, 10, and 12). 
 Urine pregnancy tests (βhCG) will be conducted for all female patients of 
childbearing potential. 
 Serious adverse events and AESI (refer to Section 8.3.8) will be reviewed. 
All Visit 12 assessments should be conducted for patients who discontinue the study prior 
to Month 36. 
6.4 
Follow-up for Patients with In Vitro Neutralizing Activity 
Patients identified with neutralizing activity during the 3-year study period will be 
encouraged to continue participation in the study and complete all protocol-specified 
assessments until the end of the study period (even if the decision is made to discontinue 
metreleptin).  At the end of the 3-year study period, these patients should be enrolled in 
the separate MYALEPT Immunogenicity Follow-up program in order to continue 
immunogenicity assessments.  Evidence of in vitro neutralizing activity will be 
considered either Category D or E results in the cell-based assay (refer to Section 7.3.3), 
or positive results based on percent inhibition (criteria to be determined) in the receptor-
binding assay (refer to Section 7.3.2).  Instructions for consent and enrollment into this 
separate Follow-up program will be provided by the Sponsor’s safety physician. 

 
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7. 
STUDY ASSESSMENTS 
The Investigator will ensure that data are recorded on the eCRF as specified in the study 
protocol and in accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study 
Agreement (CSA).  The Investigator will sign the completed eCRF.  A copy of the 
completed eCRFs will be archived at the study site. 
The sequence for the blood sampling tubes and the amount of blood drawn is found in 
Table 2.  A smaller total volume is specified for patients weighing 40 lbs. or less. 
Table 2: Blood Sample Tubes Volumes and Sequence 
LAB TEST 
TUBE 
MINIMUM VOLUME 
REQUIRED (ML) 
PATIENTS 40 LBS. OR 
LESS 
VOLUME FOR PATIENTS 
41 LBS. OR MORE 
Chem 10 
Red Top 
0.6 
0.6 
Lipid 
Red Top  
0.6 
0.6 
CBC/Hem 
Lavender Top 
0.5 
0.5 
HbA1c 
Lavender Top 
2 
7 
Antibody and Leptin 
Gold SST 
4 
4 
 
Total Vol Collected:  
7.7 
12.7 
 
7.1 
Efficacy Assessments 
Blood samples for measurement of HbA1c (%), fasting glucose (mg/dL), and 
triglycerides (mg/dL) will be collected at the times specified in the Study Plan (Table 1). 
7.2 
Safety Assessments 
7.2.1 
Laboratory Safety Assessments 
Blood and urine samples for determination of clinical chemistry, hematology, and 
urinalysis will be collected at the times specified in the Study Plan (Table 1). 

 
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Laboratory variables to be measured are presented in Table 3: 
Table 3: Laboratory Safety Variables 
Hematology/hemostasis (whole blood) 
Clinical chemistry (serum) 
Hemoglobin (Hb)  
Creatinine 
Leukocyte count 
Bilirubin, total 
Leukocyte differential count (absolute count) 
Alkaline phosphatase (ALP) 
Platelet count 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
Urinalysis (dipstick; microscopic if abnormal) 
Albumin 
U-Hb/Erythrocytes/Blood  
Potassium 
U-Protein/Albumin  
Calcium, total 
U-Glucose  
Sodium 
The Investigator should make an assessment of the available laboratory results with 
regard to clinically relevant abnormalities.  The laboratory results should be signed and 
dated and retained at the study site as source data for laboratory variables.  Refer to 
Section 8.3 for reporting of AEs based on laboratory test results. 
If a patient has an AST or ALT ≥3x upper limit of normal (ULN) and total bilirubin 
≥2x ULN, refer to Appendix B for further instruction in cases of combined increase of 
aminotransferase and total bilirubin 
7.2.2 
Physical Examination 
A complete physical examination will be performed at the times specified in the Study 
Plan (Table 1) and include an assessment of the following: general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, abdomen, musculo-skeletal (including spine and 
extremities), and neurological systems.  
For all pediatric patients (≤18 years of age), a Tanner pubertal development assessment 
should be conducted at Visits 8, 10, and 12. 

