Clinical trial NCT04159415
Conditions: Generalized Lipodystrophy
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-01-07; Completion date: 2024-09-24
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of the study are to estimate the effects of REGN4461 on glycemic parameters in the subset of patients with elevated baseline hemoglobin A1c levels (HbA1c ≥7%) and to estimate the effects of REGN4461 on fasting triglyceride levels in the subset of patients with elevated baseline fasting triglycerides (TG ≥250 mg/dL).

The secondary objectives are to estimate the effects of REGN4461 on a composite endpoint of changes in either HbA1c or fasting TG for all patients, estimate the effects of 3 dose levels of REGN4461 on glycemic parameters and fasting TG, to estimate the effects of REGN4461 on insulin sensitivity, to evaluate the safety and tolerability of REGN4461 and to evaluate the pharmacokinetics (PK) and immunogenicity of REGN4461.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Placebo intervention 2: Low-Dose REGN4461 intervention 3: High-dose REGN4461
Intervention descriptions: intervention 1: Intravenous (IV) infusion loading dose or subcutaneous (SC) injection weekly (QW). intervention 2: IV infusion loading dose or SC injection QW. intervention 3: IV infusion loading dose or SC injection QW.

Protocol documents:
Prot_000.pdf: 
IND Number: 139310 
EudraCT: 2019-000614-11 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
REGN4461, A LEPTIN RECEPTOR AGONIST ANTIBODY, IN PATIENTS WITH 
GENERALIZED LIPODYSTROPHY 
Compound: 
REGN4461 
Clinical Phase: 
2 
Protocol Number: 
R4461-GLD-1875 
Protocol Version: 
R4461-GLD-1875 Amendment 4 
Amendment 4 Date of Issue: 
See appended electronic signature page 
Amendment 3 Admin Date of Issue: 
08 Dec 2022  
Amendment 3 Date of Issue: 
12 Jul 2022  
Amendment 2 Date of Issue: 
25 Jun 2021 
Amendment 1 Date of Issue: 
24 May 2019 
Original Date of Issue: 
30 Jan 2019 
Medical/Study Director: 
 
 
 
 
 
 
 
 
 
 
 
 
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NCT04159415


Clinical Study Protocol 
R4461-GLD-1875 Amendment 4 
Regeneron Pharmaceuticals, Inc. 
Page 2 of 143 
CONFIDENTIAL 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity. For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but not 
limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to 
disclosure to third parties of any information and/or data related to, or contained within, this 
submission, it will be given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
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CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 4 
Description of Change 
Brief Rationale 
Section # and Name  
Clinical Protocol 
Synopsis: Study Design 
Section 3.1.2 Rationale for 
Study Design 
Section 6.1Study 
Description and Design 
Table 7 Open-Label 
Treatment Period 5 
(OLTP 5) 
Section 9.1.5 Footnotes 
for the Schedule of Events 
Table 7: Open-Label 
Treatment Period 5, 
footnote 13  
Section 9.1.6 Early 
Termination Visit 
 
Amendment 3 Admin 
Description of Change 
Brief Rationale 
Section # and Name  
Table 7 Open-Label 
Treatment Period 5 
(OLTP 5) 
Section 3.1.2 Rationale for 
Study Design 
 
Amendment 3 
The original protocol along with Amendment 1 and Amendment 2 were designed to test 2 
weight-based dosing regimens. The low dose (
 subcutaneously [SC] once a week [QW] for  
patients 
 and 
 SC QW for patients 
) was designed to achieve REGN4461 
trough concentrations of 
, whereas the higher dose (
 SC QW for patients 
 
and 
 SC QW for patients 
) was designed to achieve REGN4461 trough 
concentrations of 
. Pre-specified interim analysis, conducted after the last patients 
reached the 8-week primary endpoint, 
 
 
 
 
 
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Clinical Study Protocol 
 
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CONFIDENTIAL 
 
 Simulations, updated using the 
higher clearance rates observed in this population, indicate that 
 SC QW for both weight 
tiers are more likely to  achieve the target REGN4461 trough concentration of 
 and 
optimal pharmacodynamic effects.  A 12-month treatment extension is being implemented to 
evaluate safety, pharmacodynamic effects and exposure for this higher dose. 
Description of Change 
Brief Rationale 
Section # and Name  
Clinical Study Protocol 
Synopsis: Objectives, Study 
Design, Treatments, Study 
Duration  
Section 2.2 Secondary 
Objectives 
Section 3.1.2 Rationale 
for Study Design 
Section 3.1.3 Rationale 
for Dose Selection 
Section 3.1.4 Rationale 
for Endpoints 
Section 3.3.1 Risk-
Benefit for REGN4461 
Section 6.1 Study 
Description and Duration 
Figure 1 Study Flow 
Diagram 
Section 8.1 
Investigational and 
reference Treatments 
Table 2 
 
 
 
 
Section 8.3.1 Dose 
Modification 
Section 8.7.1 Permitted 
Medications 
Section 9 Schedule of 
Events 
Table 6 Open-Label 
Treatment Period 4 
(OLTP 4) 
Table 7 Open-Label 
Treatment Period 5 
(OLTP 5) 
Section 9.1.4 Footnotes 
for the Schedule of 
Events Table 6: Open-
Label Treatment Period 
4, footnote 18 (deleted) 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name  
Section 9.1.5 Footnotes 
for the Schedule of 
Events Table 7: Open- 
Label Treatment Period 
5 
Section 9.2.2.1 Vital 
Signs 
Section 9.2.2.2 Physical 
Examination, Body 
Weight, Height, and 
Tanner Stages 
Section 9.2.2.4 
Menstrual History, 
Pregnancy Status 
Reporting, and 
Confirmation of 
Contraception 
Section 9.2.3 Laboratory 
Testing 
Section 9.2.4.1 Fasting 
Triglycerides 
Section 9.2.4.2 Fasting 
Glucose 
Section 9.2.4.3 
Hemoglobin A1C 
Section 9.2.4.6 Lipid 
Panel 
Section 9.2.4.7 Urine 
Protein, Creatinine, and 
Albumin 
Section 9.2.4.11 
Assessment of Body 
Composition 
Section 9.2.4.12 
Assessment of Hepatic 
Fat Content and Liver 
Size** 
Section 9.2.4.13 
Assessment of Liver 
Stiffness by Vibration-
Controlled Transient 
Elastography (VCTE) 
Section 9.2.6.1 
REGN4461 
Concentration 
Measurements 
Section 9.2.6.2 Soluble 
LEPR (sLEPR) 
Section 9.2.6.3 
Circulating Biomarkers 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name  
for Pharmacodynamic 
Assessments 
Section 9.2.6.4 
Immunogenicity 
Measurements and 
Samples 
Section 11 Statistical 
Plan 
Section 11.4.1 Patient 
Disposition 
Section 11.4.3.2 
Secondary Efficacy 
Analysis 
Section 11.4.4.1 Adverse 
Events 
Section 3.1.2 Rationale 
for Study Design 
Section 3.1.3 Rationale 
for Dose Selection 
Section 3.1.2 Rationale 
for Study Design 
Section 6.1 Study 
Description and Duration 
Section 8.3.2.1 Reasons 
for Permanent 
Discontinuation of Study 
Drug 
Section 9.1.4 Footnotes 
for the Schedule of 
Events Table 6: 
Open-Label Treatment 
Period 4, footnote #1 
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Clinical Study Protocol 
 
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Page 7 of 143 
 
CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name  
Clinical Study Protocol 
Synopsis: Treatments 
Section 6.1 Study 
Description and Duration 
Section 8.1 
Investigational and 
Reference Treatments 
Table 6 Open Label 
Treatment Period 4 
(OLTP 4) 
Section 9.1.4 Footnotes 
for the Schedule of 
Events Table 6: Open 
Label Treatment Period 
4 
Section 9.2.4.12 
Assessment of Hepatic 
Fat Content and Liver 
Size** 
Title Page 
Clinical Study Protocol 
Synopsis: Treatments 
Section 
3.3.1 
Risk-
Benefit for REGN4461 
Table 3 Screening and 
Placebo Run-In 
Section 9.1.1 Footnotes 
for 
the 
Schedule 
of 
Events 
Table 
3: 
Screening and Placebo 
Run-In, footnote #7 
Table 4 Double-Blind 
Treatment Period 1 
Section 9.1.2 Footnotes 
for 
the 
Schedule 
of 
Events Table 4: Double 
Blind Treatment Period 
1, footnote #7 
Table 5 Double-Blind 
Treatment Periods 2 and 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Section # and Name  
3 
Section 9.1.3 Footnote 
for 
the 
Schedule 
of 
Events Table 5: Double 
Blind Treatment Periods 
2 and 3, footnote #6 and 
#21(deleted) 
Section 9.1.4 Footnotes 
for 
the 
Schedule 
of 
Events Table 6: Open 
Label Extension Open 
Label Treatment Period 
4, footnotes #7, and #9 
Section 11.4.6 Analysis 
of Anti-Drug Antibody 
Data 
Amendment 2 
The main purpose of this amendment is to modify the inclusion criteria for study eligibility to 
select a patient population that is most likely to have generalized lipodystrophy and therefore 
would be most likely to respond to REGN4461 treatment.  
Language was also added to remind investigators to discontinue REGN4461 treatment starting at 
week 52 in patients who, in their opinion, do not demonstrate clinical benefit to REGN4461, and 
to continue REGN4461 treatment at and beyond week 52 (until a common treatment end date) 
only in patients who demonstrate a clinical benefit in response to REGN4461.  
Adjustments to study assessments were made to improve the timing and quality of the data 
obtained and to decrease patient burden. Other more minor changes were made to align with the 
sponsor’s latest protocol template, to acknowledge impact of the COVID-19 pandemic on the 
study, and to increase clarity. The following table outlines the changes made to the protocol and 
the rationale.  
Description of Change 
Brief Rationale 
Sections Changed 
Section 7.2.1 Inclusion Criteria, 
criterion #2 
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Page 9 of 143 
 
CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Clinical Study Protocol 
Synopsis: Study Design 
Section 3.1.2 Rationale for 
Study Design 
Section 6.1 Study Description 
and Duration 
Section 8.3.2.1 Reasons for 
Permanent Discontinuation of 
Study Drug 
Table 6: Open-Label Extension 
Section 9.1.4Footnotes for the 
Schedule of Events Table 6: 
Open-Label Extension, 
footnote s #1c and #1d (added) 
Section 7.2.1 Inclusion Criteria, 
criterion #6 
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Clinical Study Protocol 
 
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Page 10 of 143 
 
CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Section 7.2.2 Exclusion 
Criteria, criterion #4 (added) 
Section 7.2.2 Exclusion 
Criteria, criterion #7 
Section 7.2.2 Exclusion 
Criteria, criterion #12 (added) 
Section 7.2.2 Exclusion 
Criteria, criterion #11 
(removed) 
Section 7.2.2 Exclusion 
Criteria, criterion #13 
Section 7.2.2 Exclusion 
Criteria, criterion #14 
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Page 11 of 143 
 
CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Section 7.2.2 Exclusion 
Criteria, criterion #16 
Clinical Study Protocol 
Synopsis: Dose/Route/Schedule 
Section 3.1.3 Rationale for 
Dose Selection 
Figure 1: Study Flow Diagram 
Section 8.3.1 Dose 
Modification 
Height measurement: 
Table 3: Screening and Placebo 
Run-In 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Physical examination: 
Table 6: Open-Label Extension 
Lipid panel and free fatty acids: 
Section 9.1.2 Footnotes for the 
Schedule of Events Table 4: 
Double Blind Treatment 
Period 1, footnote #15 
Section 9.1.3 Footnotes for the 
Schedule of Events Table 5: 
Double Blind Treatment 
Periods 2 and 3, footnote #13 
Section 9.1.4 Footnotes for the 
Schedule of Events Table 6: 
Open Label Extension, footnote 
#13 
Section 9.2.4.9 Mixed Meal 
Tolerance Test 
Hematology and blood 
chemistry:  
Table 3: Screening and Placebo 
Run-In 
Section 9.1.1 Footnote for the 
Schedule of Events Table 3: 
Screening and Placebo Run-In, 
footnote #12 (added) 
ADA sample collection 
removed from 
 
Table 6: Open-Label Extension 
 
 
 
Section 6.1 Study Description 
and Duration 
Table 6: Open-Label Extension 
Section 9.1.4 Footnotes for the 
Schedule of Events Table 6: 
Open-Label Extension, 
footnote #1 
Removal of all whole blood 
RNA sample collections:  
Section 5.6 Pharmacodynamic, 
Other Biomarker, and Research 
Variables 
Section 9.2.7 
Pharmacodynamic and 
Exploratory Biomarker 
Procedures 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Section 9.2.9.1 Whole Blood 
RNA Samples (Optional) 
Section 9.2.9 Future 
Biomedical Research 
(Optional) 
Section 9.2.9.1 
Pharmacogenomic Analysis 
(Optional) 
Table 3: Screening and Placebo 
Run-In 
Table 4: Double-Blind 
Treatment Period 1 
Table 5 : Double-Blind 
Treatment Periods 2 and 3 
Table 6: Open-Label Extension 
Table 6: Open-Label Extension 
Table 5: Double Blind 
Treatment Periods 2 and 3 
Section 9.2.5.6 Patient Global 
Impression of Change 
Section 8.1 Investigational and 
Reference Treatments 
Clinical Study Protocol 
Synopsis: Procedures and 
Assessments 
Table 3: Screening and Placebo 
Run-In (assessment added) 
Section 9.1.1 Footnotes for the 
Schedule of Events Table 3: 
Screening and Placebo Run-In, 
footnote #7 
Section 9.1.2 Footnotes for the 
Schedule of Events Table 4: 
Double Blind Treatment Period 
1, footnote #7 
Section 9.1.3 Footnotes for the 
Schedule of Events Table 5: 
Double Blind Treatment 
Periods 2 and 3, footnote #6 
Section 9.1.4 Footnotes for the 
Schedule of Events Table 6: 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Open-Label Extension, 
footnote #7 
Section 9.2.2.2 Physical 
Examination, Body Weight, 
Height, and Tanner Stages 
Section 3.1.4 Rationale for 
Endpoints 
Table 5: Double-Blind 
Treatment Periods 2 and 3 
(assessment added) 
Section 9.1.3 Footnotes for the 
Schedule of Events Table 5: 
Double Blind Treatment 
Periods 2 and 3, footnote #17 
(added) 
Table 6: Open-Label Extension 
(assessment added) 
Section 9.1.4 Footnotes for the 
Schedule of Events Table 6: 
Open-Label Extension, #20 
(footnote added) 
Section 9.2.5.7 Exit Interview 
in Relation to Hunger and 
Eating Behavior PROs 
Section 9.1.1 Footnotes for the 
Schedule of Events Table 3: 
Screening and Placebo Run-In, 
Footnote #8 
Section 9.1.2 Footnotes for the 
Schedule of Events Table 4: 
Double-Blind Treatment Period 
1, Footnote #22 
Section 9.1.3 Footnotes for the 
Schedule of Events Table 5: 
Double-Blind Treatment 
Periods 2 and 3, Footnote #21 
Section 9.1.4 Footnotes for the 
Schedule of Events Table 6: 
Open-Label Extension, 
Footnote #18 
Section 9.2.2.2 Physical 
Examination, Body Weight, 
Height, and Tanner Stages 
Section 9.1.1 Footnotes for the 
Schedule of Events Table 3: 
Screening and Placebo Run-In, 
footnote #13 
Section 9.1.2 Footnotes for the 
Schedule of Events Table 4: 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Double Blind Treatment Period 
1, footnote #17 
Section 9.1.3 Footnotes for the 
Schedule of Events Table 5: 
Double Blind Treatment 
Periods 2 and 3, footnote #15 
Section 9.1.4 Footnotes for the 
Schedule of Events Table 6: 
Open-Label Extension, 
footnote #15 
Section 3.1.4 Rationale for 
Endpoints 
Section 6.1 Study Description 
and Duration 
Section 9.2.8 
 
 
Section 8.7.2 Permitted 
Medications 
Section 5 Study Variables 
Section 9.1.1 Footnotes for the 
Schedule of Events Table 3: 
Screening and Placebo Run-In, 
footnote #4 
Section 3.1.2 Rationale for 
Study Design 
Section 8.3.2 Study Drug 
Discontinuation 
Section 9.1.6  Early 
Termination Visit 
Section 8.5.1 Blinding 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Table 3: Screening and Placebo 
Run-In 
Section 9.1.1 Footnotes for the 
Schedule of Events Table 3: 
Screening and Placebo Run-In, 
footnote #2 
Table 4: Double-Blind 
Treatment Period 1 
Table 5: Double-Blind 
Treatment Periods 2 and 3 
Table 6: Open-Label Extension 
Section 9.2.4.5 Insulin/C-
peptide 
Section 9.1.2 Footnotes for the 
Schedule of Events Table 4: 
Double-Blind Treatment Period 
1, footnote #13 
Section 9.1.3 Footnotes for the 
Schedule of Events Table 5: 
Double-Blind Treatment 
Periods 2 and 3, footnote #11 
Section 9.1.4 Footnotes for the 
Schedule of Events Table 6: 
Open-Label Extension, 
footnote #11 
Section 9.2.4.8 Insulin 
Sensitivity Measurement 
Section 9.2.3 Laboratory 
Testing 
Section 9.2 Study Procedures 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Section 8.7 Concomitant 
Medications and Procedures 
Section 9.2.3 Laboratory 
Testing 
Section 3.1.2 Rationale for 
Study Design 
Section 6.1 Study Description 
and Duration 
Section 11.4.3 Efficacy 
Analyses 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Clinical Study Protocol 
Synopsis: Statistical Plan 
Section 11.2 Justification of 
Sample Size 
Section 4.3 Exploratory 
Endpoints 
Section 5.6 Pharmacodynamic, 
Other Biomarker, and Research 
Variables 
Section 1 Introduction 
Section 3.1.1 Rationale for 
Study Population 
Title page 
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CONFIDENTIAL 
Description of Change 
Brief Rationale 
Sections Changed 
Clinical Study Protocol 
Synopsis: End of Study 
Definition 
Section 3.3 Benefit-Risk 
Section 6.1.2 End of Study 
Definition 
Section 8.4.2.1 Systemic 
Injection Reactions 
Section 9.1 Schedule of Events 
Section 9.2.9 Future 
Biomedical Research 
(Optional) 
Section 9.2.9.1 
Pharmacogenomic Analysis 
(Optional) 
Section 10.3.2 Serious Adverse 
Event 
Section 10.6 Safety Monitoring 
Section 13.1 Monitoring of 
Study Sites 
Throughout the protocol.  
Section 3.1.2 Rationale for 
Study Design (removed 
redundant text not relevant to 
this section)  
 
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CONFIDENTIAL 
Amendment 1 
The following table outlines the changes made to the protocol and the affected sections. 
Change and Rationale for Change 
Section Changed 
Section 7.2.1 Inclusion Criteria #2, #4, #5 
Section 7.2.2 Exclusion Criteria #10, #12,  
Clinical Study Protocol Synopsis: Secondary 
Objectives, Procedures and Assessments 
Section 1 Introduction 
Section 10.4.3. 
Other Events that Require 
Accelerated Reporting to Sponsor 
Section 10.3.3 Adverse Events of Special Interest 
Section 8.4.1.2 Termination of the Intravenous 
Infusion 
Section 8.7.2 Permitted Medications 
Section 9.2.2.2 Physical Examination, Body 
Weight, Height and Tanner Stages 
Table 6 Open-Label Extension  
Section 6.1.1 Sub-Study 
Section 23 References 
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CONFIDENTIAL 
Change and Rationale for Change 
Section Changed 
 
Section 3.1.2 Rationale for Study Design 
Section 6.1 Study Description and Duration 
Study Flow Diagram Figure 1  
Section 8.4.1.2 Termination of Intravenous 
Infusion 
Section 9.2.2 Study Procedures 
Section 9.2.2.5 Hypoglycemia monitoring 
(Section added) 
Section 9.2.3 Laboratory Testing  
Section 9.2.4.8 Insulin Sensitivity Measurement 
Section 9.2.4.11 Assessment of Body 
Composition 
Section 9.2.4.12 Assessment of Fat Content and 
Liver Size 
Section 9.2.4.13 Assessment of Liver Stiffness by 
vibration-controlled transient elastography  
Section 9.2.10 Future Biomedical Research 
(Optional) 
 
Synopsis: Objectives and Secondary Endpoints 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Section 3.1.4 Rationale for Endpoints 
Section 4.2 Secondary Endpoints 
Section 4.3 Exploratory Endpoints 
Section 5.2 Efficacy Variable 
Section 5.4 Pharmacokinetic Variables 
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CONFIDENTIAL 
Change and Rationale for Change 
Section Changed 
Section 5.6 Pharmacodynamic and Other 
Biomarker Variables 
Table 3 Footnote #4, #7, #11, #13, and #17 
Table 4  Footnote #7, #12, #13, #14, #15, #18 and 
#19 
Table 5  Footnote #6, #10, #11, #12, #13, #15, 
and #17 
Table 6  Footnotes #7, #10, #11, #12, #13, #15, 
#16 and #17 
Section 9.1.6 Unscheduled Visits 
Section 11 Statistical Plan 
Section 7.2.2 Exclusion Criterion #15 
Section 5.2 Efficacy Variable 
Section 5.4 Pharmacokinetic Variables 
Section 5.6 Pharmacodynamic and other 
Biomarker Variables 
Section 8.1 Investigational and Reference 
Treatments 
Section 9.1.1 Table 3 Footnote #2, #3, #5, #12 
Section 9.1.2 Table 4 Footnote #2, #4,  
Section 9.1.3 Table 5 Footnote #3, #19 
Section 9.1.4 Table 6 Footnote #1, #5, #9 #14 
#19 
Section 9.2.2.1 Vital Signs 
Section 9.2.4.9 Mixed Mean Tolerance Test 
Section 9.2.5.1 Daily Appetite and Eating 
Behavior PRO 
Section 9.2.6 Pharmacokinetic, Drug 
Concentration, Immunogenicity Samples 
Section 9.2.6.3 Circulating Biomarker for 
Pharmacodynamic Assessment 
Section 9.2.10 Future Biomedical Research 
(Optional) 
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CONFIDENTIAL 
Change and Rationale for Change 
Section Changed 
Section 11.3.7 MRI Analysis Set 
Section 11.4.3.2 Secondary Efficacy Analysis  
Section 11.4.5.1 Analysis of Drug Concentration 
Data 
Section 9.1 Schedule of Events: Table 4 Double-
Blind Treatment Period 1 and Table 5 visit 
numbers  
Throughout the protocol 
 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled Study of REGN4461, 
a Leptin Receptor Agonist Antibody, in Patients with Generalized 
Lipodystrophy 
Site Location(s) 
 
Principal Investigator 
The study will be conducted globally at approximately 10 sites. 
Rebecca Brown, MD; National Institutes of Health, United States 
Objectives 
The primary objectives of the study are to: 
• 
Estimate the effects of REGN4461 on glycemic parameters in the 
subset of patients with elevated baseline hemoglobin A1c levels 
(HbA1c ≥7%) 
• 
Estimate the effects of REGN4461 on fasting triglyceride levels 
in the subset of patients with elevated baseline fasting 
triglycerides (TG ≥250 mg/dL) 
The secondary objectives of the study are to: 
• 
Estimate the effects of REGN4461 on a composite endpoint of 
changes in either HbA1c or fasting TG for all patients 
• 
Estimate the effects of 3 dose levels of REGN4461 on glycemic 
parameters and fasting TG  
• 
Estimate the effects of REGN4461 on insulin sensitivity 
• 
Evaluate the safety and tolerability of REGN4461 
• 
Evaluate the pharmacokinetics (PK) and immunogenicity of 
REGN4461 
Study Design 
This is a phase 2, randomized, double-blind, placebo-controlled study of 
the efficacy and safety of REGN4461 in patients with generalized 
lipodystrophy (GLD) who are not receiving recombinant methionyl human 
leptin (rhLeptin, metreleptin) therapy.  
The study comprises:  
• 
• 
• 
• 
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• 
Note: Patients who complete the end of treatment (EOT) visit for 
Open Label Treatment Period 5 (OLTP 5) and have secured 
access to continued REGN4461 treatment through other means, 
(eg, another Regeneron-sponsored clinical trial, compassionate 
use, or an expanded access program), may forgo any or all of 
visits 119-121 and proceed to end of study (EOS) visit. These 
patients will be considered study completers. 
• 
 
After the 
 single-blind placebo run-in period where baseline testing 
will be performed, patients will be randomized 1:1 to 1 of 2 
 
double-blind treatment arms, stratified based on screening HbA1c 
(HbA1c ≤8% or HbA1c >8%). The study design involves an intra-patient 
dose escalation to maximize information from each patient enrolled and to 
allow for intra-patient comparisons between dose levels. The 2 dose levels 
were selected to maximize the likelihood to observe efficacy and obtain 
exposure-response information to guide future clinical development. 
Treatment Arm A: This arm consists of 3 sequential 8-week periods in 
which patients receive the following treatments:  
• 
Placebo 
• 
Low-dose REGN4461 
• 
High-dose REGN4461 
Treatment Arm B: This arm consists of 3 sequential 8-week periods in 
which patients receive the following treatments:  
• 
Low-dose REGN4461 
• 
High-dose REGN4461 
• 
High-dose REGN4461  
For DBTP 1-3 and OLTP 4, two dose levels (“high dose” and “low dose”) 
of REGN4461 will be tested, and each dose level will be tiered 
 
.  
Tier 1: patients 
  
• 
Low-dose REGN4461: 
 intravenous (IV) load 
 
 subcutaneous (SC) QW 
• 
High-dose REGN4461: 
 SC QW 
Tier 2: patients 
 
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• 
Low-dose REGN4461: 
 IV load 
 
 SC QW 
• 
High-dose REGN4461: 
 SC QW 
For OLTP 5, all eligible patients will receive a 
 IV loading dose 
 SC QW for 
. Patients that 
experience excessive weight loss and/or clinically significant (in the 
opinion of the investigator) spontaneous hypoglycemia (<70 mg/dL), 
defined as hypoglycemia that occurs in the absence of exogenous insulin 
or insulin secretagogues, prior to OLTP 5 will be ineligible for the dose 
increase and will remain on their OLTP 4 dose. In addition, patients 
receiving 
 SC QW that experience excessive weight loss and or 
significant spontaneous hypoglycemia during OLTP 5 will decrease their 
weekly SC dose from 
 QW. 
Study Duration 
The study duration is expected to be at least 128 weeks, based on 
enrollment rate estimates.  
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End of Study Definition 
The end of study is defined as the date that the last patient completes the 
last study visit, withdraws from the study, or is lost to follow-up (ie, the 
patient can no longer be contacted by the investigator). 
Population 
 
 
Sample Size: 
Up to 26 patients will be enrolled 
 
Target Population: 
The target population is patients with a clinical diagnosis of GLD 
12 years of age (or lower limit of age approved by Health Authority, 
Ethics Committee [EC], and Institutional Review Board [IRB]) who are 
not currently treated with metreleptin and have either HbA1c 7% or 
fasting TG 250 mg/dL. 
Treatment(s) 
 
 
Study Drug: 
 
 
 
 
 
REGN4461  
Placebo matching REGN4461.  
 
Dose/Route/Schedule: 
In the initial 4-week single-blind run-in period, patients will receive IV 
placebo infusion, followed by placebo SC injections administered 
subsequently on a weekly basis for 
. The dosing regimens of 
REGN4461 in the double-blind period will be tiered according to baseline 
body weight (Tier 1: 
, Tier 2:
), and are as follows:  
Tier 1: patients with baseline body weight 
:  
• 
Low-dose REGN4461: 
 IV load 
 
 SC QW 
• 
High-dose REGN4461: 
 SC QW 
Tier 2: patients with baseline body weight 
: 
• 
Low-dose REGN4461: 
 IV load 
 
 SC QW 
• 
High-dose REGN4461: 
 SC QW 
In OLTP 4, all patients will receive high-dose REGN4461 (
 
SC QW in Tier 1 or 
 SC QW in Tier 2). After week 52, the 
REGN4461 dose may be adjusted downward based upon the safety, 
tolerability, PK, or PD data obtained during the study. During OLTP 5, all 
eligible patients will receive 
 IV loading dose, followed 
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 SC QW for 
. During OLTP 5, the 
REGN4461 dose may be adjusted downward to 
 SC QW based 
upon the safety, tolerability, PK, or PD data obtained during the study. 
Endpoint(s) 
 
 
Primary: 
The primary endpoints of the study are: 
• 
In patients with elevated baseline HbA1c (HbA1c ≥7%), 
absolute change from baseline to the end of the double-blind 
treatment period 1 (DBTP 1) in: 
− 
HbA1c (week 8) 
− 
Fasting glucose (week 8) 
− 
Weighted mean glucose (WMG) (week 8) 
• 
In patients with elevated baseline fasting TG (fasting TG 
≥250 mg/dL), percent change from baseline to the end of the 
DBTP 1 (week 8) in fasting TGs 
 
Secondary: 
The secondary endpoints of the study are: 
• 
Change from baseline to week 8 in composite endpoint 
comprising absolute change in either HbA1c or percent change in 
fasting TG for all patients. 
• 
Absolute change from baseline in fasting glucose over time for 
all patients and patients with elevated baseline HbA1c 
(HbA1c ≥7%) 
• 
Percent change from baseline in fasting TG over time in all 
patients and in patients with elevated baseline fasting TG 
(TG ≥250 mg/dL) 
• 
Absolute change from baseline in HbA1c over time for all 
patients 
and 
patients 
with 
elevated 
baseline 
HbA1c 
(HbA1c ≥7%) 
• 
Absolute change from baseline in WMG over time for all patients 
and patients with elevated baseline HbA1c (HbA1c ≥7%) 
• 
Change from baseline in glucose AUC0-4 during a mixed meal 
tolerance test (MMTT) at weeks 8, 16, and 24 for all patients and 
in patients with elevated baseline HbA1c (HbA1c ≥7%) 
• 
Change from baseline in glucose infusion rate per kilogram body 
mass during hyperinsulinemia-euglycemic clamp (clamp study) 
at week 8 and week 52, for all patients and patients with elevated 
baseline HbA1c (HbA1c ≥7%) 
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• 
Change from baseline in glucose clearance rate (kITT) during 
insulin-tolerance test (ITT) at week 8 and week 52 for all patients 
and patients with elevated baseline HbA1c (HbA1c ≥7%) 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Concentrations of total REGN4461 in serum over time 
• 
To assess the incidence of treatment emergent anti-drug 
antibodies to REGN4461 and titer over time  
Procedures and Assessments 
The following procedures will be performed for the sole purpose of 
determining study eligibility or characterizing the baseline characteristics 
of the study population: medical history, demographics, HIV serology, and 
hepatitis testing (HBsAg, HCV), menstrual history, and pregnancy status. 
Safety procedures include: vital signs, physical examination, body weight, 
height, Tanner staging, Menstrual history/pregnancy status reporting/ 
confirmation of contraception and hypoglycemia monitoring and 
electrocardiogram.  
Laboratory procedures include: hematology, blood chemistry, urinalysis, 
pregnancy testing, lipid panel, endocrine hormones and other laboratory 
testing. 
Efficacy procedures include: fasting glucose assessment, fasting TG 
assessment, hemoglobin A1C, fructosamine, insulin/C-peptide, lipid 
panel, lipoprotein analysis by NMR, urine protein/urine creatinine, WMG, 
MMTT, liver volume and fat content by MRI and MRI-Proton Density Fat 
Fraction (MRI-PDFF), respectively, whole body composition by DXA, 
vibration-controlled transient elastography (VCTE), and patient-reported 
outcomes. 
Statistical Plan 
No formal statistical hypothesis testing will be conducted. The size of the 
study is determined by study feasibility constraints due to the limited 
number of GLD patients in the world not being treated with metreleptin. It 
is determined that up to 26 patients will be enrolled for the study with 
approximately a 20% dropout rate. The primary objective is to estimate the 
treatment effect of REGN4461 on glycemic and lipid parameters. With 20 
patients (10 patients per study arm) completing the study, the study has a 
minimal detectable change (MDC) of 1% absolute value reduction in 
HbA1c (standard deviation [SD]=1.5%, within-group comparison) and a 
28% reduction in fasting TG (SD=40%, within-group comparison). For 
within-group comparison, the study would have 80% power to detect a 
1.5% reduction in HbA1c absolute value from baseline to week 8 for a 
2-sided alpha of 0.05 test (standard deviation =1.5%).  
For most primary continuous endpoints, the study assesses the treatment 
effect of REGN4461 from baseline to the end of the double-blind period 1 
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(week 8) (within-group and between-group comparison). Summary 
statistics, including mean change from baseline, standard error (SE), 
corresponding 95% confidence interval, and nominal p-value will be 
provided for within- and between-group comparison, using a mixed effect 
model repeated measurement model (MMRM). Mean changes (+/- SE) 
will be plotted over time by treatment arm.  
For secondary endpoints, summary statistics, including mean change from 
baseline, SE, 95% confidence interval, and nominal p-value will be 
provided using a similar MMRM. The treatment effect of REGN4461 
changes from baseline over time will be provided based on each scheduled 
assessment time point.  
Summary statistics will be provided comparing the effects of REGN4461 
low-dose and high-dose regimens on HbA1c, fasting glucose, WMG, 
fasting TG, and MMTT.  
As a secondary objective, the REGN4461 treatment effect will be 
evaluated using a composite “Z score” of HbA1c and TG. MMRM will be 
used to evaluate the effects of REGN4461 on both between-group and 
within-group comparisons. Mean, SE, and 95% confidence interval will be 
provided.  
Change from baseline to week 8 for patients in Treatment Arm A will be 
provided. If there is no significant change in HbA1c or TG, defined as 
change in HbA1c (absolute value change) 0.4% or TG change (percent 
change) 20%, then those patients’ changes from week 8 to week 16 will 
be pooled together with patients’ changes in Treatment Arm B from 
baseline to week 8, to evaluate the treatment effect of the low-dose 
regimen. Similarly, if there is no significant change from baseline to week 
8 for patients in Treatment Arm A, data from patients in Treatment Arm A 
(change from week 16 to week 24) will be pooled together with data from 
patients in Treatment Arm B (change from week 8 to week 16), to estimate 
the treatment effect of increasing the dose from low-dose regimen to high-
dose regimen.  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
mAb 
Monoclonal antibody 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
DBTP 
Double blind treatment period 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DXA 
Dual-energy X-ray absorptiometry 
EC 
Ethics Committee 
eCOA 
Electronic clinical outcome assessment 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FBR 
Future Biomedical Research 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLD 
Generalized lipodystrophy 
GLP 
Good Laboratory Practice 
HbA1c 
Hemoglobin A1c 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HRQoL 
health-related quality of life  
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IA 
Interim Analysis 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IP 
Investigational product 
IRB 
Institutional Review Board 
ITT 
insulin-tolerance test 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LEPR 
Leptin receptors 
MDC 
Minimal detectable change  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MMRM 
Mixed effect repeated measurement model 
MMTT 
Mixed meal tolerance test 
NAS 
Non-alcoholic fatty liver disease activity score 
NASH 
Non-alcoholic steatohepatitis 
NMR 
Nuclear magnetic resonance 
NOAEL 
No observed adverse effect level 
OLTP 
Open-Label Treatment Period 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PDFF 
Proton Density Fat Fraction 
PedsQLTM 
The Pediatric Quality of Life Inventory  
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
QW 
Once a week 
PK 
Pharmacokinetic 
PRO 
Patient reported outcomes 
PT 
Preferred term 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
REMS 
Risk evaluation and mitigation strategy 
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SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SF-36 
Short Form-36 survey 
sLEPR 
Soluble form of the leptin receptor 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TP 
Treatment period 
ULN 
Upper limit of normal 
US 
United States 
VCTE 
Vibration-controlled transient elastography 
WBC 
White blood cell 
WMG 
Weighted mean glucose 
WOCBP 
Women of Childbearing Potential 
 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................23 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................30 
1. 
INTRODUCTION ......................................................................................................40 
2. 
STUDY OBJECTIVES ..............................................................................................41 
2.1. 
Primary Objectives .....................................................................................................41 
2.2. 
Secondary Objectives .................................................................................................41 
2.3. 
Exploratory Objectives ...............................................................................................41 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................42 
3.1. 
Rationale .....................................................................................................................42 
3.1.1. 
Rationale for Study Population ...................................................................................42 
3.1.2. 
Rationale for Study Design .........................................................................................43 
3.1.3. 
Rationale for Dose Selection ......................................................................................44 
3.1.4. 
Rationale for Endpoints ..............................................................................................48 
3.2. 
Hypothesis ..................................................................................................................49 
3.3. 
Benefit-Risk ................................................................................................................49 
3.3.1. 
Risk-Benefit for REGN4461 ......................................................................................49 
4. 
ENDPOINTS ..............................................................................................................50 
4.1. 
Primary Endpoints ......................................................................................................50 
4.2. 
Secondary Endpoints ..................................................................................................50 
4.3. 
Exploratory Endpoints ................................................................................................51 
5. 
STUDY VARIABLES................................................................................................51 
5.1. 
Demographic and Baseline Characteristics ................................................................51 
5.2. 
Efficacy Variables ......................................................................................................51 
5.3. 
Safety Variables ..........................................................................................................52 
5.4. 
Pharmacokinetic Variables .........................................................................................52 
5.5. 
Anti-Drug Antibody Variables ...................................................................................52 
5.6. 
Pharmacodynamic, Other Biomarker, and Research Variables ..................................52 
6. 
STUDY DESIGN .......................................................................................................52 
6.1. 
Study Description and Duration .................................................................................52 
6.1.1. 
Sub-Studies .................................................................................................................56 
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6.1.2. 
End of Study Definition ..............................................................................................57 
6.2. 
Planned Interim Analysis ............................................................................................57 
6.3. 
Study Committees .......................................................................................................57 
6.3.1. 
Steering Committee ....................................................................................................57 
6.3.2. 
Data Monitoring Committee .......................................................................................57 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............57 
7.1. 
Number of Patients Planned .......................................................................................57 
7.2. 
Study Population .........................................................................................................57 
7.2.1. 
Inclusion Criteria ........................................................................................................57 
7.2.2. 
Exclusion Criteria .......................................................................................................58 
7.3. 
Premature Withdrawal from the Study .......................................................................61 
7.4. 
Replacement of Patients .............................................................................................61 
8. 
STUDY TREATMENTS............................................................................................61 
8.1. 
Investigational and Reference Treatments ..................................................................61 
8.2. 
Run-in Treatment(s) ....................................................................................................64 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................64 
8.3.1. 
Dose Modification ......................................................................................................64 
8.3.2. 
Study Drug Discontinuation .......................................................................................64 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................64 
8.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................65 
8.4. 
Management of Acute Reactions ................................................................................65 
8.4.1. 
Acute Intravenous Infusion Reactions ........................................................................65 
8.4.1.1. 
Interruption of the Intravenous Infusion .....................................................................65 
8.4.1.2. 
Termination of the Intravenous Infusion ....................................................................66 
8.4.2. 
Acute Injection Reactions ...........................................................................................66 
8.4.2.1. 
Systemic Injection Reactions ......................................................................................66 
8.4.2.2. 
Local Injection Site Reactions ....................................................................................67 
8.5. 
Method of Treatment Assignment ..............................................................................67 
8.5.1. 
Blinding ......................................................................................................................67 
8.5.2. 
Emergency Unblinding ...............................................................................................67 
8.6. 
Treatment Logistics and Accountability .....................................................................68 
8.6.1. 
Packaging, Labeling, and Storage ..............................................................................68 
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8.6.2. 
Supply and Disposition of Treatments .......................................................................68 
8.6.3. 
Treatment Accountability ...........................................................................................68 
8.6.4. 
Treatment Compliance ................................................................................................69 
8.7. 
Concomitant Medications and Procedures .................................................................69 
8.7.1. 
Prohibited Medications ...............................................................................................69 
8.7.2. 
Permitted Medications ................................................................................................69 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................70 
9.1. 
Schedule of Events .....................................................................................................70 
9.1.1. 
Footnotes for the Schedule of Events Table 3: Screening and Placebo Run-In .........74 
9.1.2. 
Footnotes for the Schedule of Events Table 4: Double-Blind Treatment 
Period 1 .......................................................................................................................80 
9.1.3. 
Footnotes for the Schedule of Events Table 5: Double-Blind Treatment 
Periods 2 and 3 ............................................................................................................87 
9.1.4. 
Footnotes for the Schedule of Events Table 6: Open-Label Treatment Period 
4 ..................................................................................................................................93 
9.1.5. 
Footnotes for the Schedule of Events Table 7: Open-Label Treatment Period 
5 ................................................................................................................................101 
9.1.6. 
Early Termination Visit ............................................................................................102 
9.1.7. 
Unscheduled Visits ...................................................................................................103 
9.2. 
Study Procedures ......................................................................................................103 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit ...................................103 
9.2.2. 
Safety Procedures .....................................................................................................103 
9.2.2.1. 
Vital Signs ................................................................................................................103 
9.2.2.2. 
Physical Examination, Body Weight, Height, and Tanner Stages ...........................103 
9.2.2.3. 
Electrocardiogram .....................................................................................................104 
9.2.2.4. 
Menstrual History, Pregnancy Status Reporting, and Confirmation of 
Contraception ............................................................................................................104 
9.2.2.5. 
Hypoglycemia Monitoring ........................................................................................104 
9.2.3. 
Laboratory Testing ....................................................................................................104 
9.2.4. 
Efficacy Procedures ..................................................................................................106 
9.2.4.1. 
Fasting Triglycerides ................................................................................................106 
9.2.4.2. 
Fasting Glucose ........................................................................................................107 
9.2.4.3. 
Hemoglobin A1C ......................................................................................................107 
9.2.4.4. 
Fructosamine .............................................................................................................107 
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9.2.4.5. 
Insulin/C-peptide ......................................................................................................107 
9.2.4.6. 
Lipid Panel ................................................................................................................107 
9.2.4.7. 
Urine Protein, Creatinine, and Albumin ...................................................................107 
9.2.4.8. 
Insulin Sensitivity Measurement ..............................................................................107 
9.2.4.9. 
Mixed Meal Tolerance Test ......................................................................................108 
9.2.4.10. 
Weighted Mean Glucose ...........................................................................................108 
9.2.4.11. 
Assessment of Body Composition ............................................................................108 
9.2.4.12. 
Assessment of Hepatic Fat Content and Liver Size** ..............................................108 
9.2.4.13. 
Assessment of Liver Stiffness by Vibration-Controlled Transient 
Elastography (VCTE) ...............................................................................................109 
9.2.5. 
Patient-Reported Outcome Measures .......................................................................109 
9.2.5.1. 
Daily Appetite and Eating Behavior PRO ................................................................109 
9.2.5.2. 
Questions Assessing Sensation of Body Temperature .............................................109 
9.2.5.3. 
Short Form – 36 Survey ............................................................................................109 
9.2.5.4. 
Pediatric Quality of Life Inventory Generic Core Scales .........................................110 
9.2.5.5. 
Patient Global Impression of Severity ......................................................................110 
9.2.5.6. 
Patient Global Impression of Change .......................................................................110 
9.2.5.7. 
Exit Interview in Relation to Hunger and Eating Behavior PROs ...........................110 
9.2.6. 
Pharmacokinetic/Drug Concentration and Immunogenicity Samples ......................111 
9.2.6.1. 
REGN4461 Concentration Measurements ...............................................................111 
9.2.6.2. 
Soluble LEPR (sLEPR) ............................................................................................111 
9.2.6.3. 
Circulating Biomarkers for Pharmacodynamic Assessments ...................................111 
9.2.6.4. 
Immunogenicity Measurements and Samples ..........................................................112 
9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures .....................................112 
9.2.7.1. 
Endocrine Hormones ................................................................................................112 
9.2.7.2. 
Immunophenotyping .................................................................................................112 
9.2.8. 
 ..........................................................................112 
9.2.9. 
Future Biomedical Research (Optional) ...................................................................113 
9.2.9.1. 
Pharmacogenomic Analysis (Optional) ....................................................................113 
10. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING ...........................114 
10.1. 
Obligations of Investigator .......................................................................................114 
10.2. 
Obligations of Sponsor .............................................................................................114 
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10.3. 
Definitions ................................................................................................................114 
10.3.1. 
Adverse Event ...........................................................................................................114 
10.3.2. 
Serious Adverse Event ..............................................................................................114 
10.3.3. 
Adverse Events of Special Interest ...........................................................................115 
10.3.4. 
Infusion Reactions ....................................................................................................116 
10.4. 
Recording and Reporting Adverse Events ................................................................116 
10.4.1. 
Adverse Events .........................................................................................................116 
10.4.2. 
Serious Adverse Events ............................................................................................116 
10.4.3. 
Other Events that Require Accelerated Reporting to Sponsor .................................116 
10.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study .........................117 
10.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results ...........................117 
10.4.6. 
Follow-up ..................................................................................................................117 
10.5. 
Evaluation of Severity and Causality .......................................................................118 
10.5.1. 
Evaluation of Severity ..............................................................................................118 
10.5.2. 
Evaluation of Causality .............................................................................................119 
10.6. 
Safety Monitoring .....................................................................................................120 
10.7. 
Investigator Alert Notification ..................................................................................121 
11. 
STATISTICAL PLAN..............................................................................................121 
11.1. 
Statistical Hypothesis ................................................................................................121 
11.2. 
Justification of Sample Size......................................................................................122 
11.3. 
Analysis Sets .............................................................................................................123 
11.3.1. 
Efficacy Analysis Sets ..............................................................................................123 
11.3.2. 
Safety Analysis Set ...................................................................................................123 
11.3.3. 
Pharmacokinetic Analysis Sets .................................................................................123 
11.3.4. 
Anti-Drug Antibody Analysis Sets ...........................................................................124 
11.3.5. 
Glycemic Analysis Set ..............................................................................................124 
11.3.6. 
Triglyceride Analysis Set .........................................................................................124 
11.3.7. 
MRI Analysis Set ......................................................................................................124 
11.3.8. 
Clamp Analysis Set ...................................................................................................124 
11.3.9. 
Clamp Glycemic Analysis Set ..................................................................................124 
11.3.10. 
Insulin-Tolerance Test Analysis Set .........................................................................124 
11.3.11. 
Insulin-Tolerance Test Glycemic Analysis Set ........................................................124 
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11.3.12. 
 ........................................................................................124 
11.4. 
Statistical Methods ....................................................................................................124 
11.4.1. 
Patient Disposition ....................................................................................................125 
11.4.2. 
Demography and Baseline Characteristics ...............................................................125 
11.4.3. 
Efficacy Analyses .....................................................................................................125 
11.4.3.1. 
Primary Efficacy Analysis ........................................................................................125 
11.4.3.2. 
Secondary Efficacy Analysis ....................................................................................126 
11.4.4. 
Safety Analysis .........................................................................................................128 
11.4.4.1. 
Adverse Events .........................................................................................................128 
11.4.4.2. 
Other Safety ..............................................................................................................129 
11.4.4.3. 
Treatment Exposure ..................................................................................................129 
11.4.4.4. 
Treatment Compliance ..............................................................................................129 
11.4.5. 
Pharmacokinetics ......................................................................................................130 
11.4.5.1. 
Analysis of Drug Concentration Data .......................................................................130 
11.4.5.2. 
Analysis of Pharmacokinetic Parameters .................................................................130 
11.4.6. 
Analysis of Anti-Drug Antibody Data ......................................................................130 
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ............................131 
11.5. 
Interim Analysis ........................................................................................................131 
11.6. 
Statistical Considerations Surrounding the Premature Termination of the 
Study .........................................................................................................................131 
12. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................131 
12.1. 
Data Management .....................................................................................................131 
12.2. 
Electronic Systems ....................................................................................................131 
13. 
STUDY MONITORING ..........................................................................................132 
13.1. 
Monitoring of Study Sites .........................................................................................132 
13.2. 
Source Document Requirements ..............................................................................132 
13.3. 
Case Report Form Requirements ..............................................................................132 
14. 
AUDITS AND INSPECTIONS ...............................................................................132 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................133 
15.1. 
Good Clinical Practice Statement .............................................................................133 
15.2. 
Patients Confidentiality and Data Protection ............................................................134 
15.3. 
Institutional Review Board/Ethics Committee .........................................................135 
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16. 
PROTOCOL AMENDMENTS ................................................................................135 
17. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................135 
17.1. 
Premature Termination of the Study .........................................................................135 
17.2. 
Close-Out of a Site ....................................................................................................135 
18. 
STUDY DOCUMENTATION .................................................................................136 
18.1. 
Certification of Accuracy of Data .............................................................................136 
18.2. 
Retention of Records ................................................................................................136 
19. 
DATA QUALITY ASSURANCE ............................................................................137 
20. 
CONFIDENTIALITY ..............................................................................................138 
21. 
FINANCING AND INSURANCE ...........................................................................138 
22. 
PUBLICATION POLICY ........................................................................................138 
23. 
REFERENCES .........................................................................................................139 
24. 
INVESTIGATOR’S AGREEMENT ........................................................................142 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................143 
 