 
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7.2.3 
Vital Signs 
Vital sign measurements will include sitting systolic and diastolic blood pressure and 
heart rate and body temperature.  Vital signs and sitting blood pressure and pulse rate 
should be measured after the patient rests for approximately 5 minutes and with the 
patient in a sitting position.  The blood pressure measurement should be repeated after at 
least 30 seconds and the average of the 2 readings recorded. 
7.3 
Immunogenicity 
7.3.1 
Collection of Samples for Measurement of Antibodies to Metreleptin 
and Leptin and In Vitro Neutralizing Activity 
Blood samples for the measurement of antibodies to metreleptin and human leptin will be 
collected at the times specified in the Study Plan (Table 1).  A cell-based assay and a 
receptor-binding assay will be used to measure in vitro neutralizing activity in all samples 
that test positive for antibodies to metreleptin and/or leptin (titer ≥5).  The study lab 
manual will provide specific instructions for collection, processing, packaging, and 
shipping of all samples. 
Additional safety samples for measurement of antibodies to metreleptin and human leptin 
will be collected if clinically indicated (e.g., loss of response to MYALEPT, or if patient 
develops a severe infection and/or sepsis), or at the discretion of the Investigator.  The 
date, time of collection, and results (values, units, and reference ranges) will be recorded 
on the appropriate eCRF. 
7.3.2 
Determination of Antibodies to Metreleptin and Leptin 
A Receptor Binding Electrochemiluminescent Immunoassay (ECLIA) Procedure for the 
Detection of Neutralizing Antibodies to Metreleptin and Leptin in Human Serum has 
been developed and validated to detect antibodies to both endogenous leptin and 
metreleptin (this method was previously submitted and approved by the FDA as part of 
our post-marketing commitments). 
Antibodies to metreleptin are detected using a bridging ELISA format method.  Full 
details of this method will be described in a separate report. 

 
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7.3.3 
Determination of Metreleptin In Vitro Neutralizing Activity 
There are no clinical indicators clearly associated with in vitro neutralizing activity; 
detection of neutralizing activity is achieved using an in vitro cell-based assay method.  If 
no activity is detected upon initial testing with the cell-based assay, the result is reported 
as Category A.  If activity is detected at the initial test concentration, the sample is 
retested at the same concentration, and if no activity is detected on retest, the initial result 
is attributed to assay noise, and the sample is reported as Category B.  If activity is 
detected on both tests at initial concentration, the sample is diluted and retested until 
activity is no longer detected.  Depending on the number of dilutions required to dilute 
activity below the detectable threshold, the result is reported as Category C, D, or E.  
Category D and E results are considered to represent high potency in vitro neutralizing 
activity.  The clinical relevance of in vitro neutralizing activity results in any category has 
not been determined, and is a topic of current investigation.  
In addition, the receptor binding Electro-chemiluminescence (ECLIA) Procedure for the 
detection of neutralizing Antibodies to Metreleptin and Leptin in Human Serum has been 
developed and validated to detect antibodies to both endogenous leptin and metreleptin 
(this method was previously submitted and approved by the FDA as part of Aegerion’s 
post-marketing commitments).  The results are reported as percent inhibition and 80% 
inhibition is currently utilized as the neutralizing antibody threshold.  
7.4 
Pharmacokinetics 
No formal pharmacokinetic (PK) analyses of metreleptin will be conducted; leptin 
concentrations will be measured. 
7.4.1 
Collection of Samples for Measurement of Leptin  
Blood samples for the measurement of leptin will be collected at the times specified in 
the Study Plan (Table 1).  The centralized laboratory will provide specific instructions for 
collection, processing, packaging, and shipping of all samples. 
Additional safety samples for measurement of leptin will be collected if clinically 
indicated (e.g., loss of response to MYALEPT, or if patient develops a severe infection 
and/or sepsis), or at the discretion of the Investigator.  The date, time of collection, and 
results (values, units, and reference ranges) will be recorded on the appropriate eCRF. 

 
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7.4.2 
Determination of Leptin Concentration 
Samples for determination of leptin concentration in plasma will be analyzed by a local 
laboratory using an appropriate bioanalytical method.  Full details of the analytical 
methods used will be described in a separate bioanalytical report. 
7.4.3 
Storage and Destruction of Pharmacokinetic Samples 
Any residual back-up PK samples may be used for future exploratory biomarker research 
or in the development of the ligand-binding assay.  PK samples may be disposed of after 
finalization of the Bioanalytical Report, unless further analyses are necessary.   
Incurred sample reproducibility analysis, if any, will be performed alongside the 
bioanalysis of the test samples.  The results from the evaluation will not be reported in 
the Clinical Study Report but separately in a Bioanalytical Report. 
7.5 
Pharmacodynamics 
Pharmacodynamic samples will not be evaluated in this study. 
7.6 
Pharmacogenetics 
Pharmacogenetic samples will not be taken during the study. 
7.7 
Biomarker Analysis  
No biomarkers, with the exception of those described in Table 1, will be analyzed. 
8. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
All adverse events, including SAEs, adverse events leading to discontinuation, and AESIs 
will be recorded on the eCRF.  Additionally, all SAE and AESI that require immediate 
reporting will be captured on the SAE/AESI form and sent to the pharmacovigilance 
department (see Section 8.6).     