LIST OF TABLES 
Table 1: 
Planned Tiered Weight-Based Dosing Regimen of REGN4461 ................................46 
Table 2: 
 
 ......................63 
Table 3: 
Screening and Placebo Run-In....................................................................................71 
Table 4: 
Double-Blind Treatment Period 1 ..............................................................................76 
Table 5: 
Double-Blind Treatment Periods 2 and 3 ...................................................................83 
Table 6: 
Open-Label Treatment Period 4 (OLTP 4) .................................................................90 
Table 7: 
Open-Label Treatment Period 5 (OLTP 5) .................................................................96 
Table 8: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG Separately (N=20, 10 Treated vs. 10 Placebo, Assuming 
Approximately 20% Dropout Rate from 26 Patients) ..............................................122 
Table 9: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG in the Subset Analyses (N=20, Assuming Approximately 
20% Dropout Rate from 26 Patients) ........................................................................123 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................53 
 
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1. 
INTRODUCTION 
REGN4461, a leptin receptor (LEPR) agonist, is a fully human monoclonal antibody (mAb) that 
is being investigated for the treatment of conditions associated with leptin deficiency, including 
lipodystrophy. Generalized lipodystrophy (GLD) is an ultra-rare condition characterized by 
near-complete loss of adipose tissue (lipoatrophy). There are an estimated 300 to 400 patients with 
GLD identified worldwide and an estimated prevalence of approximately 0.23 to 0.96 cases per 
million (Chiquette, 2017). Adipose tissue functions to store energy and signal the status of energy 
stores by secreting hormones (adipokines) such as leptin, which regulates energy intake, energy 
expenditure, and reproductive function. Severe lipoatrophy and leptin deficiency in GLD manifest 
as hyperphagia, insulin resistance, diabetes, hypertriglyceridemia, pancreatitis, infertility, and 
hepatic steatosis (progressing to non-alcoholic steatohepatitis [NASH] and advanced liver 
disease).  
Recombinant methionyl human leptin (rhLeptin) (metreleptin, Myalept®) is the only approved 
treatment option to treat the complications of leptin deficiency in patients with GLD. Currently, 
rhLeptin is approved in the United States (US) for GLD, and in Japan and Europe for lipodystrophy 
(both general and partial). However, immunogenicity (>80% of patients develop anti-drug 
antibodies and ~6% develop neutralizing antibodies) (Myalept, 2015) and the requirement for once 
daily injections can limit the effectiveness of metreleptin in some patients. In the US, metreleptin 
carries a black box warning noting that anti-metreleptin antibodies might cross react to endogenous 
leptin. In the US, metreleptin is only available through a risk evaluation and mitigation strategy 
(REMS) program in order to restrict prescribing to only trained, certified physicians, to reserve 
access for eligible patients, and to ensure that the benefits of the therapy outweigh risks. There is 
thus an unmet need in GLD for effective therapies that are safer, administered less frequently, and 
can treat patients with neutralizing antibodies to the only approved therapy, metreleptin.  
REGN4461 binds and activates leptin receptors (LEPR) signaling. REGN4461 is not related to 
endogenous leptin, and therefore should not have elevated risks of anti-drug antibodies 
cross-reacting with endogenous leptin. Once-weekly administration of REGN4461 improved 
glycemic control, insulin sensitivity, hypertriglyceridemia, food intake, body weight, hepatic mass, 
and steatosis in lipodystrophic humanized LEPR mice. In toxicology studies (a non-GLP single- 
and repeated-dose pilot study and a GLP 13-week toxicology study in monkeys), REGN4461 
administration resulted in either reduction in body weight gain or body weight loss. These effects 
are consistent with a role of leptin in regulation of body weight. No adverse reactions of treatment 
have been identified to date. A first-in-human (FIH), double-blind, placebo-controlled study of 
REGN4461 in healthy volunteers (R4461-HV-1794) is completed. In the initial (Part A) 
single-ascending dose portion of the study, participants were randomized 3:1 to REGN4461 vs. 
placebo in 1 of 7 cohorts to receive doses 
 intravenously (IV) up to 
 IV, 
and 
 subcutaneously (SC) and 
 SC. In Part B of the study, participants were 
randomized to 4 distinct cohorts defined by sex, baseline leptin levels and BMI to receive 
 
 
. Results of the R4461-HV-1794 study indicate that REGN4461 was well 
tolerated by healthy volunteers when administered via IV and SC routes at the doses tested. There 
were no safety signals identified from the TEAEs observed in the REGN4461-treated groups 
compared to placebo group in either part of the study.  
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objectives 
The primary objectives of the study are to: 
• Estimate the effects of REGN4461 on glycemic parameters in the subset of patients 
with elevated baseline hemoglobin A1c levels (HbA1c ≥7%) 
• Estimate the effects of REGN4461 on fasting triglyceride levels in the subset of patients 
with elevated baseline fasting triglycerides (TG ≥250 mg/dL) 
2.2. 
Secondary Objectives 
The secondary objectives are to: 
• Estimate the effects of REGN4461 on a composite endpoint of changes in either HbA1c 
or fasting TG for all patients 
• Estimate the effects of 3 dose levels of REGN4461 on glycemic parameters and fasting 
TG  
• Estimate the effects of REGN4461 on insulin sensitivity 
• Evaluate the safety and tolerability of REGN4461 
• Evaluate the pharmacokinetics (PK) and immunogenicity of REGN4461 
2.3. 
Exploratory Objectives 
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3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Rationale  
3.1.1. 
Rationale for Study Population 
The patient population for this study is patients with a clinical diagnosis of congenital or acquired 
GLD who are not currently treated with metreleptin. The majority of patients with GLD have 
marked improvements in metabolic parameters with leptin replacement. These results closely 
mirror preclinical data with REGN4461 and recombinant leptin in a murine model of 
lipodystrophy. Some GLD patients are untreated with metreleptin because metreleptin is not 
approved in their country, because they are unwilling or unable to perform daily SC administration 
of metreleptin, or because they have experienced an adverse effect from metreleptin or developed 
neutralizing antibodies to metreleptin. The treatment effect of metreleptin was greater and more 
directionally consistent in patients with GLD and baseline levels of HbA1c ≥7% or 
TG ≥250 mg/dL (FDA, 2013). Therefore, the patient population in this study is limited to patients 
with GLD with baseline HbA1c ≥7% or TG ≥250 mg/dL, in order to reduce variability and more 
clearly evaluate the effects of REGN4461 in the small subset of patients available that are not 
being treated with metreleptin. Acquired and congenital forms of GLD are included, as both groups 
of patients experience clinical benefit from metreleptin (Myalept, 2015). 
Data from the REGN4461 first-in-human study (R4461-HV-1794) demonstrate that REGN4461 
is pharmacologically active only in low-leptin individuals (≤8.0 ng/ml), consistent with LEPR 
being saturated in individuals with higher leptin levels. All reported patients with congenital GLD 
have very low leptin levels and are anticipated to respond to REGN4461. However, rare patients 
with acquired GLD have higher leptin levels as a result of preserved visceral adiposity, despite 
generalized subcutaneous lipoatrophy. Therefore, for patients with acquired GLD additional 
inclusion criteria have been incorporated into this study in order to select patients with a greater 
likelihood of response to a LEPR agonist antibody. The inclusion criterion for low leptin levels 
(≤8.0 ng/ml) is based on the responder analyses from study R4461-HV-1794. Alternatively, low 
body adipose mass (<20% for females, <14% for males, based on the first percentile from the 
National Health and Nutrition Examination Survey cohort III data) independent of leptin 
concentrations is also acceptable, as leptin levels are proportionate to body fat mass (Meral, 2018) 
(Diker-Cohen, 2015).  
The metabolic complications of GLD manifest early in life, leading to significant morbidity and 
mortality among pediatric patients (Lima, 2017). The mean age of death in a large 
rhLeptin-untreated cohort was 27 years old, with patients dying as young as age 11 from diabetic 
complications (Lima, 2017). Patients with GLD therefore begin metreleptin early in life, and 
metreleptin has been demonstrated to be safe and effective in pediatric patients (Brown, 2017). 
The study includes adolescents (ages 12 to 17 years), as these patients have a high, unmet medical 
need and the preclinical toxicology studies support inclusion of these patients. In healthy, 
adolescent monkeys of comparable developmental stage to the proposed patient population (peri-
pubescent), no adverse effects of continuous exposure (weekly dosing up to 
 via IV 
infusion) were identified (R4461-TX-17003; 13-week GLP toxicology study). The primary effect 
REGN4461 exhibited in adolescent monkeys was decreased body weight gain or body weight loss, 
consistent with the expected pharmacology of a LEPR agonist. Upon cessation of exposure during 
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a dose-free recovery phase, body weight changes were demonstrated to be reversible and lacked 
any adverse physiological effects on the animals, including microscopic evaluation of the 
developing reproductive organs, and functional evaluations of the central nervous system. 
3.1.2. 
Rationale for Study Design 
 
 
 
 
The purpose of the single-blind placebo run-in period is to stabilize diet and metabolic parameters. 
Because the primary mechanism by which LEPR agonism improves metabolic parameters is 
through improvement of hyperphagia and reductions in caloric intake, changes in diet and 
medications that can occur upon enrollment in a clinical study might have a considerable impact 
on study endpoints. For instance, in the initial study of metreleptin, the effect of study enrollment 
on improvement of TG was nearly as large as the effect of 1 month of metreleptin therapy 
(Oral, 2002). In the current study, the randomized, placebo-controlled study period (
 
) will evaluate the effects of REGN4461 and assess study effects in patients randomized 
to placebo. The length of the DBTP 1 (8 weeks) was chosen to provide enough time for metabolic 
parameters to improve, but also to minimize the length of time some patients are treated with 
placebo. In GLD patients, initiation of metreleptin can improve, and in some patients even 
normalize, fasting glucose and fasting TG within days to 1 month (Brown, 2018) (Ebihara, 2007) 
(Vatier, 2016). Reductions in HbA1c upon metreleptin initiation have been demonstrated within 2 
weeks (Brown, 2018). After 4 months of treatment with metreleptin, patients with GLD 
experienced a mean reduction in HbA1c of ~1.5% from a baseline of 9.2%, and a reduction in 
median TG of 50% from a median baseline of 580 mg/dL. After 6 months, metreleptin was 
reported to lower HbA1c by 2.7% in the subgroup of patients with baseline HbA1c >8% (mean 
baseline of 9.8%), and lower mean fasting TG by 72% in the subgroup of patients with a baseline 
fasting TG >300 mg/dL (mean baseline of 914 mg/dL (Diker-Cohen, 2015). A 
 treatment 
period is also long enough to see improvements in hepatic steatosis, which has been reported to 
improve within 2 weeks of initiation (Brown, 2018) (Javor, 2005) (Oral, 2002) (Petersen, 2002).  
Two dose levels have been selected for the double-blind portion of this study (DBTP 1-3, 
Section 3.1.3). There is uncertainty regarding the optimal dose of REGN4461 in GLD because: 
(1) PK in healthy volunteers might differ from PK in GLD patients due to potentially different 
levels of the target receptor (LEPR); (2) very high doses of REGN4461 were associated with 
diminished efficacy in cellular reporter assays of LEPR activity, in a LEPR humanized mouse 
model of lipodystrophy, and in healthy cynomolgus monkeys (ie, an inverse U-shaped 
dose-response or ‘hook effect’ was observed); and (3) REGN4461 is an agonist antibody and 
therefore might not need to saturate the target receptor for maximal efficacy. Therefore, the study 
design involves an intra-patient dose escalation in DBTP 2 and DBTP 3 to maximize information 
from each patient enrolled, and to allow for intra-patient comparisons between the 2 dose levels. 
Exploration of 2 dose levels in the DBTPs will help to minimize bias and leverage objective 
measures. The low-dose and high-dose treatment regimens will be defined by body weight tiers, 
as described in Section 3.1.3, in order to ensure equivalent exposure in all patients.  
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The Open-Label Treatment Period (OLTP) 4 (from week 24 through at least week 52) will explore 
the durability of treatment effects of the 
 doses. Long-term effects of 
REGN4461 on HbA1c, TG, insulin sensitivity, liver disease, and body composition will be 
assessed at week 52 by serum studies, insulin sensitivity assessment (clamp or insulin-tolerance 
test [ITT]), liver volume and fat content (by magnetic resonance imaging [MRI] and MRI-Proton 
Density Fat Fraction [PDFF], respectively), whole body composition (by Dual-energy X-ray 
absorptiometry [DXA]), vibration-controlled transient elastography (VCTE), and 
 
.  
A pre-specified interim analysis (IA) was performed when the last enrolled patient reached the 
week 8 primary endpoint. The IA revealed that GLD patients had lower than predicted REGN4461 
concentrations and no significant treatment effects on glycemic and lipid parameters at week 8. A 
population PK analysis was performed and indicated faster clearance of REGN4461 in this GLD 
population. As the study progressed to week 36, clinically meaningful treatment effects were 
observed for HbA1c and triglycerides in these patients. Therefore, a higher dose (ie, 
 SC 
QW) is predicted to achieve the target trough concentrations in GLD patients and to increase the 
likelihood of rapidly achieving optimal treatment effects. REGN4461 appears to be generally well 
tolerated for the doses observed, with no safety concerns identified with regards to TEAEs, AESIs, 
and laboratory parameters. As such, an additional treatment period at a dose of 
 SC QW 
(OLTP 5) has been added in order to assess the safety 
 that is proposed to be 
used in future studies of REGN4461 in the GLD population. To rapidly achieve desired 
concentrations quickly, 
 IV is required at the start of this higher-dose 
treatment period (OLTP 5). 
The OLTP 5 
 
 with dose reduction as described in Section 3.1.3. Long-term effects of 
REGN4461 on HbA1c, TG, liver disease, and body composition will be assessed at week 52 by 
serum studies, liver volume and fat content (by magnetic resonance imaging [MRI] and MRI-
Proton Density Fat Fraction [PDFF], respectively), whole body composition (by Dual-energy 
X-ray absorptiometry [DXA]), vibration-controlled transient elastography (VCTE), and 
 
 
Conditions that will mark the end of OLTP 4 and the beginning of OLTP 5 are detailed in 
Section 6.1.  
After the last dose of study drug, patients enter a 16-week follow-up period to assess the efficacy, 
safety, and PK after discontinuation of REGN4461. The duration of off-drug follow-up (16-weeks) 
is sufficient to allow concentrations to fall below the limit of quantitation. Patients who complete 
the EOT visit associated with OLTP 5 and secure access to REGN4461 treatment outside of the 
study are not required to complete follow-up period visits, and may instead complete the EOS visit 
and complete the study. This design element was instituted to allow patients experiencing 
improvements in metabolic parameters to seek continued treatment with REGN4461, should they 
choose to do so.  
3.1.3. 
Rationale for Dose Selection 
REGN4461 dose levels and dosing frequency have been selected based on tolerability and PK data 
from a single ascending dose (Part A) FIH study in healthy volunteers (R4461-HV-1794), PK-PD 
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analyses of glucose control and body weight effects in a mouse model of lipodystrophy, and 
body-weight effect data in healthy cynomolgus monkeys. A 2-tiered dosing paradigm for fixed SC 
dose considers the wide range of body weights for adult and adolescent patients planned for the 
current study.  
In preclinical species, PD effects were associated with a wide range of exposures to REGN4461, 
while the sustainability of the effects was observed under dosing conditions where target-mediated 
clearance (TMC) of REGN4461 was saturated. Transgenic mice expressing nuclear sterol 
regulatory element-binding protein 1c (nSrebp1c) in adipose tissue through the aP2 promoter 
(aP2-nSrebp1cTg/+) are reported to develop a syndrome with characteristic features of GLD 
(Shimomura, 1999). aP2-nSrebp1cTg mice have a near-absence of white adipose tissue and are 
severely insulin-resistant, hyperglycemic, and dyslipidemic. aP2-nSrebp1cTg/+ mice also develop 
an enlarged fatty liver. This mouse model provided the first evidence that leptin resolves the 
metabolic complications of GLD (Shimomura, 1999). Since aP2-nSrebp1cTg/+ mice recapitulate 
the clinical manifestations of GLD, they represent a useful model for pharmacological testing of 
REGN4461. Considering REGN4461 does not bind mouse LEPR (REGN4461-PH-17036), aP2-
nSrebp1cTg/+ mice were crossed with mice expressing a humanized ectodomain of LEPR 
(Leprhu/hu) as described in REGN4461-PH-17041, to generate an aP2-nSrebp1cTg/+Leprhu/hu line. 
In this mouse model of lipodystrophy, single doses of REGN4461 resulted in normalization of 
glucose concentrations and loss of body weight. These effects were evident at concentrations of 
REGN4461 
 but were notably more sustained at concentrations that 
saturated the TMC pathway. In monkey studies, sustained body-weight effects (either body weight 
loss or reduced body weight gain compared to control animals) were observed at steady-state 
concentrations 
. However, greater overall effects 
 
. Given 
that leptin-binding receptors are widely expressed, but that target (signaling) receptors are limited 
to the central nervous system, it is presumed that the preclinical PK/PD data reflect the need to 
saturate TMC associated with binding to peripheral LEPR to achieve adequate exposures in the 
brain. In addition, the interspecies differences in concentration required to saturate TMC and 
deliver sustained PD effects may be a consequence of differences in peripheral target burden. 
 
 
 
 
Because patients with GLD lack adipose tissue and may therefore have a lower peripheral target 
burden and altered PK profiles compared to healthy volunteers, it is important to explore a lower 
dose level in this study. The low dose level, 
 SC, 
 
 
, thereby maximizing the opportunity to observe intra-patient comparisons 
between low- and high-dose levels. 
 
  
REGN4461 was well-tolerated in healthy adult volunteers in R4461-HV-1794 when administered 
as single doses 
 IV and 
 SC. Maximal concentration of 
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 IV dose, which is more 
 
 current study. Predicted AUCinf over the entire 52-week study 
period for each tier is expected to be at least 10-fold lower than the AUCcumulative (at the no observed 
adverse effect level [NOAEL]) estimated from a PK model derived from 3 preclinical toxicology 
studies in cynomolgus monkeys. Therefore, considering both maximal concentration and total 
exposure following repeated dosing, the proposed high dose is expected to be well tolerated. 
The current study includes both adult and adolescent patients with body weight potentially much 
lower than a typical adult of 70 kg. The effect of weight on the PK of REGN4461 was examined 
based 
 
 
 respectively. Though this magnitude of between-patient variability is typical and 
reflects inter-individual differences not only in body weight/volume of distribution but also in 
absorption and elimination, the impact of body weight over the larger range of patient weights 
expected in this study could necessitate dose adjustment. 
 
 
 
 
 
 As discussed above, these exposure levels are believed to 
be efficacious and well-tolerated and to adequately differentiate between the low and high doses. 
Therefore, the selected doses for patients with weights of less than 50 kg are considered 
appropriate. No dose changes will be made during the study if the weight tier for a patient changes 
during treatment.  
Table 1: 
Planned Tiered Weight-Based Dosing Regimen of REGN4461 
 to 
assess whether the doses selected achieved the expected drug levels and PK profiles and effects 
on glycemic and lipid parameters. The dose levels in the current study may be adjusted down after 
the IA. 
During the Open-Label Treatment Period 4 (OLTP 4), patients will receive 
 REGN4461 
SC QW 
 REGN4461 SC QW 
. After week 
52, dose reduction may occur if deemed necessary based on the IA of safety, tolerability, PK, or 
PD data.  
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The pre-specified IA was performed when the last enrolled patient reached the week 8 primary 
endpoint 
 
 
 
 
 
 
 
 
 
 
An additional treatment period at a dose of 
 SC QW (OLTP 5) has been added in order to 
assess the safety of the 
 SC QW dose regimen, the proposed regimen for future studies of 
REGN4461 in the GLD population.  
 
 
 
 
 
 
  
• Patient that has lost excessive weight. For the purposes of this study, excessive 
weight loss is defined as >10% change from baseline and/or is considered as 
excessive in the opinion of the investigator and in consultation with the study's 
medical monitor. 
and/or  
• Patient has experienced clinically significant (in the opinion of the investigator) 
spontaneous hypoglycemia (<70 mg/dL), defined as hypoglycemia that occurs in the 
absence of exogenous insulin or insulin secretagogues.  
 