 
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8.1 
Definition of Adverse Events 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical 
condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged 
liver) or the clinically significant abnormal results of an investigation (e.g., laboratory 
findings).  In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has 
been administered. 
8.2 
Definitions of Serious Adverse Events 
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, wash-out, 
follow-up), that fulfills one or more of the following criteria: 
 Results in death 
 Is immediately life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
 Is a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
For further guidance on the definition of an SAE, refer to Appendix A. 
In addition, for the purposes of this protocol, the following adverse events of special 
interest (AESI) must be handled as SAEs and are reportable to Aegerion or designee (see 
Section 8.6) within the SAE timeframe regardless whether the adverse events did not 
meet the serious criteria described above in this section:  
 The presence of Category D or E in vitro neutralizing activity (or the relevant 
corresponding test result from the ligand-binding method) to metreleptin 
 Necrotizing pancreatitis 
 Hepatic adverse events including potential DILI 

 
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 Severe hypoglycaemia 
 Severe hypersensitivity reactions 
 New diagnoses of autoimmune disorders (for instance, autoimmune hepatitis, 
glomerulonephritis, lupus erythematosus, antiphospholipid antibody syndrome, 
rheumatoid arthritis)  
 Autoimmune disease exacerbation  
 Serious infection resulting in hospitalization 
 All cancers (excluding non-melanoma skin cancer) by cancer type  
 Exposed pregnancies and pregnancy outcomes 
8.3 
Recording of Adverse Events 
8.3.1 
Time Period for Collection of Adverse Events 
Adverse events (AE), including serious adverse events (SAE), AEs leading to 
discontinuation and AESIs will be recorded from the signing of the informed consent or 
if the AE or AESI is related to study procedure. 
8.3.2 
Follow-up of Unresolved Adverse Events 
Any SAEs, AEs leading to discontinuation and AESIs that are unresolved at the patient’s 
last assessment as appropriate in the study are followed up by the Investigator for as long 
as medically indicated, but without further recording in the eCRF.  Aegerion retains the 
right to request additional information for any patient with ongoing AE/SAE(s) at the end 
of the study, if judged necessary. 
8.3.3 
Variables  
The following variables will be collected for each AE leading to discontinuation and 
AESI: 
 AE (verbatim) 
 Date and time when the AE started and stopped 
 Maximum intensity 
 Maximum common terminology criteria for AE grade 
 Whether the AE is serious or not 

 
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 Investigator causality rating against metreleptin (yes or no) 
 Action taken with regard to metreleptin 
 AE led to patient’s withdrawal from study (yes or no) 
 Outcome 
In addition, the following variables will be collected for SAEs: 
 Date AE met criteria for SAE 
 Date Investigator became aware of SAE 
 Reason AE is serious  
 Date of hospitalization 
 Date of discharge 
 Probable cause of death 
 Date of death 
 Autopsy performed 
 Causality assessment in relation to study procedure(s) 
 Description of AE 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 8.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists 
for several hours may be considered severe nausea, but not an SAE unless it meets the 
criteria presented in Section 8.2.  On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mild stroke but would be an SAE when it 
satisfies the criteria in Section 8.2. 
Intensity rating scale to be used: 
 Mild (awareness of sign or symptom, but easily tolerated) 
 Moderate (discomfort sufficient to cause interference with normal activities) 
 Severe (incapacitating, with inability to perform normal activities) 
8.3.4 
Causality Collection 
The Investigator will assess causal relationship between metreleptin and each AE with 
the answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by metreleptin?’ 

 
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The causal relationship will also be assessed for other medications and study procedures.   
A guide to the interpretation of the causality question is provided in Appendix A. 
8.3.5 
Adverse Events Based on Signs and Symptoms 
All adverse events, including SAEs, AEs leading to discontinuation, or AESIs 
spontaneously reported by the patient or care provider, or are reported in response to the 
open question from the study personnel or revealed by observation will be collected and 
recorded in the eCRF.  When collecting AEs, the recording of diagnoses is preferred 
(when possible) over recording a list of signs and symptoms.  However, if a diagnosis is 
known and there are other signs or symptoms that are not generally part of the diagnosis, 
the diagnosis and each sign or symptom will be recorded separately. 
8.3.6 
Adverse Events Based on Examinations and Tests 
The results from protocol-mandated laboratory tests and vital signs will be summarized in 
the clinical study report.  Deterioration, as compared to baseline, in protocol-mandated 
laboratory values and vital signs should be reported as. 
8.3.7 
Any new or aggravated clinically significant abnormal medical finding 
at a physical examination as compared with the baseline assessment 
should also be reported. Hy’s Law 
Cases where a patient has an AST or ALT ≥3x ULN and total bilirubin ≥2x ULN may 
need to be reported as SAEs.  Refer to Appendix B for further instruction in cases of 
combined increase of aminotransferase and total bilirubin. 
8.3.8 
Adverse Events of Special Interest 
Adverse events of special interest will be collected and recorded in the eCRF. 
A sample should be collected for measurement of in vitro neutralizing activity in all 
patients with the following AEs of special interest: suspected loss of response (worsening 
of metabolic control) or suspected loss of endogenous leptin action (severe infections or 
sepsis). 
For patients who become pregnant during the study, a sample should also be collected to 
measure in vitro neutralizing activity at the time the pregnancy is identified. The patient 

 
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will be allowed to continue in the study; however, the decision as to whether to continue 
metreleptin therapy during the pregnancy will be at the discretion of the treating 
physician.  The pregnancy and all pregnancy outcomes should be reported as an AESI 
and followed by the patients’ prescribing physician.  
8.4 
Reporting of Serious Adverse Events 
All SAEs must be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s).  All SAEs will be recorded in the 
eCRF. 
Should an SAE occurs during the course of the study, Investigators or other site 
personnel must inform Aegerion or designee per Section 8.6 within 1 day, i.e., 
immediately but no later than 24 hours of when he or she becomes aware of it. 
The designated Aegerion representative or designee will work with the Investigator to 
ensure that all the necessary information is provided to the Aegerion Patient Safety data 
entry site in a timely manner for fatal and life-threatening events of initial receipt for all 
other SAEs. 
For  all SAEs, including fatal or life-threatening ,where important or relevant information 
is missing, active follow-up is undertaken immediately.  Investigators or other site 
personnel inform Aegerion representatives or designee of any follow-up information on a 
previously reported SAE within 1 calendar day, i.e., immediately but no later than 24 
hours of when he or she becomes aware of it. 
8.5 
Overdose 
An overdose is considered a dose of metreleptin that exceeds the maximum dose of 
10 mg/day for patients >40 kg (refer to the US prescribing information) and should be 
recorded on the AE CRF when an AE is associated with the overdose.  If no AE is 
associated with the overdose, the event should be recorded on the Overdose CRF.   
 An overdose with associated SAEs is recorded as the SAE diagnosis/symptoms on the 
relevant SAE modules in the eCRF and on the Overdose eCRF module. 

 
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If an overdose on an Aegerion study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate Aegerion representatives or 
designee immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated Aegerion representative or designee works with the Investigator to ensure 
that all relevant information is provided to the Aegerion Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply, see 
Section8.4.  For other overdoses, reporting must occur within 30 days. 
8.6 
Reporting Adverse Events 
The principal investigator or site personnel are responsible for detecting, documenting, 
and reporting all events that meet the definition of an AE or SAE. 
All SAEs and unanticipated events, occurring after the signing of the ICF up until either 
the scheduled Follow-up Visit or at least 4 weeks after the last dose of study medication 
in the case of an early termination, and regardless of study medication relationship, must 
be reported via email or by fax to Aegerion or designee within 24 hours of investigator 
awareness of the event on the SAE/AESI form. 
Serious Adverse Event Contact Information: 
Email:  AegerionPV@ubc.com 
Facsimile:  US +1 877 200 2781 
Facsimile:  Rest of World +41 22 596 44 46 
This form will capture data surrounding the event, e.g., the nature of the symptom(s), 
time of onset in relation to initiation of therapy, duration, intensity, and whether or not 
therapy was interrupted or discontinued.  The principal investigator’s assessment of 
causal assessment of the event to metreleptin exposure will also be included.  In addition, 
relevant medical history, concomitant medications, laboratory and diagnostic tests 
reports, and procedures as well as all pertinent medical information related to the event 
will be collected. 

 
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Should there be incomplete or missing information, Aegerion or designee will forward 
SAE queries directly to the investigator requesting additional information.  It is the 
investigator’s responsibility to be diligent in providing this information to Aegerion or 
designee as soon as it is available.  Initial reports of SAEs should never be left on 
telephone voicemails. 
8.7 
Pregnancy 
Any pregnancy that occurs during study participation must be reported as an AESI via the 
safety monitoring system described above.  If a patient becomes pregnant, they will be 
allowed to continue in the study; however, the decision as to whether to continue 
metreleptin therapy during the pregnancy will be at the discretion of the treating 
physician. 
Information related to pregnancy will be collected using the appropriate sections of the 
eCRF.  The pregnancy will be followed to determine the outcome.  At the end of the 
pregnancy, information on the status of the mother and child will be collected. 
8.8 
Management of Metreleptin-related Toxicities 
There have been reports of generalized hypersensitivity (e.g., urticaria or generalized 
rash) in patients taking metreleptin.  If a hypersensitivity reaction occurs, patients should 
discuss the proper clinical treatment for the event(s), including possible discontinuation 
of metreleptin with the Investigator. 
Dosage adjustments, including possible large reductions, of insulin or insulin 
secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk 
of hypoglycemia. 
Refer to the USPI for further details (MYALEPT Prescribing Information). 