 
 
Predicted area under the curve at steady state (AUCtau) for the 
 SC QW dosing regimen 
administered to GLD patients is approximately 
 
 
  
Based on the above observations, a fifth treatment period (OLTP 5) was introduced with 
Amendment 3 in which all eligible patients 
 
. 
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3.1.4. 
Rationale for Endpoints 
Clinical studies of metreleptin in lipodystrophy patients demonstrated improvement in HbA1c, 
fasting TG, and fasting glucose (FDA, 2013). Regulators globally have approved metreleptin based 
on changes seen in these parameters, and therefore these endpoints have been chosen for this study. 
Due to the variability of TG and HbA1c endpoints, several design elements have been utilized to 
reduce variability and enhance the ability to observe a treatment effect in this small study of 
metreleptin-untreated patients. The averaging of multiple, fasting TG observations will improve 
the accuracy of the fasting TG estimate in the baseline and treatment periods, compared to only 
single values. Since fasting and blood draws can be burdensome on patients with lipodystrophy, 
particularly in metreleptin-untreated patients with hyperphagia, measurements of fasting TG will 
be limited to the end of the study periods. Since effects on HbA1c are delayed and quite variable, 
mixed meal tolerance test (MMTT), weighted mean glucose (WMG), and fasting blood glucose 
will also be assessed as a short-term measure of glycemic control. 
A secondary composite endpoint comprising change in HbA1c or change in TG will be calculated 
to assess the overall effects of REGN4461 on metabolic parameters in the enrolled population. 
There is significant heterogeneity in baseline metabolic abnormalities among patients with GLD, 
and the treatment effect on a given endpoint (eg, HbA1c, TG) is expected to vary according to the 
baseline abnormality. For example, estimates suggest that only ~one-third of patients have 
abnormalities in both HbA1c and fasting TG. This observation is consistent with prior studies in 
GLD patients (FDA, 2013). Most patients identified have elevated TG, while a smaller fraction of 
patients have uncontrolled HbA1c (<40%). Significant inter-patient differences in diet, medication 
adherence, and underlying disease pathology are possible contributors to this heterogeneity in 
metabolic manifestations of lipodystrophy. The composite endpoint will assess the overall impact 
of REGN4461 in this heterogeneous population, by assessing the effects on glycemic parameters 
among patients with abnormal baseline glycemic control and effects on fasting TG among patients 
with elevated baseline fasting TG, in a single composite endpoint. 
REGN4461 improved insulin sensitivity in a mouse model of lipodystrophy and is expected to 
improve insulin sensitivity in patients with GLD. The gold-standard assessment of insulin 
sensitivity is the hyperinsulinemic-euglycemic clamp study (clamp study). Patients with 
metreleptin-untreated GLD are insulin-resistant and require high insulin infusion rates 
(120 mU/m2·min) to suppress endogenous glucose production and stimulate glucose uptake. In a 
recent study of 14 lipodystrophy patients, a statistically significant 30% increase in insulin 
sensitivity, as measured by glucose infusion rate to maintain euglycemia, was observed within 
2 weeks of metreleptin administration to previously untreated patients (Brown, 2018). Inclusion 
of a clamp study at baseline, week 8, and week 52 will provide a sensitive assessment of metabolic 
effects of REGN4461. At clinical sites that do not have the capability to perform a clamp study, 
an ITT will be used instead. 
REGN4461 is expected to reduce hepatic steatosis, similar to what has been observed with 
metreleptin therapy (Brown, 2018) (Javor, 2005) (Oral, 2002) (Petersen, 2002). REGN4461 
reduced hepatic fat in a mouse model of lipodystrophy. Patients will undergo baseline and 
on-treatment MRI (weeks 8, 24, and 52 for all patients, and at the start and at the end of OLTP 5 
for all eligible patients) to evaluate the effects of REGN4461 on hepatic volume and fat content. 
Liver fat content and liver volume assessment by MRI-PDFF and MRI, respectively, will be 
performed only at sites with the requisite technical capability. Baseline, week 52, and at the start 
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and at the end of OLTP 5 VCTE evaluation will assess long-term impact of REGN4461 on liver 
fibrosis. Liver fibrosis assessment will be performed only at sites with VCTE capability. Since 
hepatic steatosis can progress to NASH, cirrhosis, and liver failure in patients with lipodystrophy, 
an 
 may be performed (in adult patients who have consented to participate in 
this sub-study) at baseline and after treatment to evaluate the effects on the non-alcoholic fatty 
liver disease activity score (NAS) and fibrosis.  
It is expected that REGN4461 will decrease appetite, a therapeutic effect in GLD patients with 
hyperphagia. In order to quantify these effects, hunger and eating behaviors will be assessed during 
the study by a daily de novo lipodystrophy-specific PRO measure. To ensure the measure is fit for 
purpose under the context of use, we will also conduct exit interviews between weeks 6 and 8 (or 
at the early termination visit before week 8, if applicable). The qualitative data from the exit 
interviews will also be used to interpret trial results and to further understand whether the observed 
changes were meaningful from the perspective of the patient. 
Excessive appetite suppression could have an impact on muscle mass. Therefore, body weight will 
be monitored throughout the study. In addition, whole body DXA imaging will be performed at 
baseline and during the treatment period to quantify the short- and long-term effects of REGN4461 
on fat and lean tissue mass. Whole body DXA will be performed only at sites with these 
capabilities. 
3.2. 
Hypothesis 
REGN4461 will improve the metabolic complications of leptin deficiency in patients with GLD 
who are untreated with metreleptin. 
3.3. 
Benefit-Risk 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the Sponsor does not intend to screen any patients in this study until 
the impact of the COVID-19 pandemic is deemed manageable and no longer interfering with the 
conduct of trials at individual sites, and patients can safely participate in this study. Until then, the 
Sponsor plans to obtain approvals from Health Authorities/Ethics Committees to enable initiation 
of study sites for this study, as allowed by local laws and regulations. 
3.3.1. 
Risk-Benefit for REGN4461 
For patients with generalized lipodystrophy, REGN4461 has the potential to be a better alternative 
than metreleptin to reduce metabolic complications of lipodystrophy (as discussed in the most 
current version of the Investigators’ Brochure). In addition, because the structure of REGN4461, 
a monoclonal antibody, is distinct from leptin, there is no expected risk of REGN4461-treated 
patients developing neutralizing antibodies that cross-react to endogenous leptin. To date, no 
important identified risks have been established with REGN4461. Important potential risks have 
been established based on observations from nonclinical studies, the mechanism of action of 
REGN4461 (including class effects), and risks associated with mAbs in general. These potential 
risks include:  
• Decreased lymphocytes  
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• Hypoglycemia in patients with concomitant use of insulin and insulin secretagogues  
• Systemic hypersensitivity reactions  
• Clinical consequences of immunogenicity (ADA formation)  
REGN4461 has not been administered to pregnant humans, and embryofetal toxicity studies have 
not been conducted. As such, embryofetal toxicity remains a potential risk. 
A risk-benefit statement with respect to the overall development program is provided in the 
Investigators’ Brochure.  
4. 
ENDPOINTS 
4.1. 
Primary Endpoints 
The primary endpoints of the study are: 
• In patients with elevated baseline HBA1c (HbA1c ≥7%), absolute change from 
baseline to the end of the DBTP 1 in: 
− HbA1c (week 8) 
− Fasting glucose (week 8) 
− WMG (week 8) 
• In patients with elevated baseline fasting TG (fasting TG ≥250 mg/dL), percent change 
from baseline to the end of the DBTP 1 in fasting TGs  
4.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
• Change from baseline to week 8 in composite endpoint comprising absolute change in 
either HbA1c or percent change in fasting TG for all patients 
• Absolute change from baseline in fasting glucose over time for all patients and patients 
with elevated baseline HbA1c (HbA1c ≥7%) 
• Percent change from baseline in fasting TG over time in all patients and in patients with 
elevated baseline fasting TG (TG ≥250 mg/dL) 
• Absolute change from baseline in HbA1c over time for all patients and patients with 
elevated baseline HbA1c (HbA1c ≥7%) 
• Absolute change from baseline in WMG over time for all patients and patients with 
elevated baseline HbA1c (HbA1c ≥7%) 
• Change from baseline in glucose AUC0-4 during an MMTT at weeks 8, 16, and 24 for 
all patients and patients with elevated baseline HbA1c (HbA1c≥7%) 
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• Change from baseline in glucose infusion rate per kg body mass during 
hyperinsulinemia-euglycemic clamp at week 8 and week 52, for all patients and 
patients with elevated baseline HbA1c (HbA1c ≥7%) 
• Change from baseline in glucose clearance rate (kITT) during ITT at week 8 and 
week 52 for all patients and patients with elevated baseline HbA1c (HbA1c ≥7%) 
• Treatment-emergent adverse events 
• Concentrations of total REGN4461 in serum over time 
• Assessment of incidence of anti-drug antibodies to REGN4461 and titer over time  
4.3. 
Exploratory Endpoints 
5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics include standard demography (eg, age, race, weight, height, etc.), disease 
specific-characteristics including fasting glucose, HbA1c, WMG, MMTT, low-density lipoprotein 
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting TG, disease 
characteristics including detailed GLD history (medical history, and medication history including 
previous lipid-modifying therapies and control of diabetes) for each patient. 
5.2. 
Efficacy Variables 
Efficacy variables include HbA1c, fasting glucose, WMG, fasting TG, AUC0-4h from MMTT, 
glucose infusion rate per kg body mass from clamp, and glucose clearance rate (kITT) from ITT, 
liver volume as measured by MRI, and liver fat content as measured by MRI-PDFF. 
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5.3. 
Safety Variables 
Safety variables include adverse events, body weight, vital signs, 12-lead-ECG, physical 
examination, and laboratory safety tests. 
5.4. 
Pharmacokinetic Variables 
Concentrations of total REGN4461 and soluble leptin receptor (sLEPR) will be measured at 
prespecified sampling times. 
5.5. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include ADA status and titer over time. 
5.6. 
Pharmacodynamic, Other Biomarker, and Research Variables 
Pharmacodynamic, other biomarker and research variables include:  
• Liver stiffness from VCTE 
• Urine protein, creatinine, albumin 
• Angiopoietin-like 3 (ANGPTL3) 
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) 
• Endocrine hormone panel (eg, luteinizing hormone [LH], follicle-stimulating hormone 
[FSH], estradiol [E2], and testosterone) 
• Immunophenotyping studies (T cell subsets) 
• NAS score from histologic assessment of liver core needle biopsy (in patients who 
consent) 
• Transcriptomic profiling studies on RNA extracted from liver biopsies 
• Biomarkers of insulin resistance, appetite control, liver fibrosis. 
• Biomarkers of lipid parameters (lipid panel, lipoprotein analysis by NMR) 
• Patient-reported outcomes measuring quality of life (as measured by the SF-36 and 
PedsQLTM),  
• Patient-reported outcomes measuring impacts on hunger and eating behaviors 
• Patient-reported outcomes measuring impact on sensation of body temperature 
6. 
STUDY DESIGN  
6.1. 
Study Description and Duration 
This is a phase 2, randomized, double-blind, placebo-controlled study of the efficacy and safety of 
REGN4461 in patients with GLD who are not receiving recombinant methionyl human leptin 
(rhLeptin, metreleptin) therapy. 
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The study comprises 
 
 
 
  Patients who complete the EOT visit associated with 
OLTP 5 and have secured access to continued REGN4461 treatment through other means, (eg, 
another Regeneron-sponsored clinical trial, compassionate use, or an expanded access program), 
may forgo any or all of the off-drug follow-up visits 119-121 and proceed to the EOS visit. These 
patients will be considered study completers. 
Patients who are ≥12 years of age, (or lower limit of age approved by Health Authority, EC, and 
IRB) at the screening visit with a clinical diagnosis of GLD, will undergo screening, including 
measurement of HbA1c and fasting TG. Eligible patients will then begin the single-blind placebo 
run-in period within 4-weeks of screening. 
The 24-week DBTP consists of the following:  
• 
 
 
• 
 
 
• 
 
 
 
  
 
 
 
Figure 1: 
Study Flow Diagram 
4-Week Screening Period 
The screening period will last for up to 4 weeks (days -56 to -29). Patients will undergo screening 
assessments as per the schedule outlined in Table 3 to determine their eligibility for study 
participation. Patients may be re-screened if they fail the screening for reasons related to incidental 
or transitory conditions (eg, medication use, concomitant illness, medical condition). If patients 
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are re-screened within the original 4-week screening period, only screening test(s) (eg, an out-of-
range laboratory value) that resulted in initial screen failure should be repeated.  
4-Week Single-Blind Placebo Run-in Period (Week -4 to Day 1) 
At the beginning of the placebo run-in period, patients will receive an IV placebo infusion, 
followed 1 week later by SC injections of placebo, administered once weekly for 3 weeks. After 
the first administration of placebo at the study site, subsequent administration may either be 
continued at the clinical site, or by the site personnel or another healthcare professional at a remote 
location (eg, the patient’s home, school, or place of work). 
Blood samples will be collected to measure fasting lipid and glucose levels during the run-in 
period. These blood samples may be collected at a clinical unit, at home by a visiting nurse, or at 
an outpatient clinic visit. Patients will also receive training on a clinical outcome assessment 
(COA), if available, which they will use to record patient-reported outcome (PRO) measures. 
At the end of the placebo run-in period, patients will undergo MMTT assessment, WMG 
assessment, insulin-sensitivity assessment, and VCTE assessment. The insulin-sensitivity 
assessment will be a clamp study for patients who visit qualified sites where a qualified clamp 
research unit and experienced investigator are available. Patients presenting to sites without a 
qualified clamp research unit will undergo an ITT in lieu of a clamp study. The patients who 
present to sites that are not qualified and experienced to perform clamp (and additionally are not 
qualified and experienced to perform ITT testing) will not undergo insulin-sensitivity assessment. 
Additionally, patients will undergo baseline liver volume and fat content by MRI, and whole-body 
composition by DXA imaging (at sites with the requisite capability). Adult patients will have the 
 during the placebo run-in period. Baseline efficacy labs 
(eg, HbA1c, fasting glucose, and fasting TG) will be collected on study day 1 prior to study drug 
administration. 
 
After baseline testing, patients will be randomized 1:1 to placebo (Treatment Arm A), or 
REGN4461 (low-dose regimen) (Treatment Arm B), stratified based on screening HbA1c 
(HbA1c ≤8% or HbA1c >8%) to ensure equal representation of patients with very elevated HbA1c 
in each study arm. On study day 1, patients in Treatment Arm A will receive an IV infusion of 
placebo and patients in Treatment Arm B will receive an IV 
 REGN4461. 
Starting on day 
 and continuing weekly through days 
 patients will receive 
weekly SC injections of either placebo or 
 
, administered by either a trained visiting nurse at a remote location or by trained study staff 
at a study site (see Table 2 for details of dosing schedule). At the end of DBTP 1, patients will 
undergo in-clinic assessments including laboratory assessments for PD, MMTT, WMG, and 
insulin sensitivity (clamp or ITT), liver volume and fat content by MRI, and whole body 
composition by DXA imaging (at sites with the requisite capability) (see Table 4 for details). The 
primary endpoints are assessed at the end of DBTP 1 (week 8).  
Double-Blind Treatment Periods 2 and 3 (Weeks 8 to 16 and 16 to 24) 
The DBTP 2 begins at week 8 and will continue until week 16. On week 8, patients in Treatment 
Arm A will begin the REGN4461 low-dose regimen, and patients in Treatment Arm B will 
transition to the REGN4461 high-dose regimen (Table 2).  
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During the 
 
 
 
 
 
 
 
 
 
At the end of DBTP 2, patients will undergo in-clinic assessments including laboratory 
assessments for PD, MMTT, and WMG (see Table 5 for details). 
The DBTP 3 begins 
 
 
, patients will undergo in-clinic assessments including laboratory 
assessments for PD, MMTT, WMG, liver volume and fat content by MRI, and whole body 
composition by DXA imaging (see Table 6 for details). 
Open-Label Treatment Period 4 (OLTP 4)  
The open-label period begins at week 24 through at least week 52 during which time all patients 
will initially continue to receive weekly SC administration of 
 
 
 
. REGN4461 may be administered at the clinical site, by the 
site personnel or another healthcare professional at a remote location (eg, satellite site, patient’s 
home, school, or place of work), or self-administered/administered by the patient or designated 
person, respectively. For patients who choose to self-administer REGN4461, training on 
self-administration must be performed by qualified study personnel, and the first occurrence of 
self-administration must be observed by same. In-clinic assessments including physical 
examination and laboratory assessments for PK, PD, and safety parameters will occur every 
3 months during the entire length of the OLTP 4 or as-needed based on study staff assessment via 
monthly phone contacts. Study personnel contact with patient via either phone or in-person 
assessments must occur at least once monthly throughout the study.  
The final insulin sensitivity assessment (clamp or ITT), evaluation will occur at the week 52 visit 
(see Table 6 for details). 
. Additional 
week 52 assessments include VCTE examination, liver volume and fat content by MRI, and whole 
body composition by DXA imaging. Following the 
 
 until the end of OLTP 4 is reached. During the cycling visits, at “each” 
, patients 
will only undergo sample collections for safety (hematology, blood chemistry, pregnancy testing, 
urinalysis, fasting TG, glucose, and HbA1c) and PK. When cycling, patients will not undergo 
sample collections for fructosamine, insulin/C-peptide, lipid panel, urine protein, creatinine, or 
albumin.  
OLTP 4 will end at the earliest when all 4 of the following criteria are fulfilled: (1) all active 
patients have completed the week 52 visit, (2) all data have been collected and validated through 
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the time when the last active patient randomized into the study completes the week 24 visit, (3) 
results of the primary analyses of safety and efficacy are available to the sponsor, and (4) Protocol 
Amendment 3 has been approved at the site. Once all four of these criteria are met, the OLTP 4 
will end at the latest four weeks after approval of Protocol Amendment 3 at each site.  Based on 
these factors, the sponsor will determine the end of OLTP 4 for each patient. 
Open-Label Treatment Period 5 (OLTP 5) 
 after the end of OLTP 4 (defined above), patients will enter OLTP 5. At the onset of 
OLTP 5 all patients will receive 
 