 
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9. 
METRELEPTIN AND OTHER TREATMENTS 
9.1 
Metreleptin 
No study medication will be provided for this trial; patients who have been prescribed 
metreleptin will be included in the study and will receive the prescribed dosage of 
metreleptin as indicated in the USPI. 
9.2 
Dose and Treatment Regimens 
Based on clinical response (e.g., inadequate metabolic control) or other considerations 
(e.g., tolerability issues, excessive weight loss [especially in pediatric patients]), the dose 
of metreleptin may be decreased or increased to the maximum dosage as summarized in 
Table 4; refer to the USPI for further details. 
Table 4: MYALEPT Recommended Dosage 
BASELINE WEIGHT 
STARTING DAILY DOSE 
(INJECTION VOLUME) 
DOSE ADJUSTMENTS 
(INJECTION VOLUME) 
MAXIMUM DAILY DOSE 
(INJECTION VOLUME) 
Patients ≤40 kg (males 
and females) 
0.06 mg/kg 
(0.012 mL/kg) 
0.02 mg/kg 
(0.004 mL/kg) 
0.13 mg/kg 
(0.026 mL/kg) 
Male patients >40 kg 
2.5 mg  
(0.5 mL) 
1.25 mg (0.25 mL) to 
2.5 mg (0.5 mL) 
10 mg 
(2 mL) 
Female patients >40 kg 
5 mg 
(1 mL) 
1.25 mg (0.25 mL) to 
2.5 mg (0.5 mL) 
10 mg 
(2 mL) 
9.3 
Labeling 
No labels will be prepared for this study.  Patients will receive commercially available 
metreleptin. 
9.4 
Storage 
Metreleptin should be stored according to the current USPI. 
9.5 
Compliance 
The administration of metreleptin (dose and duration) should be recorded in the 
appropriate sections of the Case Report Form. 

 
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Information regarding the patient’s prescription renewal will be used to support treatment 
compliance. 
9.6 
Accountability 
Study drug will not be provided.  
9.7 
Concomitant and Other Treatments 
Patients receiving immunomodulatory drugs should not be enrolled in this study (refer to 
Section 4.4). 
9.7.1 
Other Concomitant Treatment 
Unless excluded (Section 4.4), medication considered necessary for the patient’s safety 
and well-being may be given at the discretion of the Investigator and should recorded in 
the appropriate sections of the eCRF.  Special attention should be paid to recording 
changes to the patient’s anti-diabetic of lipid lowering treatments as these modifications 
may affect efficacy determination. 
10. 
STATISTICAL ANALYSES  
10.1 
Statistical Considerations 
Analyses will be performed by Aegerion or designee. 
A comprehensive Statistical Analysis Plan will be prepared and finalized before database 
lock. 
10.2 
Sample Size Estimate 
Ten patients who have been prescribed metreleptin for generalized lipodystrophy will be 
included in this study; patients will be evaluated for a period of 3 years. 
Pooled data from 2 previous studies of metreleptin for lipodystrophy (NIH 
991265/20010769 and FHA101 [NCT00677313, FHA101]) indicated the proportion of 
patients who developed binding antibodies to metreleptin at titers ≥25 was 80% after 
treatment with metreleptin.  If 10 patients are enrolled in this study, there is 87.9% 

 
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certainty that a minimum of 6 out of the 10 patients will have a titer of binding antibody 
≥25.  The expected distribution of maximum titer for these 10 patients is presented in 5. 
Table 5: Expected Number of Patients with Maximum Antibody Titer 
MAXIMUM TITER 
NUMBER OF PATIENTS 
0 
1 
5 
1 
25 
1 
125 
2 
625 
3 
3125 
2 
15625 
0 
Studying 10 patients in this rare population is adequate to confirm previous 
immunogenicity results from both the obesity and lipodystrophy development programs.  
Following patients for 3 years should be adequate to assess time to peak titer since 
previous data suggest a range of 4 to 7 months.  In vitro neutralizing activity will also be 
measured in all antibody positive samples, and may be detected by either the receptor 
cell-based assay or the ligand-binding assay (under development).  However, if 0 out of 
10 enrolled patients is observed with in vitro neutralizing activity, the point estimate 
(90% confidence interval) for the proportion of patients with neutralizing activity is 0.00 
(0.00, 0.26) (computed in StatXact version 7.0).  Because generalized lipodystrophy is a 
rare disease and events of in vitro neutralizing activity are infrequent, it is not feasible to 
gain a precise estimate of in vitro neutralizing activity; this study is not designed to 
determine this estimate. 
10.3 
Definitions of Analysis Sets 
The following will be used for all analyses: 
 Patients treated with at least one dose of metreleptin will be included in the 
assessment of safety and tolerability. 
 Patients treated with a dose of metreleptin and with baseline and postdose efficacy 
data will be included in the assessment of immunogenicity and efficacy analyses. 

 
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10.4 
Outcome Measures for Analyses 
Anti-metreleptin, anti-HuL percent inhibition and binding antibody titers, and category of 
in vitro neutralizing activity to metreleptin in the cell-based assay will be used to assess 
immunogenicity.  Antibody samples will be tested for in vitro neutralizing activity using 
the newly developed receptor-binding assay for metreleptin and cell-based assay 
methods. 
HbA1c and fasting triglycerides will be used to assess efficacy. 
Serious adverse events, AESIs, AEs leading to discontinuation, vital signs, clinical 
chemistry, hematology, and urinalysis data will be used to assess safety and tolerability. 
The following outcome will be measured: 
 Maximum of antibody titer (anti-metreleptin, anti-HuL) by visit 
 Percent inhibition of metreleptin and leptin by visit 
10.5 
Methods for Statistical Analyses 
There will be no hypothesis testing.  All data will be summarized by descriptive statistics 
and/or listings.  In general, continuous variables will be summarized by n, mean, SD, 
median, min and max.  Number of patients and percentage of patients in a category will 
be provided.   
Descriptive statistics will be provided for immunogenicity variables (Section 10.4).  The 
maximum antibody titer (anti-metreleptin or anti-HuL) during a visit will be summarized 
by visit.  Categorization of in vitro neutralizing activity as assessed by cell- based assay 
will be summarized across visits; the rate of Category D and E in vitro neutralizing 
activity with 90% and 80% exact confidence intervals will be computed.  The results are 
reported as percent inhibition and 80% inhibition is currently utilized as the neutralizing 
antibody threshold.  activity Results for in vitro neutralizing activity will be summarized 
across visits; however, there will be no formal comparison of the 2 assay methods for the 
detection and relative potency of Category D or E in vitro neutralizing activity.   
Maximum antibody titers, neutralizing activities detected by both methods, and 
metreleptin exposure for each patient will be plotted over time.  Maximum antibody 

 
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titers, neutralizing activities detected by both methods, and any associated clinical events 
(i.e., loss of efficacy or AE) will be summarized.  
All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of patients who experienced at least 1 AE will 
be summarized by system organ class and preferred term.  AEs will be summarized by 
relationship to the study medication and by severity.  Deaths, SAEs, AESIs, and AEs 
leading to discontinuation will be tabulated and/or listed.  SAEs, AESIs and AEs leading 
to discontinuation will be summarized respectively by peak antibody titers (anti-
metreleptin, anti-HuL) and by in vitro neutralizing activity categories or percent 
inhibition. 
Clinical laboratory results (hematology, chemistry, and urinalysis), and vital signs results 
will be summarized using descriptive statistics for each visit.  
Change from baseline in HbA1c and percent change from baseline in fasting triglycerides 
will be summarized for each visit by overall patient population, by peak antibody titers 
(anti-metreleptin, anti HuL), and by in vitro neutralizing activity categories or percent 
inhibition   , respectively. 
11. 
STUDY AND DATA MANAGEMENT  
11.1 
Training of Study Site Personnel 
Before the first patient is entered into the study, an Aegerion representative or designee 
will review and discuss the requirements of the Clinical Study Protocol and related 
documents with the investigational staff and also train them in any study-specific 
procedures and the EDC system(s) utilized. 
The Principal Investigator will ensure that appropriate training relevant to the study is 
given to all of these staff, and that any new information relevant to the performance of 
this study is forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 

 
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11.2 
Monitoring of the Study 
During the study, an Aegerion representative will have regular contacts with the study 
site, including visits to: 
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed. 
 Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating patients.  This will 
require direct access to all original records for each patient (e.g., clinic charts). 
 Ensure withdrawal of informed consent to the use of the patient’s biological samples 
is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient. 
The Aegerion representative or designee will be available between visits if the 
Investigator(s) or other staff at the center needs information and advice about the study 
conduct. 
11.2.1 
Source Data 
Source data will be stored at the individual study sites. 
11.2.2 
Study Agreements 
The Principal Investigator at each center should comply with all the terms, conditions, 
and obligations of the CSA, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the CSA, the terms of Clinical 
Study Protocol shall prevail with respect to the conduct of the study and the treatment of 
patients and in all other respects, not relating to study conduct or treatment of patients, 
the terms of the CSA shall prevail. 
Agreements between Aegerion and the Principal Investigator should be in place before 
any study-related procedures can take place, or patients are enrolled. 