 SC QW for 
. The following conditions would exempt a 
patient from 
: patients that have lost excess weight 
and/or experience significant spontaneous hypoglycemia previously in the study. Excess weight 
loss is defined for this protocol as >10% change from baseline and/or considered as excessive in 
the opinion of the investigator and in consultation with the study's medical monitor. Furthermore, 
any patient that experiences excess weight loss and/or significant spontaneous hypoglycemia as 
described above during OLTP 5 will undergo a dose reduction to 
 SC QW. After 52 weeks 
in OLTP 5, study drug will be discontinued. 
The REGN4461 
 SC QW 
maintenance doses may be administered at the clinical site, by the site personnel or another 
healthcare professional at a remote location (eg, satellite site, patient’s home, school, or place of 
work), or self-administered/administered by the patient or designated person, respectively. For 
patients who choose to self-administer REGN4461, training on self-administration must be 
performed by qualified study personnel, and the first occurrence of self-administration must be 
observed by the same study personnel. In-clinic assessments including physical examination and 
laboratory assessments for PK, PD, and safety parameters will occur at a frequency depicted in 
Table 7. Study personnel contact with the patient via either phone or in-person assessments must 
occur at least once monthly throughout the study. 
Patients who complete the EOT visit associated with OLTP 5 and have secured access to continued 
REGN4461 treatment through other means, (eg, another Regeneron-sponsored clinical trial, 
compassionate use, or an expanded access program), may forgo any or all of the off-drug follow-
up visits 119-121 and proceed to the EOS visit. These patients will be considered study completers. 
Off-Drug Follow-up Period 
When study drug is discontinued, patients will enter the 16-week off-drug follow-up period. The 
off-drug follow-up period will be used for safety monitoring, to assess REGN4461 PK, ADA, and 
explore PD effects at varying drug levels (Table 7).  
6.1.1. 
Sub-Studies 
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6.1.2. 
End of Study Definition 
The end of study is defined as the date that the last patient completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the patient can no longer be contacted by the 
investigator).  
6.2. 
Planned Interim Analysis  
No formal IA is planned. An unblinded team within Regeneron Pharmaceuticals, Inc., consisting 
of Regeneron staff not responsible for direct site interactions, will review the PK, PD, efficacy, 
and safety data to confirm the adequacy of the dose. The investigator, Regeneron study team 
responsible for site interactions, and patients will remain blinded to individual patient allocation 
throughout the study. 
6.3. 
Study Committees  
6.3.1. 
Steering Committee 
The complexity of this study requires a close partnership with the lipodystrophy experts. A steering 
committee will be formed to advise the sponsor on the strategic direction, goals, and execution of 
the study.  
6.3.2. 
Data Monitoring Committee 
An internal Data Monitoring Committee (DMC) will monitor patient safety by conducting reviews 
of individual and aggregate patient data. The DMC charter will be provided with DMC operational 
details. The DMC charter activities will align with the study protocol and statistical analysis plan 
(SAP). 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Up to 26 patients will be enrolled. 
7.2. 
Study Population  
The target population is patients with a clinical diagnosis of GLD who are at least 12 years of age 
(or lower limit of age approved by Health Authority, EC, and IRB) and are not currently treated 
with metreleptin. 
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female patients, ≥12 years of age at the screening visit (or lower limit of age 
approved by Health Authority, EC, and IRB) 
2. Diagnosis of congenital or acquired GLD defined as follows: 
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Evidence of generalized lipoatrophy of subcutaneous fat by physical examination AND one 
of the following (based on historical records): 
a. History of congenital generalized lipodystrophy (ie, onset at birth) based on 
patient’s history or documented pathogenic mutation in GLD associated gene 
(eg, AGPAT2, BSCL2, CAV1, PTRF)  
   OR 
b. Objective evidence of low total body fat mass as demonstrated by DXA, or of low 
leptin levels as defined below, assessed within 6-months prior to screening visit: 
• Less than 20% total body fat by DXA (females), or less than 14% total body fat (males). 
Note that the quality of historical DXA images should be consistent with the 
specifications described in the imaging manual.  
OR 
• Leptin levels ≤8.0 ng/ml 
3. Presence of one or both of the following metabolic abnormalities at screening: 
a. HbA1c ≥7% 
OR 
b. Fasting TG ≥250 mg/dL 
4. Generally stable diet (based on patient’s recall) and medication regimen (that optimizes 
treatment for their metabolic disease) for at least 3 months prior to the screening visit 
5. Willing and able to comply with clinic visits and study-related procedures  
Notes: Patients incapable of completing PRO assessments or unable to undergo MRI will 
not be excluded from the study. The willingness and ability to comply with clinic visits 
and study-related procedures applies to those patients associated with the main study 
(ie, not to the sub-studies included in this protocol). 
6. Provide informed consent signed by study patient or legally acceptable representative 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Treatment with metreleptin within 1 month of the screening visit 
2. Patients with clinically significant hematologic abnormalities such as neutropenia, 
lymphopenia, or lymphadenopathy at screening  
3. Treatment with over-the-counter or prescription medications for weight loss within 
3 months prior to the screening visit 
4. Treatment with oral glucocorticoids >7.5 mg prednisone equivalents per day within 
3 months prior to screening visit or plans to begin treatment with oral glucocorticoids 
>7.5 mg prednisone equivalents per day during the study period 
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5. Any malignancy, eg, lymphoma, within the past 1 year, prior to screening visit except for 
fully treated basal cell or squamous epithelial cell carcinomas of the skin or carcinoma in 
situ of the cervix or anus 
6. Estimated GFR of <30 mL/min/1.73 m2 based on CKD-Epi equation at screening  
7. History of heart failure hospitalization, diagnosis of a myocardial infarction, stroke, 
clinically significant arrhythmia (eg, ventricular tachycardia, or any arrhythmia requiring 
medication adjustment to control) transient ischemic attack, unstable angina, percutaneous 
or surgical revascularization procedure (coronary, carotid, or peripheral vascular), or 
intracardiac device placement (eg, pacemaker) within 3 months before the screening visit 
8. Advanced heart failure (New York Heart Association Class 3 to 4) or severe and 
uncontrolled hypertension at screening 
9. History of HIV or HIV seropositivity at screening visit 
10. Uncontrolled infection with hepatitis B or hepatitis C infection, or known active 
tuberculosis at screening 
a. Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus (HBV) at 
screening. 
b. Patients with hepatitis B (HBVsAg+) who have controlled infection (serum HBV DNA 
PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis 
B) are permitted. Patients with controlled infections must undergo periodic monitoring 
of HBV DNA per local standards. Patients must remain on anti-viral therapy for at least 
6 months beyond the last dose of investigational study drug. 
c. Patients who are hepatitis C virus antibody-positive (HCVAb+) who have controlled 
infection (undetectable HCV RNA by PCR either spontaneously or in response to a 
successful prior course of anti-HCV therapy) are permitted. 
11. A history of an anaphylactic reaction to monoclonal antibody therapeutics 
12. If a patient has any medical condition which impacts HbA1c levels (eg, hemolytic anemia 
or blood transfusion), the sponsor should be consulted before the investigator decides 
whether to enroll the patient.  
13. Participation in any clinical research study evaluating an IP or therapy within 3 months and 
less than 5 half-lives of IP prior to the screening visit. Participation in clinical research 
studies that involve procedures (eg, muscle biopsies) or testing (eg, MRI) that will not 
interfere with the current study is permitted. 
14. Any physical examination findings and/or history of any illness that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to the 
patient by their participation in the study 
NOTE: A patient who has a documented, positive reverse-transcriptase polymerase chain 
reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
or positive serology for SARS-CoV-2 may be enrolled provided the following:  
a. Repeat RT-PRC testing for SARS-CoV-2 
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A) For patients with a positive test ≤90 days before screening, the patient must have
recovered from COVID-19 (all COVID-19-related symptoms and major clinical
findings which can potentially affect the safety of the patient should be resolved),
and
Had 2 negative results from a health authority-authorized nucleic acid amplification
(PCR) test for SARS-CoV-2 taken at least 48 hours apart
OR
B) For patients with a positive test >90 days before screening, then the patient must
have recovered from COVID-19 (all COVID-19-related symptoms and major
clinical findings which can potentially affect the safety of the patient should be
resolved)
OR
b. The patient provides documented vaccination for SARS-CoV-2
15. Pregnant or breast-feeding women
16. Women of childbearing potential (WOCBP)* who are unwilling to practice highly
effective contraception prior to the initial dose/start of the first treatment, during the study,
and for at least 4 months after the last dose. Highly effective contraceptive measures
include:
−
Stable use of progestogen-containing hormonal contraception, or transdermal
estrogen hormonal contraception, associated with inhibition of ovulation initiated
2 or more menstrual cycles prior to screening
−
Intrauterine device (IUD); intrauterine hormone-releasing system (IUS)
−
Bilateral tubal ligation
−
Vasectomized partner (provided that partner is the sole sexual partner of the
WOCBP patient and that the vasectomized partner has received medical assessment
of the surgical success)
−
And/or sexual abstinence†, ‡.
* Women of childbearing potential is defined as women who are fertile, following
menarche and until becoming post-menopausal unless permanently sterile. Permanent
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral
oophorectomy.
A postmenopausal state is defined as age greater than 50 years old and with no periods for 
12 months. 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
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acceptable methods of contraception. Female condom and male condom should not be used 
together.  
17. Sexually active adult or adolescent men who are unwilling to use the following forms of 
medically acceptable birth control during the study drug treatment period and for 4 months 
after the last dose of study drug: vasectomy with medical assessment of surgical success 
OR consistent use of a condom  
− Sperm donation is prohibited during the study and for 4 months after the last dose 
of study drug 
7.3. 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 9.1.6. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.3.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. Up to 26 patients will be 
enrolled to account for an expected 20% dropout rate. 
8. 
STUDY TREATMENTS  
8.1. 
Investigational and Reference Treatments 
The investigational product is REGN4461, an IgG4 monoclonal antibody agonist to the leptin 
receptor. REGN4461 will be supplied for IV or SC administration.  Placebo-matching REGN4461 
is prepared in the same formulation without the addition of protein. Instructions on dose 
preparation are provided in the Pharmacy Manual and Nursing Manual. 
Treatment Arm A will receive the following:  
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Treatment Arm B will receive the following:  
During OLTP 4 (
), both treatment arms will continue to receive weekly SC 
administration of high-dose REGN4461 (
). During OLTP 4, 
REGN4461 may be administered at the clinical site, by the site personnel or another healthcare 
professional at a remote location (eg satellite site, patient’s home, school, or place of work), or 
self-administered/administered by a designated person (eg, caregiver), respectively. For patients 
who choose to self-administer REGN4461, training on self-administration must be performed by 
qualified study personnel, and the first occurrence of self-administration must be observed by same 
study personnel. In addition, a medication administration diary will be provided to the 
patient/designee prior to initiation of self-administration or administration by a designated person 
such as a parent or caregiver. The diary must be completed upon each study drug administration. 
For self-administration/administration by a designated person, an Instructions For Use document 
shall be provided with instructions for reconstitution of IP and administration.  
During OLTP 5 (starting no sooner than when the last enrolled patient has reached 52 weeks and 
Protocol Amendment 3 has been approved at the site, please see detailed description above in the 
section describing OLTP 4) both treatment arms will receive a
 IV 
followed a week later by weekly injections of 
 SC QW for 
. Exceptions to this 
include patients who have lost >10% weight loss since baseline and/or in the opinion of the 
investigator and in consultation with the study's medical monitor the weight loss is considered 
excessive. In addition, any patient that experiences significant spontaneous hypoglycemia 
(Section 3.1.3) will not undergo the dose increase. Spontaneous hypoglycemia is defined as 
hypoglycemia that occurs in the absence of exogenous insulin or insulin secretagogues. Patients 
that do not undergo the dose increases will not undergo any loading dose at the beginning of OLTP 
5 and will continue the dose they were receiving in OLTP 4 during OLTP 5. Those patients that 
begin the 
 in OLTP 5 and experience excessive weight loss or significant 
hypoglycemia as described above will have their dose reduced to 
 SC QW. 
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Table 2: 
 
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8.2. 
Run-in Treatment(s) 
There will be a 4-week single-blind placebo run-in period (week -4 through day 1). At the 
beginning of the placebo run-in period, patients will receive an IV placebo infusion, followed 
1 week later by SC injections of placebo, administered once weekly for 
 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
At the beginning of OLTP 5 (at least week 52) patients in both treatment arms will receive a 
 IV followed a week later by weekly injections of 
 SC QW for 
 
. Exceptions to this include patients who have lost >10% weight loss since baseline and in 
the opinion of the investigator, in consultation with the study's medical monitor, are considered to 
be experiencing excessive weight loss. In addition, any patients that experiences significant 
spontaneous hypoglycemia that is considered adverse by the investigator will not undergo the dose 
increase. Spontaneous hypoglycemia  (<70 mg/dL) is defined as hypoglycemia that occurs in the 
absence of exogenous insulin or insulin secretagogues. Patients that do not undergo the dose 
increases will not undergo any loading dose at the beginning of OLTP 5 and will continue the dose 
they were receiving in OLTP 4 during OLTP 5. Those patients that begin 
 
 
 SC QW. 
8.3.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for an early termination visit which consists of assessments 
performed at the EOT visit and remaining study visits starting with the off-drug follow-up period 
(Table 6).  
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.6.  
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug  
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Severe liver injury or dysfunction for which no other reason can be found to explain, 
such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug 
capable of causing the observed injury. Liver injury is defined as follows: 
 
For individuals with normal baseline transaminase and liver enzyme levels:  
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 x upper 
limit of normal (ULN) or 
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− ALT or AST >5 x ULN for more than 2 weeks or 
− ALT or AST >3 x ULN and total bilirubin >2 x ULN (or international normalized 
ratio (INR) >1.5)  
• For individuals with abnormal baseline transaminase and liver enzyme levels:  
− ALT or AST >3 x over baseline and total bilirubin >2 x over baseline (or 
international normalized ratio (INR) >1.5)  
• Patient withdraws consent 
• Investigator’s clinical judgment that it is in the best interest of the patient 
8.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
The investigator may temporarily discontinue study drug dosing at any time, even without 
consultation with the medical monitor, if the urgency of the situation requires immediate action 
and if this is determined to be in the patient’s best interest. However, the Regeneron medical 
monitor should be contacted as soon as possible in any case of temporary or permanent study drug 
discontinuation. If a patient requires a prohibited medication at any time during the study, the 
principal investigator should contact the Regeneron medical monitor. Based on the discussions, 
study drug may be continued or temporarily or permanently discontinued. 
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Intravenous Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available in 
the treatment unit for immediate use. All infusion reactions must be reported as adverse events 
(AEs) (as defined in Section 10.4.1) and graded using the grading scales as instructed in 
Section 10.5.1. 
8.4.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed during the infusion: 
• Severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
• Vomiting 
• Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
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If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
8.4.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• Anaphylaxis* 
• Laryngeal/pharyngeal edema 
• Severe bronchospasm 
• Chest pain 
• Seizure 
• Severe hypotension 
• Other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis, etc.) 
• Any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
* Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING:  
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
 If anaphylaxis is suspected, all efforts should be made to collect additional blood samples within 
30 minutes of the onset of symptoms for measurement of serum tryptase. In case of suspected 
systemic hypersensitivity or anaphylaxis additional blood samples may also be collected for the 
assessment of REGN4461 drug concentration and immunogenicity. 
8.4.2. 
Acute Injection Reactions 
8.4.2.1. 
Systemic Injection Reactions 
Patients should be observed for 30 minutes after the first SC injection in clinic.  
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All injection reactions must be reported as AEs (as defined in Section 10.4.1) 
and graded using the grading scales as instructed in Section 10.5.1. 
Acute systemic reactions following the SC injection of study drug should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.   
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8.4.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.5.1.  
8.5. 
Method of Treatment Assignment 
All eligible patients will begin the single-blind placebo run-in period within 4 weeks of screening. 
Upon completion of a 4-week run-in period, up to 26 patients will be randomized in a 1:1 ratio in 
Treatment Arm A or Treatment Arm B. Central randomization scheme will be provided by an 
interactive voice response system (IVRS)/interactive web response system (IWRS) to the 
designated study pharmacist (or qualified designee). Randomization will be stratified according to 
HbA1c (HbA1c ≤8% vs HbA1c >8%) at the screening visit.  
8.5.1. 
Blinding  
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The Regeneron medical/study director, study 
monitor, and any other Regeneron and contract research organization (CRO) personnel who are in 
regular contact with the study site will remain blinded to all patient randomization assignments.  
An unblinded pharmacist or qualified, unblinded designee will reconstitute study drug (for IV and 
SC injections) and prepare the IV infusion bags. Further details are provided in the Pharmacy 
Manual or Nursing Manual.  
Investigators will be blinded to specific endpoints, including but not limited to HbA1c, TG, and 
other lipids, for the entire length of the double-blind treatment period (up to week 24). However, 
there may be extenuating circumstances (eg, interruptions of biospecimen shipments to the central 
laboratory due to COVID-19 restrictions, expedited laboratory results needed to assess potential 
safety finding, etc.) in which laboratory assessments may be performed at a local laboratory. Based 
on the protocol schedule of events, these assessments are not expected to be unblinding, and this 
contingency mitigates risk of losing critical study data.  
Select individuals not involved in the conduct of the study may have access to unblinded data as 
needed for safety review or other data review. 
Any unblinded analyses used for dose adequacy decisions will be executed with controlled 
dissemination to ensure the integrity of ongoing data collection. No study personnel involved in 
the day-to-day conduct of the study will have access to any patient randomization assignments 
before the database is locked for this study. 
8.5.2. 
Emergency Unblinding  
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy). 
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
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− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. 
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency. In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
8.6. 
Treatment Logistics and Accountability 
8.6.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label blinded and open-label investigational study 
drug. Lists linking medication numbers with product lot numbers will be maintained by the groups 
(or companies) responsible for study drug packaging. In order to maintain the blind (when 
applicable), these lists will not be accessible to individuals involved in study conduct. Study drug 
will be stored at a temperature of 2ºC to 8ºC; storage instructions will be provided in the Pharmacy 
Manual, Nursing Manual, and Instructions for Use document.  
8.6.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed / returned to the sponsor 
or designee.  
Patients may be allowed to receive study drug from the investigator at regular interval when 
attending visits at the clinical site for administration by a nurse, caregiver, and/or self-use. Patients 
will be provided with an appropriate transport container and instructions for use. Study drug, 
opened and unopened, must be returned to the site for appropriate reconciliation and destruction 
by the sponsor or designee.  
8.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
• Dispensed to each patient, 
• Returned from each patient (if applicable), and 
• Disposed of at the site or returned to the sponsor or designee 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
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8.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.7. 
Concomitant Medications and Procedures 
Any treatment administered or procedure performed (eg, vaccination) from the time of informed 
consent to final study visit will be considered concomitant medication or procedure. This includes 
medications that were started before the study and are ongoing during the study. 
8.7.1. 
Prohibited Medications 
Prohibited medications are: 
• Recombinant human leptin (metreleptin, Myalept), starting 1 month prior to study 
start and throughout the duration of the study 
• All over-the-counter and prescription weight loss medications eg orlistat (Xenical, 
Alli), lorcaserin (Belviq), phentermine-topiramate (Qsymia), naltrexone-bupropion 
(Contrave) starting 1 month before the study start and throughout the duration of the 
study 
8.7.2. 
Permitted Medications  
All medications except those listed in Section 8.7.1, are permitted.  
Every attempt should be made to keep concomitant medications, permitted over-the-counter 
medications, and dietary supplements stable throughout the entire duration of the study, unless in 
the judgement of the treating physician a safety concern warrants medication addition, 
discontinuation or a dose modification. 
Documentation of concomitant medications: Documentation of concomitant medications, doses of 
medications, and other medical treatments (eg, apheresis) will occur according to the schedule of 
assessments in Table 3, Table 4, Table 5, Table 6, and Table 7. All concomitant medication 
changes that occur during the course of the study must be recorded. 
Diabetes medications: If a patient is taking diabetes medications at the beginning of the study, 
REGN4461 will be added to existing therapy. Insulin and insulin secretagogues (eg, sulfonylureas) 
may be decreased in dose or discontinued in response to low blood glucose levels (glucose <100 
mg/dL), a large and clinically-significant decrease in fasting blood sugar (eg, 50% decrease in 
fasting glucose from prior values) signs/symptoms consistent with hypoglycemia, or if a safety 
concern arises. Otherwise, all attempts should be made to continue the patient’s current diabetes 
medication regimen.  
New hyperglycemia requiring medical treatment (rescue therapy) should be managed with insulin 
and reported as an AESI according to Section 10.3.3. New hyperglycemia requiring treatment is 
defined as follows: Fasting glucose ≥250 mg/dL (13.9 mmol/L) on 2 occasions including 
symptoms consistent with hyperglycemia AND increase in fasting glucose >50 mg/dL above 
baseline. 
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The insulin dose used will be determined by the treating physician after careful review of the 
patient’s diabetes history and prior diabetes treatment history, and all treatment decisions will be 
recorded.  
Lipid-lowering medications: If a patient is taking lipid-lowering medications at the beginning of 
the study, REGN4461 will be added to existing therapy. No changes to lipid lowering medications 
(medication addition, discontinuation, or dose adjustments) should be made during the course of 
the study, unless as needed for safety.  
Antidepressant medications: concomitant antidepressant medications should continue at current 
doses throughout the course of the study. Additions, discontinuations, or dose modifications of 
anti-depressant medications may occur only if a safety concern necessitates. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following: phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 3, Table 4, 
Table 5, Table 6, and Table 7. 
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Table 3: 
Screening and Placebo Run-In 
Study Period 
Screening 
Placebo Run-In 
 
In-Clinic Outpatient 
Visit1,2 
In-Clinic Outpatient 
Visit2 
In-Clinic Outpatient Visit or Remote Visit3 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Screening/Baseline 
  
  
  
  
  
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
Medical History4 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
HIV Serology and Hepatitis Testing (HBsAg, HCV) 
X 
 
 
 
 
Treatment and Medications 
 
 
 
 
 
Safety6 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
Height7 
X 
 
 
 
 
Weight 
X 
X 
 
 
 
Physical Examination8 
X 
X 
 
 
 
Tanner Staging  
X 
 
 
 
 
Electrocardiogram9 
X 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
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Study Period 
Screening 
Placebo Run-In 
 
In-Clinic Outpatient 
Visit1,2 
In-Clinic Outpatient 
Visit2 
In-Clinic Outpatient Visit or Remote Visit3 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Menstrual History, Pregnancy Status Reporting, and 
Confirmation of Contraception10 
X 
X 
X 
X 
X 
Laboratory Testing11 
 
 
 
 
 
Hematology 
X 
X12 
 
 
 
Blood Chemistry 
X 
X12 
 
 
 
Pregnancy Test (WOCBP)10 
Serum 
Urine 
 
 
 
Urinalysis 
X 
 
 
 
 
Leptin 
 
X 
 
 
 
Efficacy11 
 
 
 
 
 
Fasting Triglycerides and Glucose2 
X2 
X2  
 
 
X 
HbA1c, Fructosamine 
X 
X 
 
 
 
Insulin/C-peptide2 
X2 
X2 
 
 
 
Urine Protein, Creatinine, Albumin 
 
X 
 
 
 
COA Training13 
 
X 
 
 
 
Daily Appetite Hunger and Eating Behavior PRO13 
 
X 
X 
Sensation of Body Temperature PRO 
 
X 
 
 
 
SF-36 Questionnaire/PedsQLTM 14 
 
X 
 
 
 
Patient Global Impression of Severity 
 
X 
 
 
 
Liver MRI (volume/fat content)15 
 
X 
VCTE15 
 
X 
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Study Period 
Screening 
Placebo Run-In 
 
In-Clinic Outpatient 
Visit1,2 
In-Clinic Outpatient 
Visit2 
In-Clinic Outpatient Visit or Remote Visit3 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Whole body DXA15 
 
X 
PK/Biomarkers Procedure/Samples16 
  
  
  
  
  
Endocrine Hormones17  
 
X 
 
 
X 
ANGPTL3, PCSK9, sLEPR 
 
X 
 
 
X 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 3: Screening and Placebo Run-In 
1. Patients may be re-screened if they fail the screening for reasons related to incidental or 
transitory conditions (eg, medication use, concomitant illness, medical condition). If 
patients are re-screened within the original 4-week screening period, only screening test(s) 
(eg, an out-of-range lab value) that resulted in initial screen failure should be repeated. 
2. Procedures may be conducted on different days during the screening/baseline period, if 
needed. Blood draws for laboratory testing at the screening visit and visit 2 will be collected 
in a fasted state (after at least approximately a 12-hour fast). The duration of fasting may 
be shortened for patients with a documented clinical contraindication to fasting. 
3. Procedures may be conducted by trained study staff at a remote location (ie, at home visits, 
work, and/or school). 
4. Medical history should include detailed lipodystrophy history including prior 
medication/investigational products, genetic diagnosis (if known), imaging results, leptin 
levels (if known) and results of any previous anti-metreleptin antibody testing (if 
applicable). 
5. 
6. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
7. In individuals under 18 years of age, standing height should be recorded at least 
approximately every 3 months. Tanner staging for pubertal development should be 
performed at least approximately every 3 months until patient reaches Tanner stage 5. 
8. Complete physical examination will be performed at screening (visit 1) and includes skin, 
head, eyes, nose, throat, neck, joints, lungs, heart, pulse, abdomen (including liver and 
spleen), lymph nodes, and extremities. A brief neurologic examination should also be 
performed. Limited physical examination will be performed on all remaining visits and 
includes lungs, heart, abdomen, and skin. 
9. The electrocardiogram (ECG) can be performed up to 24 hours prior to study drug 
administration. 
10. Menstrual events and pregnancy status of WOCBP will be monitored throughout the study. 
A serum pregnancy test will be performed at screening, and a urine pregnancy test will be 
performed locally (eg, point-of-care) at subsequent visits. A positive urine pregnancy test 
should be confirmed with a serum test. 
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11. Study assessments should be performed, and blood samples are to be collected before study 
drug administration, unless otherwise indicated. For patients undergoing apheresis, study 
assessments are to be performed and blood samples are to be collected immediately before 
the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
12. Samples for hematology and blood chemistry analysis do not need to be collected at visit 2 
if visits 1 and 2 occur within 48 hours of each other. 
13. Patients must receive eCOA training at the time they receive the eCOA device. 
Additionally, patients must be trained on the Daily Appetite Hunger and Eating Behavior 
PRO prior to completion of PRO assessments. Patients will be instructed to fill out the 
Daily Appetite Hunger and Eating Behavior PRO on a daily basis. The site will check the 
patient’s adherence to completion of all study questionnaires at each designated visit.  
14. SF-36 is to be completed by patients 18 years or older, and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a PRO for patients ages 13 to 
17 years (teen report) and for patients 12 years of age (child form). 
15. Liver fat content and liver volume MRI scans, VCTE, and whole body DXA will be 
performed only at sites where these techniques are available. Liver MRI scans, VCTE, and 
whole body DXA can be performed from day -28 to day 1 prior to dosing of study drug. 
16.  Biomarker blood draw samples will be collected pre-dose.  
17. Endocrine hormones include but are not limited to luteinizing hormone, follicle-
stimulating hormone, estradiol, and testosterone (Section 9.2.7.1). 
18. 
 