 
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11.2.3 
Archiving of Study Documents 
The Investigator follows the principles outlined in the CSA. 
11.3 
Study Timetable and End of Study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  
Aegerion may also terminate the entire study prematurely if concerns for safety arise 
within this study or in any other study with metreleptin. 
11.4 
Data Management  
Data management will be performed by Aegerion or designee.  Serious adverse events 
and medical/surgical history will be classified according to the terminology of the latest 
version of MedDRA.  Medications will be classified according to the WHO Drug 
Dictionary.  Classification coding will be performed by Aegerion or designee. 
Any data collected through third-party sources will be obtained and reconciled against 
study data. 
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly.  The Data Management Plan will also clarify 
the roles and responsibilities of the various functions and personnel involved in the data 
management process. 
When all data have been coded, validated, and locked, a clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. 
11.4.1 
Serious Adverse Event Reconciliation 
Serious adverse event and AESI reconciliation reports are produced and reconciled with 
the Drug Safety database and/or the investigational site.  

 
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12. 
ETHICAL AND REGULATORY REQUIREMENTS 
12.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with International Conference on 
Harmonization (ICH)/GCP and applicable regulatory requirements. 
12.2 
Patient Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy 
legislation. 
12.3 
Ethics and Regulatory Review 
An Institutional Review Board (IRB) should approve the final study protocol, including 
the final version of the ICF and any other written information and/or materials to be 
provided to the patients.  The Investigator will ensure the distribution of these documents 
to the applicable IRB, and to the study site staff. 
The opinion of the IRB should be given in writing.  The Investigator should submit the 
written approval to Aegerion or designee before enrollment of any patient into the study.  
Aegerion or designee should approve any modifications to the ICF that are needed to 
meet local requirements. 
If required by local regulations, the protocol should be re-approved by the IRB annually. 
Before enrollment of any patient into the study, the final study protocol, including the 
final version of the ICF, will be approved by the national regulatory authority or a 
notification to the national regulatory authority will be completed, according to local 
regulations. 
Aegerion or designee will handle the distribution of any of these documents to the 
national regulatory authorities. 
Aegerion will provide regulatory authorities, IRBs and Principal Investigators with safety 
updates/reports according to local requirements. 

 
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Each Principal Investigator is responsible for providing the IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product.  Aegerion will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
12.4 
Informed Consent 
The Principal Investigator(s) at each center will: 
 Ensure each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study. 
 Ensure each patient is notified that he/she is free to discontinue from the study at any 
time. 
 Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided. 
 Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study. 
 Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File. 
 Ensure a copy of the signed ICF is given to the patient. 
 Ensure that any incentives for patients who participate in the study, as well as any 
provisions for patients harmed as a consequence of study participation, are described 
in the ICF that is approved by an Ethics Committee. 
12.5 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of coordinating 
Investigator and Aegerion. 
If there are any substantial changes to this study protocol, then these changes will be 
documented in a study protocol amendment and, where required, in a new version of the 
study protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant IRB and, if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 

 
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Aegerion will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to IRBs, see Section 12.3. 
If a protocol amendment requires a change to a center’s ICF, Aegerion and the center’s 
IRB are to approve the revised ICF before the revised form is used.  
If local regulations require, any administrative change will be communicated to, or 
approved by, each IRB. 
12.6 
Audits and Inspections 
Authorized representatives of Aegerion, a regulatory authority, or an IRB may perform 
audits or inspections at the center, including source data verification.  The purpose of an 
audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, ICH 
guidelines, and any applicable regulatory requirements.  The Investigator will contact 
Aegerion immediately if contacted by a regulatory agency about an inspection at the 
center. 
12.7 
Registration of the Trial 
This trial will be registered in an appropriate clinical trial database before initiation (e.g., 
www.clinicaltrials.gov), in accordance with regulations in the countries involved in study 
conduct.  Any results (including negative findings) will be published or otherwise made 
available to all researchers and the public in accordance with regulations. 
12.8 
Disclosure 
The PI certifies that all conflicts of interest will be disclosed in writing to the Sponsor.  
Conflict of interest is defined as a situation in which financial or other personal 
considerations have the potential to compromise or bias professional judgment or 
objectivity. 
12.9 
Data Quality Assurance 
The Sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any patients in this study, the Sponsor or Sponsor’s designee 

 
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personnel and the PI will review the protocol, the brochure for clinical investigators, the 
eCRFs and instructions for their completion and return, the procedure for obtaining 
informed consent, and the procedure for reporting AEs and SAEs.  A qualified 
representative of the Sponsor will monitor the conduct of the study, and eCRFs will be 
verified against source documents.  The Sponsor Medical Monitor will review the data 
for safety information.  Clinical data associates from the Sponsor’s representative will 
review the data for completeness and logical consistency.  Additionally, the clinical data 
associates will use automated validation programs to help identify missing data, selected 
protocol violations, out-of-range data, and other data inconsistencies.  Requests for data 
clarification or correction will be electronically provided to the investigative site for 
resolution.  Clinical data associates will assure that corrections have been applied 
properly. 
12.10 
Final Study Report 
An integrated clinical and safety report will be prepared at the conclusion of the study.  
The interim and final reports will be in accordance with the ICH E3 Guideline for 
Industry: Structure and Content of Clinical Study Reports. 
If applicable, agreement with the final Clinical Study Reports will be documented by the 
dated signature of the Coordinating Investigator(s), in compliance with Directive 
75/318/EC, Directive 2001/83/EC, and ICH E3.  The Coordinating Investigator(s) will be 
selected prior to database lock based on criteria such as: country requirements for 
identification of a Coordinating Investigator and enrollment status. 
12.11 
Insurance 
Aegerion has subscribed to an insurance policy covering, in its terms and provisions, its 
legal liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the study protocol as well as with applicable laws 
and standards. 
12.12 
Publication Policy 
The Sponsor holds all publication rights to the data obtained from this study.  Before any 
data from this study are published on the initiative of an investigator, a manuscript will be 

 
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sent to the Sponsor for review and approval at least 30 days prior to submission to the 
publisher. 
12.13 
Study Records and Source Documents 
During the trial and after termination of the trial, including after early termination of a 
trial, the PI must maintain copies of all documents and records relating to the conduct of 
the trial.  This documentation includes, but is not limited to, protocols, eCRFs and other 
data collection forms (e.g., screening forms, including those for screen failures), 
advertising for patient participation, AE reports, patient source data, correspondence with 
health authorities and IRBs/IECs, consent forms, PI’s curricula vitae/biosketch, monitor 
visit logs, laboratory reference ranges, and laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  Patient files and other source data 
must be kept for the maximum period of time permitted by the hospital, institution or 
private practice, or as specified below.  The Sponsor must be consulted if the PI wishes to 
assign the files to someone else, remove them to another location, or is unable to retain 
them for the specified period. 
The PI must retain trial records for the amount of time specified by applicable laws and 
regulations.  At a minimum, trial records must be retained for the amount of time 
specified by ICH Guidelines. 
 ICH E6 Guidance specifies that records must be retained for a minimum of two years 
after a marketing application for the indication is approved (or not approved) or 2 
years after notifying the appropriate regulatory agency that an investigation is 
discontinued. 
All trial documents shall be made available if required by relevant health authorities.  The 
PI should consult with the Sponsor prior to discarding trial and/or patient files. 
The Sponsor will retain all Sponsor-required documentation pertaining to the trial for the 
lifetime of the investigational product.  Archived data may be held on microfiche or 
electronic record, provided that back-up exists and that a paper copy can be obtained 
from it, if required. 
To maintain confidentiality, the patients will be identified by numbers and/or initials on 
the eCRFs.  Electronic CRFs for patients who fail screening must also be retained. 

 
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The Sponsor reserves the right to terminate a study site for refusal of the PI to supply 
source documentation of work performed in this clinical study. 
12.14 
Confidentiality 
All unpublished information that the Sponsor gives to the PI shall be kept confidential 
and shall not be published or disclosed to a third party without the prior written consent 
of the Sponsor. 
The PI shall not make a patent application based on the results of this study and shall not 
assist any third party in making such an application without the written authorization of 
the Sponsor unless otherwise specified in the Clinical Study Agreement. 
 

 
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Page 57 of 58 
13. 
LIST OF REFERENCES 
1. MYALEPT Prescribing Information  
Myalept (metreleptin). U.S. Prescribing Information. Available from URL: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c986f93b-855d-4ef0-
b620-5d41a0513e48 (Accessed 07Sep2016) 
2. Investigator’s Brochure for Metreleptin  
Metreleptin (Recombinant-methionyl Human Leptin) [Investigator’s Brochure]. Refer 
to current version. 
3. NCT00677313, FHA101 
ClinicalTrials.gov. An open-label treatment protocol to provide metreleptin for the 
treatment of diabetes mellitus and/or hypertriglyceridemia associated with 
lipodystrophy. https:// 
https://clinicaltrials.gov/ct2/show/NCT00677313?term=FHA101&rank=2 (Accessed 
08Nov2016).  
 

 
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APPENDICES 
Appendix A: 
Additional Safety Information 
Appendix B: 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
 

 
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AEGR-734-401 Version 4.0 
Clinical Study Protocol 
 
Confidential 
 
Appendix A: Additional Safety Information 

 
Metreleptin 
AEGR-734-401 Version 4.0 
Clinical Study Protocol 
 
Confidential 
 
Appendix B: Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 

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