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Table 4: 
Double-Blind Treatment Period 1 
Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Disposition 
  
  
  
  
  
  
  
  
  
  
  
Clinic Admission 
X 
 
 
 
 
 
 
 
 
 
 
Clinic Discharge 
 
 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X3 
 
 
 
 
 
 
 
 
Treatment and medications 
 
 
 
 
 
 
 
 
 
 
 
Safety5 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
Height7 
 
 
X 
 
 
 
 
 
 
 
 
Weight 
 
 
X8 
 
X 
X 
 
X 
 
X 
 
Tanner Staging7 
 
 
X 
 
 
 
 
 
 
 
 
Physical Examination22 
 
 
X 
 
 
 
 
 
 
 
 
Electrocardiogram9 
 
X 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Menstrual History, Pregnancy 
Status Reporting, and 
Confirmation of 
Contraception10 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing11 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
X 
 
 
X 
 
X 
 
 
X 
Blood Chemistry 
 
 
X 
 
 
X 
 
X 
 
 
X 
INR/PTT, Platelets (Local 
Lab) 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP)10 
 
X 
 
 
 
 
 
X 
 
 
 
Urinalysis 
 
 
X 
 
 
X 
 
X 
 
 
X 
Leptin12 
 
 
X12 
 
 
 
 
 
 
 
 
Efficacy11 
 
 
 
 
 
 
 
 
 
 
 
Fasting Triglycerides and 
Glucose12 
 
 
X12 
 
 
 
 
 
 
 
X12 
HbA1c 
 
 
X 
 
 
 
 
X 
 
 
 
Fructosamine 
 
 
X 
 
 
 
 
X 
 
 
 
Insulin/C-peptide12 
 
 
X12 
 
 
 
 
 
 
 
 
Lipid Panel 12 
 
 
X12 
 
 
 
 
 
 
 
 
Urine Protein, Creatinine, 
Albumin 
 
 
X 
 
 
 
 
 
 
 
 
Insulin Sensitivity 
Measurement 13, 14 
 
 
X 
 
 
 
 
 
 
 
 
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Page 78 of 143 
 
CONFIDENTIAL 
Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
MMTT15 
 
X 
 
 
 
 
 
 
 
 
 
Weighted Mean Glucose 
Assessment16 
 
X 
 
 
 
 
 
 
 
 
 
COA Training17 
X 
 
 
 
 
 
 
 
 
 
 
Daily Appetite Hunger and 
Eating Behavior PRO17 
X 
 
 
 
 
 
 
 
 
 
X 
Sensation of Body 
Temperature PRO 
X 
 
 
 
 
 
 
 
 
 
SF-36 Questionnaire/ 
PedsQLTM 18 
X 
 
 
 
 
 
 
 
 
 
Patient Global Impression of 
Severity 
X 
 
 
 
 
 
 
 
 
 
PK/Biomarker/Drug 
Concentration and ADA 
Samples19 
 
 
 
 
 
 
 
 
 
 
 
REGN4461 Concentration 
Blood Sample 
 
 
X 
 
X 
X 
 
 
 
 
 
ADA Sample 
 
 
X 
 
 
 
 
 
 
 
 
Endocrine Hormones20  
 
 
X 
 
 
 
 
X 
 
 
 
ANGPTL3, PCSK9, sLEPR 
 
 
X 
 
X 
X 
 
 
 
 
 
Immunophenotyping 
 
 
X 
 
 
 
 
 
 
 
 
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Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
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Page 80 of 143 
 
CONFIDENTIAL 
9.1.2. 
Footnotes for the Schedule of Events Table 4: Double-Blind Treatment Period 1 
1. In-clinic stay can begin within a ±2-day window. 
 assessments only needs 
to occur for patient who have consented to 
. All other patients may 
choose to be admitted on day -1. Patients will have the option to leave on the same day of 
study drug administration after being observed for at least 4 hours, provided all required 
assessments and procedures have been completed on that day.  
2. Assessments/procedures other than those occurring during in-clinic stays may be 
conducted by trained study staff at a remote location (ie, at home visits, work, and/or 
school).  
3. Randomization can occur within 24 hours prior to day 1 study drug administration if 
necessary. 
4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
6. 
 
  
7. In individuals under 18 years of age, standing height should be recorded at least 
approximately every 3 months. Tanner staging for pubertal development should be 
performed at least approximately every 3 months until patient reaches Tanner stage 5. 
8. This body weight will be used for dose tier determination. Body weight may be measured 
up to 24 hours prior to day 1 study drug administration and must be measured prior to 
randomization. 
9. The ECG can be performed up to 24 hours prior to study drug administration. 
10. Menstrual events and pregnancy status of WOCBP will be monitored throughout the study. 
A urine pregnancy test will be performed locally (eg, point-of-care). A positive urine 
pregnancy test should be confirmed with a serum test. 
11. Study assessments should be performed, and blood samples are to be collected before study 
drug administration unless otherwise indicated. For patients undergoing apheresis, study 
assessments are to be performed and blood samples are to be collected immediately before 
the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
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12. Patients must be in a fasted state (after at least approximately a 12-hour fast). The duration 
of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
13. Patients must be in a fasted state (after at least approximately a 12-hour fast) for insulin 
sensitivity assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Insulin sensitivity will be measured by 
clamp at sites where a qualified and experienced facility and staff are available. Blood 
samples for the clamp will be collected for the analysis of glucose, insulin, C-peptide at 
following times: 2 baseline samples within 30 minutes before starting insulin infusion and 
up to 4 samples during the 30 minutes steady state. Additional samples will be analyzed 
for point of care glucose measures during insulin infusion, as outlined in the study manual. 
 
 
  
For sites that do not have the ability to perform a clamp study but do have a qualified and 
experienced ITT facility and staff, patients will undergo an ITT. Patients with a history of 
seizure disorder should not undergo ITT. Blood samples will be collected for the analysis 
of glucose, insulin, C-peptide timed as follows: 2 baseline samples before starting insulin 
administration and at 5, 10, 15, 20 and 30 minutes after starting the insulin administration. 
 
 
  
14. Patients presenting to sites without qualified and experienced facility and staff to perform 
a clamp or ITT will not undergo clamp or ITT evaluation. This procedure can be done 
within 3 days prior to day 1. 
15. Patients must be in a fasted state (after at least approximately a 12-hour fast) prior to 
MMTT assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Blood samples will be collected on the 
days of the MMTT for the analysis of glucose, insulin, C-peptide, and TGs. Sampling times 
are as follows:  
• For glucose analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For insulin analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For C-peptide analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For TG analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
This procedure can be done within 3 days prior to day 1. 
16. Additional blood samples will be collected on the days of WMG assessments, timed as 
follows: (1) less than 30 minutes prior to lunch, (2) 120±10 minutes after lunch, (3) less 
than 30 minutes prior to dinner, (4) 120±10 minutes after dinner, and (5) 10 PM or bedtime. 
This procedure must be done on the same day as MMTT. Blood samples will be analyzed 
for glucose, insulin and for C-peptide.  
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17. Patients must receive eCOA training at the time they receive the eCOA device. 
Additionally, patients must be trained on the Daily Appetite Hunger and Eating Behavior 
PRO prior to completion of PRO assessments. If the patient was previously trained on both 
the eCOA and the PRO assessments, no additional training is required at this time. Patients 
will be instructed to fill out the Daily Appetite Hunger and Eating Behavior PRO on a daily 
basis. The site will check the patient’s adherence to completion of all study questionnaires 
at each designated visit.  
18. SF-36 is to be completed by patients 18 years or older, and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a self-administered PRO for 
patients ages 13 to 17 years (teen report) and for patients 12 years of age (child form). 
19. Collection of blood samples for drug concentration on day 1 will be pre-infusion/injection 
and at the end of infusion ±15 mins. On other visits, drug concentration and biomarker 
samples will be collected pre-dose. Samples for sLEPR, ANGPTL3, and PCSK9 should be 
collected at the time points that drug concentration is measured. On all visits ADA and 
drug concentration samples should be collected prior to administration of drug. 
20. Endocrine 
hormones 
include 
but 
are 
not 
limited 
to 
luteinizing 
hormone, 
follicle-stimulating hormone, estradiol, and testosterone (Section 9.2.7.1). 
21. 
 
 
 
 
 
22. Complete physical examination will be performed on day 1 (visit 8) and includes skin, 
head, eyes, nose, throat, neck, joints, lungs, heart, pulse, abdomen (including liver and 
spleen), lymph nodes, and extremities. A brief neurologic examination should also be 
performed. Limited physical examination will be performed on all remaining visits and 
includes lungs, heart, abdomen, and skin. 
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Table 5: 
Double-Blind Treatment Periods 2 and 3 
Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Admission 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Clinic Discharge 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Treatment and 
Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height6 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
Tanner Staging6 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
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Page 84 of 143 
 
CONFIDENTIAL 
Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Electrocardiogram7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Menstrual History, 
Pregnancy Status 
Reporting, and 
Confirmation of 
Contraception8 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Blood Chemistry 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Pregnancy Test 
(WOCBP)8 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Leptin10 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Triglycerides 
and Glucose10 
 
X10 
 
 
 
 
 
 
 
X10 
 
X10 
 
 
 
 
 
 
X10 
HbA1c 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Fructosamine 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Insulin/C-peptide10 
 
X10 
 
 
 
 
 
 
 
 
 
X10 
 
 
 
 
 
 
 
Lipid Panel10 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
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Page 85 of 143 
 
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Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Urine Protein, 
Creatinine, Albumin 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Insulin Sensitivity 
Measurement11,12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMTT13 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Weighted Mean 
Glucose 
Assessment14 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
COA Training15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily Appetite 
Hunger and Eating 
Behavior PRO15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Sensation of Body 
Temperature PRO 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
SF-36 Questionnaire/ 
PedsQLTM 16 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Patient Global 
Impression of 
Severity 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Patient Global 
Impression of Change 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Exit Interview 
X17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver MRI 
(volume/fat 
content) 18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 86 of 143 
 
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Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Whole body DXA18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Biomarker/Drug 
Concentration and 
ADA Samples 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
REGN4461 
Concentration Blood 
Sample 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
ADA Sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunophenotyping 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Endocrine 
Hormones20 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
ANGPTL3, PCSK9, 
sLEPR 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
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Page 87 of 143 
 
CONFIDENTIAL 
9.1.3. 
Footnotes for the Schedule of Events Table 5: Double-Blind Treatment Periods 2 
and 3  
1. In-clinic stay may begin within a ±2-day window. Patients will have the option to leave on 
the same day of study drug administration after being observed for at least 4 hours, 
provided all required assessments and procedures on that day have been completed. 
2. Assessments/procedures other than those occurring during in-clinic stays may be 
conducted by trained study staff at a remote location (ie, at home visits, work, and/or 
school). However, 
 
  
3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
5. Vital signs should be recorded 
 
  
6. In individuals under 18 years of age, standing height should be recorded at least 
approximately every 3 months. Tanner staging for pubertal development should be 
performed at least approximately every 3 months until patient reaches Tanner stage 5. 
7. The ECG can be performed up to 24 hours prior to study drug administration. 
8. Menstrual events and pregnancy status of WOCBP will be monitored throughout the study. 
A serum pregnancy test will be performed at the screening and EOS visit and urine 
pregnancy test performed locally (eg, point-of-care) at subsequent visits. A positive urine 
pregnancy test should be confirmed with a serum test. 
9. Study assessments should be performed, and blood samples are to be collected before study 
drug administration unless otherwise indicated. For patients undergoing apheresis, study 
assessments are to be performed and blood samples are to be collected immediately before 
the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
10. Patients must be in a fasted state (after at least approximately a 12-hour fast). The duration 
of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
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Clinical Study Protocol 
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Page 88 of 143 
 
CONFIDENTIAL 
11. Patients must be in a fasted state (after at least approximately a 12-hour fast) for insulin 
sensitivity assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Insulin sensitivity will be measured by 
clamp at sites where a qualified and experienced facility and staff are available. Blood 
samples for the clamp will be collected for the analysis of glucose, insulin, C-peptide at 
following times: 2 baseline samples within 30 minutes before starting insulin infusion and 
up to 4 samples during the 30 minutes long steady state. Additional samples will be 
analyzed for point of care glucose measures during insulin infusion, as outlined in the study 
manual. 
 
 
 
Patients will undergo an ITT at sites where a qualified and experienced ITT facility and 
staff are available. Patients with a history of seizure disorder should not undergo ITT. 
Blood samples will be collected for the analysis of glucose, insulin and C-peptide timed as 
follows: two baseline samples before starting insulin administration and at 5, 10, 15, 20 
and 30 minutes after starting the insulin administration. 
 
 
  
12. Patients presenting to sites without qualified and experienced facility and staff to perform 
a clamp or ITT will not undergo clamp or ITT evaluation. This procedure can be done 
 
13. Patients must be in a fasted state (after at least approximately a 12-hour fast) prior to 
MMTT assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Blood samples will be collected on the 
days of the MMTT for the analysis of glucose, insulin, C-peptide, and TGs. Sampling times 
are as follows: 
• For glucose analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For insulin analysis, -15,0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For C-peptide analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For TG analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
This procedure can be done 
 
14. Additional blood samples will be collected on the days of WMG assessments, timed as 
follows: (1) less than 30 minutes prior to lunch, (2) 120±10 minutes after lunch, (3) less 
than 30 minutes prior to dinner, (4) 120±10 minutes after dinner, and (5) 10 PM or bedtime. 
For patients who are discharged prior to completion of WMG blood draw assessments, the 
after-dinner and prior-to-bedtime assessments will not be required. This procedure must be 
done on the same day as MMTT. Blood samples will be analyzed for glucose, insulin and 
for C-peptide. 
15. Patients must receive eCOA training at the time they receive the eCOA device. 
Additionally, patients must be trained on the Daily Appetite Hunger and Eating Behavior 
PRO prior to completion of PRO assessments. If the patient was previously trained on both 
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Page 89 of 143 
 
CONFIDENTIAL 
the eCOA and the PRO assessments, no additional training is required at this time. Patients 
will be instructed to fill out the Daily Appetite Hunger and Eating Behavior PRO daily 
through week 24. The site will check the patient’s adherence to completion of all study 
questionnaires at each designated visit.  
16. SF-36 is to be completed by patients 18 years or older and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a self-administered PRO for 
patients ages 13 to 17 years (teen report) and for patients 12 years of age (child form). 
17. Exit interviews will be conducted either during in-clinic stay for DBTP2 
 
. 
18. Liver volume and fat content MRI and whole body DXA scans may be performed 
 
. These tests will only be performed at sites where these techniques 
are available. Patients may be required to fast at least 5 hours prior to an MRI scan. 
19. Collection of blood samples for drug concentration on 
 will be pre-infusion and at 
the end of infusion ±15 mins. On other visits, drug concentration and biomarker samples 
will be collected pre-dose. Samples for sLEPR, ANGPTL3, and PCSK9 will be collected 
at the time points that drug concentration is measured. On all visits ADA and drug 
concentration samples should be collected prior to administration of drug. 
20. Endocrine 
hormones 
include 
but 
are 
not 
limited 
to 
luteinizing 
hormone, 
follicle-stimulating hormone, estradiol, and testosterone (Section 9.2.7.1).  
 
 
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Page 90 of 143 
 
CONFIDENTIAL 
Table 6: 
Open-Label Treatment Period 4 (OLTP 4) 
Study Period 
 
Treatment Period 41 
  
In-Clinic2 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
 In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
 In-Clinic 
Outpatient 
Visit 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Disposition 
 
 
 
 
 
 
 
 
Clinic Admission 
X 
 
 
 
 
 
 
 
Clinic Discharge 
 
X 
 
 
 
 
 
 
Treatment and 
Medications 
 
 
 
 
 
 
 
 
Safety6 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
Height7 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
X 
 
X 
Tanner Staging7 
 
X 
 
X 
 
X 
 
X 
Physical Examination 
 
X 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Menstrual History, 
Pregnancy Status 
Reporting, and 
Confirmation of 
Contraception8 
 
X 
X 
X 
X 
X 
X 
X 
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Page 91 of 143 
 
CONFIDENTIAL 
Study Period 
 
Treatment Period 41 
  
In-Clinic2 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
 In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
 In-Clinic 
Outpatient 
Visit 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Laboratory Testing9 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
X 
 
X 
 
X 
Blood Chemistry 
 
X 
 
X 
 
X 
 
X 
INR/PTT, Platelets 
(Local Lab) 
 
 
 
 
 
 
 
X 
Pregnancy Test 
(WOCBP)8 
 
X 
 
X 
 
X 
 
X 
Urinalysis 
 
X 
 
X 
 
X 
 
X 
Efficacy9 
 
 
 
 
 
 
 
 
Fasting Triglycerides 
and Glucose10 
 
X 
 
X 
 
X 
 
X 
HbA1c 
 
X 
 
X 
 
X 
 
X 
Fructosamine 
 
X 
 
X 
 
X 
 
X 
Insulin/C-peptide10 
 
X 
 
X 
 
X 
 
X 
Lipid Panel10 
 
X 
 
X 
 
X 
 
X 
Urine Protein, 
Creatinine, Albumin 
 
X 
 
X 
 
X 
 
X 
Insulin Sensitivity 
Measurement 11,12 
 
 
 
 
 
 
 
X 
MMTT13 
X 
 
 
 
 
 
 
 
Weighted Mean 
Glucose Assessment14 
X 
 
 
 
 
 
 
 
Daily Appetite Hunger 
and Eating Behavior 
PRO 
X 
 
 
 
 
 
 
 
Sensation of Body 
Temperature PRO 
X 
 
 
 
 
 
 
 
SF-36 Questionnaire/ 
PEDs QOL15 
X 
 
 
 
 
 
 
 
Patient Global 
Impression of Severity 
X 
 
 
 
 
 
 
 
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Page 92 of 143 
 
CONFIDENTIAL 
Study Period 
 
Treatment Period 41 
  
In-Clinic2 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
 In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
 In-Clinic 
Outpatient 
Visit 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Global 
Impression of Change 
X 
 
 
 
 
 
 
 
Exit Interview 
 
 
 
 
 
 
 
X20 
Liver MRI (volume/fat 
content)16 
X 
 
 
 
 
 
 
X 
Whole body DXA16 
X 
 
 
 
 
 
 
X 
VCTE 
 
 
 
 
 
 
 
X16 
PK/Biomarker/Drug 
Concentration and 
ADA Samples9 
 
 
 
 
 
 
 
 
REGN4461 
Concentration Blood 
Sample 
 
X 
 
X 
 
X 
 
X 
ADA Sample 
 
X 
 
X 
 
 
 
X 
Endocrine Hormones19 
 
X 
 
X 
 
X 
 
X 
ANGPTL3, PCSK9, 
sLEPR 
 
X 
 
X 
 
X 
 
X 
 
 
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Page 93 of 143 
 
CONFIDENTIAL 
9.1.4. 
Footnotes for the Schedule of Events Table 6: Open-Label Treatment Period 4 
1. During the Open-Label Treatment Period, patients will be treated with study drug weekly. 
Study drug can be administered at the clinical site, by the site personnel or another 
healthcare professional at a remote location (eg, the patient’s home, school, or place of 
work), or self-administered/administered by a designated person.  
a. If medication is administered by site personnel or another healthcare professional, 
study 
personnel 
will 
monitor 
AEs, 
concomitant 
medications, 
menstrual 
history/pregnancy status reporting/confirmation of contraception weekly. Diabetes and 
lipid medication adjustments must occur at least once monthly (see footnote 5). 
b. If patients are self-administering study drug or the study drug is being administered by 
a designated person, site personnel must assess the patient for AEs, concomitant 
medications, 
menstrual 
history/pregnancy 
status 
reporting/confirmation 
of 
contraception, and diabetes and lipid medications adjustments must occur at least once 
monthly. These assessments may occur via telephone contact or in-site assessments, 
at the discretion of the investigator. 
2. In-clinic stay can begin within a ±2-day window. Patients will have the option to leave on 
the same day of study drug administration after being observed for at least 4 hours, 
provided no other procedures are required on that day. 
3. Training for study drug administration must be performed and documented for all patients 
who choose to self-administer REGN4461 during OLTP 4. Training is not required for 
patients who choose to not self-administer study drug. Training may occur at any time 
during OLTP 4 prior to first self-administration. If an appropriate designee (eg, parent or 
caregiver) will administer study drug to the patient during OLTP 4, this individual will 
undergo training as above.  
4. A medication administration diary will be provided to the patient/designee prior to 
initiation of self-administration or administration by a designated person such as a parent 
or caregiver. The diary must be completed upon each study drug administration. Training 
on the diary will be provided only to patients which will self-administer REGN4461. 
5. 
 
 
 
 
 
 
 
 
 
 
6. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated.  
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7. In individuals under 18 years of age, standing height should be recorded at least 
approximately every 3 months. Tanner staging for pubertal development should be 
performed at least approximately every 3 months until patient reaches Tanner stage 5. 
8. Menstrual events and pregnancy status of WOCBP will be monitored through the EOS 
visit. A urine pregnancy test will be performed locally (eg, point-of-care). A positive urine 
pregnancy test should be confirmed with a serum test. 
9. Study assessments should be performed, and blood samples are to be collected before study 
drug administration, unless otherwise indicated. For patients undergoing apheresis, study 
assessments are to be performed and blood samples are to be collected immediately before 
the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. At all visits, PK, ADA, and ANGPTL3/PCSK9/sLEPR samples should be 
collected prior to the administration of drug. 
10. Patients must be in a fasted state (after at least approximately a 12-hour fast). The duration 
of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
11. Patients must be in a fasted state (after at least approximately a 12-hour fast) for insulin 
sensitivity assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting.  
Insulin sensitivity will be measured by clamp at sites where a qualified and experienced 
facility and staff are available. Blood samples for the clamp will be collected for the 
analysis of glucose, insulin, C-peptide at following times: 2 baseline samples within 
30 minutes before starting insulin infusion and up to 4 samples during the 30 minutes long 
steady state. Additional samples will be analyzed for point of care glucose measures during 
insulin infusion, as outlined in the study manual. 
 
 
  
Patients will undergo an ITT at sites where a qualified and experienced ITT facility and 
staff are available. Patients with a history of seizure disorder should not undergo ITT.  
Blood samples will be collected for the analysis of glucose, insulin and C-peptide timed as 
follows: two baseline samples before starting insulin administration and at 5, 10, 15, 20 
and 30 minutes after starting the insulin administration. 
 
 
 
12. Patients presenting to sites without qualified and experienced facility and staff to perform 
a clamp or ITT will not undergo clamp or ITT evaluation. This procedure can be done 
within 
. 
13. Patients must be in a fasted state (after at least approximately a 12-hour fast) prior to 
MMTT assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Blood samples will be collected on the 
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days of the MMTT for the analysis of glucose, insulin, C-peptide, and TGs. Sampling times 
are as follows: 
• For glucose analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For insulin analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For C-peptide analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For TG analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
This procedure can be done within 3 days prior to day 168. 
14. Additional blood samples will be collected on the days of WMG assessments, timed as 
follows: (1) less than 30 minutes prior to lunch, (2) 120±10 minutes after lunch, (3) less 
than 30 minutes prior to dinner, (4) 120±10 minutes after dinner, and (5) 10 PM or bedtime. 
For patients who are discharged prior to completion of WMG blood draw assessments, the 
after-dinner and prior-to-bedtime assessments will not be required. This procedure must be 
done on the same day as MMTT. Blood samples will be analyzed for glucose, insulin and 
for C-peptide. 
15. SF-36 is to be completed by patients 18 years or older and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a self-administered PRO for 
patients ages 13 to 17 years (teen report) and for patients 12 years of age (child form). 
16. Liver volume and fat content MRI, whole body DXA may be performed up to 14 days prior 
to visit 37 and visit 65. VCTE may be performed up to 14 days prior to visit 65. These tests 
will only be performed at sites where these techniques are available. Patients may be 
required to fast at least 5 hours prior to an MRI scan. 
17.
 
 
 
 
 
18. Endocrine hormones include but are not limited to luteinizing hormone, follicle-
stimulating hormone, estradiol, and testosterone (Section 9.2.7.1). 
19. In the event that a patient has an early termination visit that occurs before week 8, the exit 
interview will be conducted during this visit.
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Table 7: 
Open-Label Treatment Period 5 (OLTP 5) 
  
Open-Label Period1 
Off-Drug Follow-up 
Period13 
  
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent 
Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of 
OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Treatment and 
Medications 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
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CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period13 
  
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent 
Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of 
OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Safety5 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs6 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
Height7 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
Weight 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
Tanner Staging7 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Physical 
Examination 
X 
  
  
  
X 
  
X 
  
  
  
X12 
  
  
  
X12 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period13 
  
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent 
Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of 
OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Menstrual 
History, 
Pregnancy 
Status 
Reporting, and 
Confirmation of 
Contraception8 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Laboratory 
Testing9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology 
X 
  
 X 
  
X 
  
X 
  
X 
  
X 
X 
X 
 
X 
Blood 
Chemistry 
X 
  
 X 
  
X 
  
X 
  
X 
  
X 
X 
X 
 
X 
Pregnancy Test 
(WOCBP)8 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
Serum 
Urinalysis 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
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 Page 99 of 143 
 
CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period13 
  
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent 
Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of 
OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Efficacy9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Fasting 
Triglycerides 
and Glucose10 
X 
  
X  
  
X 
  
X 
  
X 
  
X 
X 
X 
 
X 
HbA1c 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Lipid Panel10 
X 
  
  
  
X 
  
X 
  
X 
  
  
  
  
  
X 
Urine Protein, 
Creatinine, 
Albumin 
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
Liver MRI 
(volume/fat 
content)11 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Whole body 
DXA11 
 X 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
VCTE11 
 X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
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CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period13 
  
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-
Clinic 
Outpati
ent 
Visit or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent 
Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of 
OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
PK/Biomarker/
Drug 
Concentration 
and ADA 
Samples9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
REGN4461 
Concentration 
Blood Sample 
X 
  
X 
  
X 
  
X 
  
X  
  
X 
 
 
 
X 
ADA Sample 
X 
  
  
 
  
  
X 
  
  
  
X 
  
  
  
X 
ANGPTL3, 
PCSK9, sLEPR 
X 
  
X 
  
X 
  
X 
  
  
  
X 
 
 
 
X 
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9.1.5. 
Footnotes for the Schedule of Events Table 7: Open-Label Treatment Period 5 
1. During the open-label period, patients will be treated with study drug weekly. Study drug 
can be administered at the clinical site, by the site personnel or another healthcare 
professional at a remote location (eg, the patient’s home, school, or place of work), or 
self-administered/administered by a designated person. 
a. If medication is administered by site personnel or another healthcare professional, 
study personnel will monitor AEs, concomitant medications, menstrual 
history/pregnancy status reporting/confirmation of contraception weekly. Diabetes 
and lipid medication adjustments must occur at least once monthly (see footnote 4). 
b. If patients are self-administering study drug or the study drug is being administered 
by a designated person, site personnel must assess the patient for AEs, concomitant 
medications, menstrual history/pregnancy status reporting/confirmation of 
contraception, and diabetes and lipid medications adjustments must occur at least 
once monthly. These assessments may occur via telephone contact or in-site 
assessments, at the discretion of the investigator. 
2. Training for study drug administration must be performed and documented for all 
patients who choose to self-administer REGN4461 during OLTP 5. Training is not 
required for patients who choose to not self-administer study drug. Training may occur at 
any time during OLTP 5 prior to first self-administration. If an appropriate designee (eg, 
parent or caregiver) will administer study drug to the patient during OLTP 5, this 
individual will undergo training as above. 
3. A medication administration diary will be provided to the patient/designee prior to 
initiation of self-administration or administration by a designated person such as a parent 
or caregiver. The diary must be completed upon each study drug administration. Training 
on the diary will be provided only to patients which will self-administer REGN4461. 
4. 
 
 
 
 
 
 
 
 
 
 
 
5. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
6. Vital signs should be recorded 
 
 
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7. In individuals under 18 years of age, standing height should be recorded at least 
approximately every 3 months. Tanner staging for pubertal development should be 
performed at least every 3 months until patient reaches Tanner stage 5. 
8. Menstrual events and pregnancy status of WOCBP will be monitored through the EOS 
visit. A serum pregnancy test will be performed at the EOS visit a urine pregnancy test 
will be performed locally (eg, point-of-care). A positive urine pregnancy test should be 
confirmed with a serum test. 
9. Study assessments should be performed, and blood samples are to be collected before 
study drug administration, unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
10. Patients must be in a fasted state (after at least approximately a 12-hour fast). The 
duration of fasting may be shortened for patients with a documented clinical 
contraindication to fasting. 
11. Liver volume and fat content MRI and VCTE may be 
 
 Whole body DXA may be 
 
 If the patient had their 
 whole body DXA and/or 
liver MRI within 28 days prior to 
, the applicable procedure does not need to be 
repeated at 
. These tests will only be performed at sites where these techniques are 
available. Patients may be required to fast at least 5 hours prior to an MRI scan.  
12. Complete physical examination will be performed at the EOT and EOS visits and includes 
skin, head, eyes, nose, throat, neck, joints, lungs, heart, pulse, abdomen (including liver 
and spleen), lymph nodes, and extremities. A brief neurologic examination should also be 
performed. Limited physical examination will be performed on all remaining visits and 
includes lungs, heart, abdomen, and skin. 
13. Patients who complete the EOT visit associated with OLTP 5 and have secured access to 
continued REGN4461 treatment through other means, (eg, another Regeneron-sponsored 
clinical trial, compassionate use, or an expanded access program), may forgo any or all of 
the off-drug follow-up 
 and proceed to the EOS visit. These patients will be 
considered study completers. 
9.1.6. 
Early Termination Visit 
Patients who discontinue treatment before the end of the Open-Label Treatment Period 4 at week 
52 but who remain in the study will complete the early termination visit consisting of assessments 
listed for the EOT visit. After completing the early termination visit, patients who have 
discontinued study drug but who remain in the study will enter the off-drug follow-up period 
(Table 7).  In the off-drug follow-up period, patients will continue with monthly visits until 
16 weeks after last dose of study drug. Each of these monthly visits will consist of safety 
assessments, including laboratory tests. Patients who complete the EOT visit associated with 
OLTP 5 and have secured access to continued REGN4461 treatment through other means (eg, 
another Regeneron-sponsored clinical trial, compassionate use, or an expanded access program), 
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may forgo any or all of the off-drug follow-up visits 119-121 and proceed to the EOS visit. These 
patients will be considered study completers. 
9.1.7. 
Unscheduled Visits 
Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for 
follow-up of AEs, or for any other reason, as warranted. Additional blood samples may be 
collected if necessary. 
9.2. 
Study Procedures 
In circumstances where clinically indicated (eg, in patients with low body weight, anemia, or 
significant co-morbid illness), blood sample collections may be reduced or eliminated to maintain 
patient safety and comply with adequate blood volume considerations. A prioritization list for 
samples to be collected will be provided in the laboratory manual. For example, safety laboratory 
and PK samples will be prioritized over other blood sample collections.  
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population: medical history, demographics, HIV serology, and 
hepatitis testing (HBsAg, HCV).  
9.2.2. 
Safety Procedures 
9.2.2.1. 
Vital Signs 
Vital signs, including temperature, blood pressure, pulse, and respiration will be collected after the 
patient has been sitting or supine position at time points according to Table 3, Table 4, Table 5, 
Table 6, and Table 7. 
9.2.2.2. 
Physical Examination, Body Weight, Height, and Tanner Stages 
A thorough and complete physical examination must be performed at screening (visit 1), day 1 
(visit 8), end of the treatment (EOT), and end of study visits (EOS). Complete physical 
examination will include examination of skin, head, eyes, nose, throat, neck, joints, lungs, heart, 
pulse, abdomen (including liver and spleen), lymph nodes, and extremities, as well as a brief 
neurologic examination. Limited physical examination will include lungs, heart, abdomen, and 
skin and care should be taken to examine and assess any abnormalities that may be present. 
Physical exam will be performed according to Table 3, Table 4, Table 5, Table 6, and Table 7 and 
may be limited in scope if appropriate as indicated by the patient’s medical history.  
Physical exams for the screening visit may be conducted on a different day from the initial 
screening visit, as long as they are conducted within the screening window.  
Body weight will be measured at time points according to Table 3, Table 4, Table 5, Table 6, and 
Table 7. Body weight should be obtained with the patient wearing undergarments or very light 
clothing and no shoes. The same type/model of scale should be used throughout the study. 
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In individuals under 18 years of age, standing height should be recorded at least every 3 months 
using a stadiometer at time points according to Table 3, Table 4, Table 5, Table 6, and Table 7. 
Patients should be instructed to remove footwear and stand upright with their heels together. 
Tanner staging for pubertal development should be performed at least every 3 months at time 
points according to Table 4, Table 5, Table 6, and Table 7. If the patient reaches Tanner stage 5, 
this assessment will be no longer performed. Whenever possible, the same trained health care 
professional will conduct the Tanner staging at each assessment. 
9.2.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 3, Table 4, Table 5, 
and Table 6. 
Twelve-lead ECGs will be collected after the patient has been in the supine position for at least 10 
minutes. The electrodes should be positioned in the same location, as much as possible, for each 
ECG recording. 
The ECG will be interpreted locally by the investigator. If new and/or clinically significant changes 
in ECG parameters are observed, a repeat ECG should be immediately performed for confirmation 
before making any decision for the concerned patient. Any clinically significant abnormality 
should be documented as an AE/SAE, as applicable. 
Heart rate will be calculated from the ventricular rate (or RR interval) and recorded. The PR or 
PQ, QRS, and QT (QTcF) intervals will be recorded. The ECG recordings and reports will be 
retained with the source. 
9.2.2.4. 
Menstrual History, Pregnancy Status Reporting, and Confirmation of 
Contraception 
Assessment of menstrual cycle history for WOCBP will be conducted at baseline and at the visits 
specified in Table 3, Table 4, Table 5, Table 6, and Table 7 to identify any changes in occurrence, 
frequency, or duration following study drug treatment.  
9.2.2.5. 
Hypoglycemia Monitoring 
It is recommended that all diabetic patients prescribed insulin or insulin secretagogues 
(eg, sulfonylureas or glinides) should be instructed to routinely monitor finger stick blood glucose 
using a glucometer. Patients who have been instructed by their treating physicians to routinely 
self-monitor glucose using a glucometer will be asked to enter glucose values into an electronic 
patient diary. The purpose of the electronic patient diary is to facilitate prompt interaction with 
their study site if low blood glucose values are recorded. Low blood glucose values will trigger an 
alert for the patient to call the site and the site will be automatically notified to call the patient. 
This monitoring is not intended to replace protocol adverse events of special interest and other 
safety reporting procedures. 
9.2.3. 
Laboratory Testing 
Detailed instructions for sample collection, along with the location for analysis, are in the 
laboratory manual provided to study sites.  
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Samples for laboratory testing will be collected at visits according to Table 3, Table 4, Table 5, 
Table 6, and Table 7. On study visit days during which study drug will be administered, the 
laboratory samples are to be collected before the dose of study drug unless otherwise stated.  
Fasting is only required for laboratory tests described as “fasting” (ie, fasting TG, fasting lipid 
panel, and fasting glucose).  
For patients undergoing 
 INR/PTT and platelets will be done locally. Additional 
laboratory testing may be performed and analyzed locally, per local standard practice or local 
regulations 
. 
Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Uric acid 
Chloride 
Blood urea nitrogen (BUN) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
Magnesium 
Phosphorus 
Lactate dehydrogenase (LDH) 
 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urine Studies  
 
 
 
Endocrine Laboratory Tests 
Luteinizing hormone 
Estradiol 
Testosterone 
Protein 
Glucose 
pH 
Bilirubin 
Specific gravity 
Leukocytes 
Ketones 
Nitrite 
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Follicle-stimulating hormone 
Other Laboratory Tests 
HbA1c 
Fructosamine 
Leptin 
Pregnancy test (serum/urine) 
Hepatitis B surface antigen (sAg) 
HIV (Ab) 
INR 
PTT 
Total Protein/Creatinine/Albumin 
(Urine) 
 
Hepatitis C (Ab) 
 
Lipid Panel 
LDL-C  
HDL-C 
NMR lipoprotein analysis 
Apolipoprotein B 
Total Cholesterol  
Triglycerides 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the medical/study director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.4.5. 
9.2.4. 
Efficacy Procedures 
9.2.4.1. 
Fasting Triglycerides 
Samples for fasting TG will be collected at visits according to Table 3, Table 4, Table 5, Table 6, 
and Table 7. 
Samples should be collected after the patients have fasted for at least approximately 12 hours. The 
duration of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
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9.2.4.2. 
Fasting Glucose 
Samples for fasting glucose will be collected at visits according to Table 3, Table 4, Table 5, 
Table 6, and Table 7. 
Samples should be collected after the patients have fasted for at least approximately 12 hours. 
The duration of fasting may be shortened for patients with a documented clinical 
contraindication to fasting. 
9.2.4.3. 
Hemoglobin A1C 
Hemoglobin A1C will be collected at visits according to Table 3, Table 4, Table 5, Table 6, and 
Table 7 (see Section 9.2.3). 
9.2.4.4. 
Fructosamine 
Samples for fructosamine will be collected at visits according to Table 3, Table 4, Table 5, and 
Table 6. 
9.2.4.5. 
Insulin/C-peptide 
Samples for insulin/C-peptide will be collected at visits according to Table 3, Table 4, Table 5, 
and Table 6. 
Samples should be collected after the patients have fasted for at least approximately 12 hours. The 
duration of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
9.2.4.6. 
Lipid Panel 
Samples for lipid panel LDL-C, HDL-C, total cholesterol, and Apolipoprotein B will be collected 
at visits according to Table 3, Table 4, Table 5, Table 6, and Table 7. For patients with 
TG >400 mg/dL, direct LDL-C measurement will be used. Lipoproteins will be analyzed by NMR.  
Samples should be collected after the patients have fasted for at least approximately 12 hours. The 
duration of fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
9.2.4.7. 
Urine Protein, Creatinine, and Albumin 
Samples for urine protein, creatinine, and albumin will be collected at visits according to 
Table 3, Table 4, Table 5, Table 6, and Table 7. 
9.2.4.8. 
Insulin Sensitivity Measurement 
Insulin sensitivity will be assessed using clamp technique or ITT per site’s capability, at visits 
according to Table 3, Table 4, Table 5, and Table 6. Patients with a history of seizure disorder 
should not undergo ITT. Assessments will be performed in the fasted state. The duration of fasting 
may be shortened for patients with a documented clinical contraindication to prolonged fasting. 
Additional details on both procedures are provided in the study manual. The blood samples drawn 
during insulin sensitivity procedures may be decreased if clinically indicated, eg, in patients with 
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low body weight, anemia, or significant co-morbid illness. Details for blood sample assessments 
in at-risk patient populations will be provided in the study manual. 
9.2.4.9. 
Mixed Meal Tolerance Test 
An MMTT will be conducted at the time points specified in Table 4, Table 5, and Table 6. Blood 
samples will be collected by study personnel before and after the morning MMTT for the analysis 
of glucose, insulin, C-peptide, and TGs according to the sampling schedule as shown in Table 4, 
Table 5, and Table 6. Patients must be in a fasted state (after at least approximately a 12-hour fast) 
for insulin sensitivity assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Additional details on procedure are provided in 
the study manual.  
9.2.4.10. Weighted Mean Glucose 
Samples for WMG assessment will be collected throughout the day during in-clinic visits 
according to Table 4, Table 5, and Table 6. Additional details on the WMG assessment procedures 
are provided in the study manual. 
9.2.4.11. Assessment of Body Composition 
Patients will undergo whole body DXA scans to examine body composition. DXA is extensively 
used in clinical whole-body skeletal densitometry. Total examination times are brief (~6 to 
7 minutes) and ionizing radiation doses are minimal below 0.05 mSv.  
Whole body DXA imaging will be performed per the schedule outlined in Table 3, Table 4, 
Table 5, Table 6, and Table 7. Whole body DXA scans will be performed only at sites with whole 
body DXA capability. 
9.2.4.12. Assessment of Hepatic Fat Content and Liver Size** 
Patients will undergo MRI scans to examine hepatic volume and fat content. Liver MRI will be 
performed only at sites with technical capability. Patients for whom MRI is contraindicated 
(eg pacemaker) are still eligible to participate in the study but will not undergo MRI scans.  
MRI imaging will be performed per the schedule outlined in Table 3, Table 4, Table 5, Table 6, 
and Table 7. 
Patients may be required to fast at least 5 hours prior to an MRI scan. The duration of fasting may 
be shortened for patients with a documented clinical contraindication to fasting. Details of the MRI 
imaging protocol are included in the imaging manual.  
 
 
 
**The imaging scans in this study are performed for research purposes only. These research 
imaging scans are not intended to provide diagnosis of any disease. The sponsor will not provide 
any incidental findings to the study patient, principal investigator, any other physician treating the 
study patient or any other third party. If a site has a policy regarding return of research findings 
(incidental or otherwise), or a country has local regulations regarding these findings, or if an Ethics 
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Committee or Institutional Review Board requires return of said findings, the principal investigator 
is responsible for complying with these requirements. 
9.2.4.13. Assessment of Liver Stiffness by Vibration-Controlled Transient Elastography 
(VCTE) 
Vibration-controlled transient elastography (eg, FibroScan®) uses transient elastography to 
measure the stiffness of the liver. Some GLD patients with NASH may have increased liver 
stiffness, reflective of an accumulation of fibrotic scar tissue. VCTE is used for assessing liver 
cirrhosis and/or advanced-stage liver fibrosis. Liver stiffness will only be assessed at sites with 
VCTE capability (Table 3, Table 6, and Table 7). 
9.2.5. 
Patient-Reported Outcome Measures 
9.2.5.1. 
Daily Appetite and Eating Behavior PRO  
This PRO measure instrument is being developed specifically for this trial in order to assess 
hunger, cravings, eating behaviors, and emotional aspect of eating among patients with 
lipodystrophy. The development of the diary is in accordance with the Food and Drug 
Administration’s (FDA’s) guidance on PRO development.  
Patients will complete the PRO assessments daily, unless otherwise noted in Table 3, Table 4, 
Table 5, and Table 6. Patients who are enrolled prior to approval and availability of the PRO 
instrument will complete the daily PRO assessment once it becomes available. Patients who are 
incapable of completing the PRO (eg, illiteracy) are still eligible to participate in the study but will 
not complete PRO assessments. 
9.2.5.2. 
Questions Assessing Sensation of Body Temperature 
Self-administered questions developed specifically for this trial will assess the patient’s sensation 
of body temperature. Patients will be asked to rate how often they felt uncomfortably cold in the 
past 24 hours and how often they felt uncomfortably hot in the past 24 hours. Patients will complete 
this PRO assessments as noted in Table 3, Table 4, Table 5, and Table 6.  
9.2.5.3. 
Short Form – 36 Survey 
The Short Form – 36 Survey (SF-36) is a 36-item self-administered PRO measure assessing health-
related quality of life (HRQoL) concepts relevant across age, disease, and treatment group. The 
SF-36 will be completed by patients ages 18 years of age and older. The SF-36 assesses physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, 
and mental health. Patients answer questions assessing these concepts over the previous week 
using 3-, 5-, or 6-point Likert scales; scores range from 0 to 100, with higher scores indicating 
better health. The past-week recall has been compared to the 4-week recall and is shown to have 
comparable properties (Keller, 1997). The SF-36 is one of the most widely used and studied PRO 
measures, with good psychometric properties documented across different populations (Table 3, 
Table 4, Table 5, and Table 6).  
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9.2.5.4. 
Pediatric Quality of Life Inventory Generic Core Scales  
The Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales is a measure 
assessing HRQoL in children and adolescents. The PedsQL™ will be used to measure HRQoL in 
patients ages 12 to 17. The PedsQL™ is a 23-item measure that assesses physical functioning, 
emotional functioning, social functioning, and school/work/studies functioning. The instructions 
for PedsQL™ ask how much of a problem each item has been over the past 7 days on a 5-point 
response scale, ranging from never a problem (0) to almost always a problem (4). The measure 
will be a self-administered PRO for patients ages 13 to 17 years (teen report) and for patients 
12 years of age (child form). The items for each of the teen and child forms for patients are 
essentially identical, differing primarily in the use of developmentally appropriate language. Items 
are reverse-scored and linearly transformed to a 0 to 100 scale so that higher scores indicate better 
HRQoL. The total scale score is computed as the sum of all the items over the number of items 
answered on individual scales (Table 3, Table 4, Table 5, and Table 6). The PedsQL™ was 
developed using focus groups, cognitive interviews, pre-testing, and field testing measurement 
development protocols (Varni, 1999) and has demonstrated validity, reliability, ability to detect 
change, and responsiveness (Varni, 2001) (Varni, 2002) (Varni, 2003) (Desai, 2014). 
9.2.5.5. 
Patient Global Impression of Severity 
Patient Global Impression of Severity (PGIS) items are self-administered PRO questions assessing 
the patient’s perception of the overall severity of the symptoms of their disease and/or of a specific 
symptom of their disease. At study visits (see Table 3, Table 4, Table 5, and Table 6), patients will 
be asked to rate the severity of specific symptoms of lipodystrophy (ie hunger, cravings, eating 
behaviors) on a Likert scale ranging from “not at all” to “very much.”  
9.2.5.6. 
Patient Global Impression of Change 
Patient Global Impression of Change (PGIC) items are self-administered PRO questions assessing 
the patient’s perception of the change in overall severity of the symptoms of their disease and/or 
of a specific symptom of their disease, compared to the start of the study (Table 6). At weeks 8, 
16 and 24 patients will be asked to rate the severity of specific symptoms of lipodystrophy 
compared to before the start of the study on a 7-point Likert scale ranging from “much better” to 
“no change” to “much worse.” 
9.2.5.7. 
Exit Interview in Relation to Hunger and Eating Behavior PROs 
At the time point of the primary endpoint 
 
 patients will be interviewed to ensure the Hunger 
PRO is fit-for-purpose under the context of use for GLD patients (Table 6). Results from exit 
interviews will also be used to contextualize findings on the COA assessments. Each interview 
will last approximately 60 minutes and will be conducted by trained external interviewers 
following a semi-structured interview guide.  
 
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9.2.6. 
Pharmacokinetic/Drug Concentration and Immunogenicity Samples 
9.2.6.1. 
REGN4461 Concentration Measurements 
Samples for REGN4461 will be collected during DBTP 1 at the visits listed in Table 4, during 
DBTP 2 and 3 at the visits listed in Table 5, and during OLTP 4 and 5 at the visits listed in Table 6 
and Table 7. All samples will be collected prior to dose administrations with the exception of IV 
loading dose samples, which will be collected both prior to and after dose administrations, as 
described in table footnotes. Any unused samples may be used for future biomarker research for 
patients who consent.  
9.2.6.2. 
Soluble LEPR (sLEPR) 
Leptin circulates in the bloodstream both as a free entity and also can be bound to an sLEPR, which 
is generated via shedding of the LEPR ectodomain (Sinha, 1996) (Lammert, 2001). Soluble LEPR 
is present in circulation of healthy subjects and patients with disease. It is a non-signaling form of 
the leptin receptor that is able to bind to leptin and may regulate its bioavailability (Lou, 2010). It 
is possible that REGN4461 bioavailability might be influenced by sLEPR levels. It is also possible 
that sLEPR levels might be influenced by REGN4461, either through increasing sLEPR stability 
or shedding from LEPR. Therefore, sLEPR will be assessed at time points noted in Table 3, 
Table 4, Table 5, Table 6, and Table 7. 
9.2.6.3. 
Circulating Biomarkers for Pharmacodynamic Assessments 
Angiopoietin-Like Protein 3 (ANGPTL3) 
Angiopoietin-like protein 3 is an endogenous inhibitor of lipoprotein lipase, which regulates 
circulating levels of TG (Tikka, 2016). Levels of ANGPTL3 can be regulated by feeding, leptin, 
and/or insulin (Minicocci, 2012) (Nidhina Haridas, 2015). Levels of ANGPTL3 are elevated in 
patients with lipodystrophy and are reduced after treatment with metreleptin (Muniyappa, 2017). 
The reduction of ANGPTL3 following metreleptin treatment might affect lipase clearance of TG-
rich lipoproteins. Therefore, ANGPTL3 might be a PD marker of REGN4461 activity, increasing 
leptin receptor signaling. ANGPTL3 will therefore be assessed at time points noted in Table 3, 
Table 4, Table 5, Table 6, and Table 7.  
Total Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) 
Proprotein convertase subtilisin/kexin type 9 is a convertase enzyme that promotes degradation of 
the LDL receptor, resulting in reduced LDL clearance. Gain-of-function mutations in PCSK9 are 
associated with elevated LDL-C levels, while loss-of-function mutations are associated with lower 
serum LDL-C and protection from cardiovascular risk. PCSK9 inhibitors have been approved for 
treating hypercholesterinemia and have been efficacious at reducing serum cholesterol levels and 
decreasing the rate of major cardiovascular events. Female GLD patients had a reduction in plasma 
PCSK9 levels after 4 to 6 months of metreleptin therapy (Levenson, 2016). PCSK9 might be a 
mechanistic marker indicative of the lipid-lowering effects of REGN4461. Total PCSK9 will 
therefore be assessed at time points noted in Table 3, Table 4, Table 5, Table 6, and Table 7. 
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9.2.6.4. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 3, Table 4, Table 5, 
Table 6, and Table 7. 
 
9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures 
9.2.7.1. 
Endocrine Hormones 
Lipodystrophy patients have disruption in endocrine hormone regulation that can result in 
amenorrhea and hyperandrogenism. Hyperandrogenism and amenorrhea are corrected in a subset 
of individuals on metreleptin therapy. Metreleptin therapy resulted in lower testosterone levels 
within 4 months of therapy and restored regular menstrual cycles in patients with irregular 
menstrual cycles or primary amenorrhea (Musso, 2005). Endocrine levels will be assessed at time 
points noted in Table 3, Table 4, Table 5, and Table 6. Endocrine hormones include, but are not 
necessarily limited to, luteinizing hormone, follicle-stimulating hormone, estradiol, and 
testosterone. 
9.2.7.2. 
Immunophenotyping 
In patients with congenital GLD, infections have been described as one of the major causes of 
mortality, which suggests a compromised immune system (Lima, 2018). As leptin signaling is 
associated with inducing immune cell activation (Dayakar, 2016), it is possible that REGN4461 
treatment in patients with lipodystrophy might affect, in a positive manner, immune cell numbers 
or function. To explore this possibility, whole blood will be collected for performing flow 
cytometry analysis of immune cell populations, including T cell subsets (Table 4 and Table 5). 
9.2.8. 
 
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9.2.9. 
Future Biomedical Research (Optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2.9.1. 
Pharmacogenomic Analysis (Optional) 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
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10. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
10.1. 
Obligations of Investigator 
The investigator must promptly report to the IRB/EC all unanticipated problems involving risks to 
patients, according to local regulations. This may include death from any cause and all SAEs 
related to the use of the study drug. It is recommended that all SAEs be reported to the IRB/EC, 
according to local regulations. 
10.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IRBs/ECs, as appropriate, and to the 
investigators in a blinded manner.  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected. Any worsening of or new onset of 
symptoms related to GLD which occur during the screening/washout period prior to study drug 
administration will be considered expected. 
In addition, the sponsor will report in all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and ECs/IRBs as appropriate. 
10.3. 
Definitions 
10.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
10.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger) 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization – 
In-patient hospitalization is defined as admission to a hospital (any duration), or an 
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emergency room stay for longer than 24 hours. Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event 
or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity – (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event – Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse)  
Note: In addition to the criteria above, a new diagnosis or progression of a malignancy in patients 
enrolled in the study will also be considered an SAE. 
Criteria for reporting SAEs must be followed for these events. See Section 10.4 for more 
information on recording and reporting SAEs. 
10.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 10.4.3). AESI for this study include: 
• Hypoglycemia, defined as blood glucose <54 mg/dL.  
• New onset diabetes mellitus (NODM) 
For patients with no diabetes at baseline: 
a. Two values of fasting (≥8 hr) plasma glucose ≥126 mg/dL (7.0 mmol) during 
treatment period 
OR 
b. Two values of HbA1c ≥6.5% (48 mmol/mol) during treatment period 
Patients who meet either of these criteria during the PBO run-in period will be 
considered to have diabetes at baseline. 
• Hyperglycemia requiring treatment: this is defined as: 
a. HbA1c ≥10.5% AND increase in HbA1c of ≥1.5% from baseline value 
OR 
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b. Fasting glucose ≥250 mg/dL on 2 occasions including symptoms consistent with 
hyperglycemia AND increase in fasting glucose >50 mg/dL above baseline 
• Development of new or worsening of autoimmune disease 
• Moderate or severe hypersensitivity reactions 
10.3.4. 
Infusion Reactions 
 
 
 
10.4. 
Recording and Reporting Adverse Events  
10.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study.  
Information on follow-up for AEs is provided in Section 10.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 10.4.5. 
10.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  
Information not available at the time of the initial report must be documented in a follow-up report. 
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
• SAE with an onset within 30 days of the end of study or within 112 days of last study 
drug administration if the patient early-terminated from the study – the SAE will be 
reported to the sponsor. The investigator should make every effort to obtain follow-up 
information on the outcome until the event is considered chronic and/or stable. 
• SAE with an onset day greater than 30 days from the end of study/early termination 
visit – only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor. The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
10.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
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Symptomatic Overdose of Study Drug: Accidental or intentional overdose of at least 2 times the 
intended dose of study drug within the intended therapeutic window, if associated 
with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study patient, or female partner of a male study 
patient, during the study or within 112 days of the last dose of study drug. Any 
complication of pregnancy affecting a female study patient or female partner of a 
male study patient, and/or fetus and/or newborn that meets the SAE criteria, must 
be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: All AESIs, serious and nonserious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, 
per Section 10.4.2. Adverse events of special interest for this study are detailed in 
Section 10.3.3.  
10.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
10.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• The test result is associated with accompanying symptom(s), and/or 
• The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• The test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event that the investigator feels an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 10.5.1. 
10.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
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10.5. 
Evaluation of Severity and Causality 
10.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
Mild: Does not interfere in a significant manner with the patient’s normal functioning level. It 
may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms but may 
be given because of personality of the patient. 
Moderate: Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptom may be needed. 
Severe: Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health. Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild: Mild transient reaction; infusion interruption not indicated; intervention not indicated 
Moderate: Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated 
for ≤24 hours 
Severe: Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for 
clinical sequelae; life-threatening consequences; urgent intervention indicated; death 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade): 
Mild: Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate: Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe: Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
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10.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the blinded investigator and will be a 
clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
study drug. 
Related: There is a reasonable possibility that the event may have been caused by the study 
drug. 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below. 
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
• Due to external causes such as environmental factors or other treatment(s) being 
administered 
• Due to the patient’s disease state or clinical condition 
• Does not follow a reasonable temporal sequence following the time of administration 
of the dose of study drug 
• Does not reappear or worsen when dosing with study drug is resumed 
• Is not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
• Could not be explained by environmental factors or other treatment(s) being 
administered 
• Could not be explained by the patient’s disease state or clinical condition 
• Follows a reasonable temporal sequence following the time of administration of the 
dose of study drug  
• Resolves or improves after discontinuation of study drug  
• Reappears or worsens when dosing with study drug  
• Is known or suspected to be a response to the study drug based upon preclinical data or 
prior clinical data 
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Relationship of Adverse Events to Study Conduct: 
The relationship of AEs to study conduct will be assessed by the blinded investigator and will be 
a clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by study 
conduct. 
Related: There is a reasonable possibility that the event may have been caused by study 
conduct. 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below. 
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study conduct? 
No: 
• Due to external causes such as environmental factors or other treatment(s) being 
administered 
• Due to the patient’s disease state or clinical condition 
• Does not follow a reasonable temporal sequence following the course of the study 
• Does not reappear or worsen when dosing with study participation is resumed 
Yes: 
• Could not be explained by environmental factors or other treatment(s) being 
administered 
• Could not be explained by the patient’s disease state or clinical condition 
• Follows a reasonable temporal sequence following the course of the study 
• Resolves or improves after discontinuation from study participation 
• Reappears or worsens when study participation is resumed 
10.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical/study director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, Global Patient Safety; Biostatistics and Data Management). Safety monitoring will be 
performed on an ongoing basis (eg, individual review of SAEs) and on a periodic, cumulative 
aggregate basis. 
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10.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure and has a reasonable, suspected causal 
relationship to the study drug). 
11. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study. The SAP may be revised during the study 
to accommodate amendments to the clinical study protocol and to make changes to adapt to 
unexpected issues in study execution and data that may affect the planned analyses. The final SAP 
will be issued before the database is locked. 
The first-step analysis will be conducted as soon as all patients have been randomized and all data 
through week 36 has been entered, cleaned and locked. The first-step analysis will be conducted 
on all randomized patients who receive study treatment. These statistical analyses will include the 
primary and secondary endpoints collected during the double-blind period, as well as the 
open-label week 36 visit in OLTP 4. 
The second-step analysis will be conducted as soon as all patients have been randomized and all 
data through week 56 has been entered, cleaned and locked. The second-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include pharmacokinetic and safety measures. 
The third-step analysis will be conducted as soon as all patients have been randomized and all data 
through week 64 has been entered, cleaned and locked. The third-step analysis will be conducted 
on all randomized patients who receive study treatment. These statistical analyses will include 
efficacy, pharmacokinetic and safety measures. 
The fourth-step analysis will be conducted as soon as all patients have been randomized and all 
data through week 76 has been entered, cleaned and locked. The fourth-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include efficacy, pharmacokinetic and safety measures. 
The fifth-step and final analysis will be conducted at the end of the study, and will consist of the 
final analysis for efficacy, pharmacokinetic and safety measures. 
Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
No formal statistical hypothesis will be tested. This study will assess the effects of REGN4461 on 
glycemic parameters in a subset of patients with elevated baseline HbA1c (≥7%) and fasting serum 
TG in a subset of patients with elevated baseline TG (≥250 mg/dL). HbA1c at screening visit 
(HbA1c ≤8% vs. HbA1c >8%) is the stratification factor for patient randomization. 
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11.2. 
Justification of Sample Size 
The size of the study is determined by feasibility assessments. Due to the limited number of 
patients not being treated with metreleptin in the world, up to 26 patients will be enrolled for the 
study, with approximately a 20% dropout rate. The primary objective is estimating the treatment 
effect of REGN4461 on glycemic and lipids parameters.  
Metreleptin demonstrated a 2% drop in HbA1c (standard deviation [SD]=1.5%) and a 50% drop 
in fasting TG (SD=40%) from baseline to month 4 (Myalepta, 2018) (FDA, 2013). As a 
conservative treatment effect estimation for 8 weeks, the anticipated drop in HbA1c is 1.5%. The 
change in fasting TG is expected to be the same at week 8 as at week 16. With 20 patients 
completing the study (10 patients per study arm, assuming approximately a 20% dropout rate from 
26 patients), the minimal detectable change (MDC) and power for the study are provided in Table 8 
as below, for a 2-sided alpha of 0.05 test.  
Table 8: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG Separately (N=20, 10 Treated vs. 10 Placebo, Assuming 
Approximately 20% Dropout Rate from 26 Patients) 
 
Number of 
Treated 
Patients 
Within-
Group 
Between-
Group 
Within-Group 
Between-Group 
 
 
MDC (half of the confidence 
interval), alpha=0.05 
Power for a 1.5% reduction in 
HbA1c, 60 mg/dL reduction in 
fasting glucose/MWG, and 50% 
reduction in fasting TG  
HbA1c* 
10 
1% 
1.4% 
80% 
56% 
Fasting 
Glucose* 
10 
53 mg/dL 
70 mg/dL 
60% 
38% 
WMG& 
10 
40 mg/dL 
53 mg/dL 
84% 
60% 
Fasting 
TG* 
10 
28% 
37% 
93% 
75% 
*Assuming SD for HbA1c is 1.5%, fasting glucose is 76 mg/dL, and fasting TG is 40% (FDA, 2013).  
& SD for WMG is 75% of SD for fasting glucose (57 mg/dL). 
If the glycemic and lipid subsets for the primary analysis have fewer patients with abnormal TGs 
or fasting glucose values, the table below (Table 9) provides minimal detectable change and power 
for the subset analysis. 
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Table 9: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG in the Subset Analyses (N=20, Assuming Approximately 
20% Dropout Rate from 26 Patients) 
  
Number of 
Treated 
Patients in the 
Subset* 
Within-
Group 
Between-
Group 
Within-
Group 
Between-
Group 
  
MDC (half of the confidence 
interval), alpha=0.05 
Power for a 1.5% reduction in 
HbA1c, 60 mg/dL reduction 
in fasting glucose/WMG and 
50% reduction in fasting TG 
HbA1c$ 
5 
1.7% 
2.1% 
40% 
28% 
Fasting 
Glucose$ 
5 
88 mg/dL 
107 mg/dL 
27% 
19% 
WMG$ 
5 
66 mg/dL 
80 mg/dL 
43% 
31% 
Fasting TG$ 
9 
30% 
39% 
90% 
70% 
*Assuming 50% of the patients have elevated baseline HbA1c and 90% of the patients have elevated baseline TG. 
$Assuming SD for HbA1c is 1.5%, fasting glucose is 76 mg/dL, and fasting TG is 40% (FDA, 2013). SD for WMG 
is 75% of SD for fasting glucose (57 mg/dL). 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients who received any study drug and have 
at least 1 post-baseline assessment; it is based on the treatment allocated (as randomized). Efficacy 
endpoints will be analyzed using the FAS. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK population includes all treated patients who received any study drug and who had a 
qualified result for drug concentration on day 1 (baseline) and at least 1 non-missing result 
following the first dose of study drug. 
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11.3.4. 
Anti-Drug Antibody Analysis Sets 
The ADA population includes all treated patients who received any study drug and who had at 
least 1 non-missing ADA result following the first dose of study drug. Patients will be analyzed 
according to the treatment actually received. 
11.3.5. 
Glycemic Analysis Set 
The glycemic analysis set includes all patients who are in the FAS and have elevated baseline 
HbA1c (HbA1c ≥7%). 
11.3.6. 
Triglyceride Analysis Set 
The triglyceride analysis set includes all patients who are in the FAS and have elevated baseline 
fasting TG (TG ≥250 mg/dL). 
11.3.7. 
MRI Analysis Set 
The MRI analysis set includes all patients who are in the FAS and eligible for the MRI test (some 
patients are not eligible for the MRI due to MRI contraindications or some sites do not have the 
technical capability to perform liver MRI).  
11.3.8. 
Clamp Analysis Set 
The clamp analysis set includes all patients who are in the FAS and eligible for the clamp test 
(some patients are at the sites where there is no clamp capability).  
11.3.9. 
Clamp Glycemic Analysis Set 
The clamp glycemic analysis set includes all patients who are in the clamp analysis set and have 
elevated baseline HbA1c (HbA1c ≥7%). 
11.3.10. 
Insulin-Tolerance Test Analysis Set 
The ITT analysis test includes all patients who are in the FAS, are not eligible for the clamp test, 
and are eligible for the qualified ITT (some patients are at the sites without clamp capability, but 
which have qualified ITT).  
11.3.11. 
Insulin-Tolerance Test Glycemic Analysis Set 
The ITT glycemic analysis set includes all patients who are in the ITT analysis set and have 
elevated baseline HbA1c (HbA1c ≥7%). 
11.3.12. 
 
 
  
11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, median, SD, minimum, and maximum.  
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For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: met the inclusion criteria regarding the target 
indication and signed the informed consent form (ICF) 
• The total number of randomized patients: received a randomization number 
• The total number of patients who completed OLTP 4 (defined as at least 51 weeks of 
study treatment exposure and week 52 visit performed) 
• The total number of patients who completed OLTP 5 (defined as at least 103 weeks of 
study treatment exposure and week 104 visit performed) 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patient prematurely discontinued from treatment, along with reasons for 
discontinuation 
• The total number of patients in each analysis set  
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment arm 
(Treatment Arm A or Treatment Arm B), and by all patients combined.  
11.4.3. 
Efficacy Analyses 
The goal of the study is to estimate the effect of REGN4461 on metabolic parameters in patients 
with GLD. Comparisons to baseline and between-group comparison will be provided with nominal 
p-values. There will be no statistical hypothesis testing and no multiplicity will be applied. 
Logarithm transformation will be performed to normalize the fasting TG. 
11.4.3.1. Primary Efficacy Analysis 
The primary objective is estimating the treatment effect of REGN4461 on improving metabolic 
abnormalities. The glycemic endpoint will be run in the glycemic subset of patients (subset with 
baseline HbA1c ≥7%), and fasting TG endpoint will be run in the TG subset of patients (subset 
with baseline TG ≥250 mg/dL). 
For primary endpoints, fasting TG, fasting glucose, HbA1c, and WMG, the study assesses the 
treatment effect of REGN4461 from baseline to week 8 for patients receiving REGN4461 in the 
DBTP 1 (within-group comparison) and for all patients (between-group comparison). Published 
data (Oral, 2002) suggest that fasting glucose and fasting TG had the greatest improvement within 
the first 2 months following metreleptin initiation.  
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Summary statistics including mean change from baseline, standard error (SE), corresponding 95% 
confidence interval, and nominal p-value will be provided by treatment group (REGN4461 or 
placebo at the DBTP 1), using a mixed effect repeated measurement model (MMRM), which will 
account for the missing data. The model includes the factors (fixed effects) for treatment, week, 
and treatment-by-week interaction. Relevant baseline HbA1c and/or TG will be included as a 
continuous covariate. An unstructured covariance structure will be used (if that does not converge, 
then structured covariance structures such as autoregressive heterogeneous [ARH] will be 
assessed). If the model does not converge with the MMRM, analysis of covariance (ANCOVA) 
will be used to estimate the treatment effect of REGN4461. Additional details will be provided in 
the SAP.  
Mean absolute value changes in WMG (mg/dL), HbA1c (%), fasting glucose (mg/dL), and mean 
percent change in fasting TG will be summarized by treatment group at the DBTP 1. Mean changes 
(±SE) will be plotted over time by the treatment group. A spaghetti plot will be provided for 
primary endpoints by the treatment group.  
In addition, posterior probability that the improvement in each of the primary endpoints is greater 
than zero will be computed at week 8 separately for patients receiving REGN4461. Non-
informative prior will be used for the posterior probability. The posterior probability will also be 
used to assess the treatment effect of REGN4461. 
11.4.3.2. Secondary Efficacy Analysis 
Most of the secondary endpoints will use the FAS for the analyses. Other secondary endpoints will 
use a subset of patients, eg, with elevated baseline HbA1c; with elevated baseline TG; qualify to 
perform the MRI test; at sites with clamp capability, etc, in the FAS.  
For secondary endpoints measured in the double-blind period, summary statistics, including mean 
change from baseline, SE, 95% confidence interval, and nominal p-value will be provided using 
the MMRM with contrast. For secondary endpoints measured after the double-blind period (after 
week 24), descriptive statistics will be provided. Unless otherwise specified, all secondary analyses 
will be considered as within-group comparison. Details will be provided in the SAP.  
For HbA1c endpoint: 
• 
 
 
 
• 
 
 
 
For fasting glucose and fasting TG endpoints: 
• 
 
 
 
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• 
 
 
 
For WMG and MMTT: 
• 
 
 
• 
 
 
 
For clamp and ITT endpoints: 
• 
 
  
Change from week 8 to week 16 for patients in Treatment Arm A will be provided as above to 
estimate the treatment effect of the low dose. If the patients do not have a significant reduction in 
HbA1c or TG from baseline to week 8, defined as change in HbA1c (absolute value change is less 
than -0.4%, change in TG [percent change] is less than -20%), then their data from week 8 to week 
16, after they have switched to the low dose of REGN4461, will be pooled with data from baseline 
to week 8 for patients in Treatment Arm B, to evaluate the treatment effect of low dose on fasting 
glucose, fasting TG, WMG, MMTT, and HbA1c. Similarly, if there is not a significant reduction 
from baseline to week 8 for patients in Treatment Arm A, data from patients in Treatment Arm A 
(change from week 16 to week 24) will be pooled together with data from patients in Treatment 
Arm B (change from week 8 to week 16) to estimate the treatment effect of increasing the dose 
from a low-dose regime to a high-dose regime. MMRM or ANCOVA will be used.  
Mean and/or percent change from baseline will be plotted over time by treatment group based on 
the DBTP 1.  
For the secondary objective, the REGN4461 treatment effect will be evaluated based on a 
composite “Z score” of HbA1c and TG to see whether REGN4461 can improve the metabolic 
abnormality. The composite score is constructed as follows:  
For every patient, the composite “Z score” is derived based on HbA1c and fasting TG in the 
placebo run-in period (at baseline) and at the end of DBTP 1 (week 8). The REGN4461 treatment 
effect for each patient is calculated as: 
Z(𝐻𝑏𝐴1𝑐_𝑐ℎ𝑔)  = 𝐻𝑏𝐴1𝑐𝐵𝐿−𝐻𝑏𝐴1𝑐𝑤𝑒𝑒𝑘8
𝑆𝐷(𝐻𝑏𝐴1𝑐) 
 
Z(𝑙𝑜𝑔𝑇𝐺_𝑐ℎ𝑔)  = 𝑙𝑜𝑔𝑇𝐺𝐵𝐿−𝑙𝑜𝑔𝑇𝐺𝑤𝑒𝑒𝑘 8 
𝑆𝐷(𝑙𝑜𝑔𝑇𝐺) 
 
SD(HbA1c) and SD(logTG) will be computed using the baseline data from all patients:  
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𝑍(𝑐𝑜𝑚𝑝𝑜𝑠𝑖𝑡_𝑐ℎ𝑔)
=
{
 
 
𝑍(𝐻𝑏𝐴1𝑐_𝑐ℎ𝑔) 𝑖𝑓 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐻𝑏𝐴1𝑐≥7% 𝑎𝑛𝑑 𝑇𝐺< 250 𝑚𝑔/𝑑𝐿
𝑍(𝑙𝑜𝑔𝑇𝐺_𝑐ℎ𝑔), 𝑖𝑓 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐻𝑏𝐴1𝑐< 7% 𝑎𝑛𝑑 𝑇𝐺≥250 𝑚𝑔/𝑑𝐿
𝑍(𝐻𝑏𝐴1𝑐_𝑐ℎ𝑔) + 𝑍(𝑙𝑜𝑔𝑇𝐺_𝑐ℎ𝑔)
2
, 𝑖𝑓 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐻𝑏𝐴1𝑐≥7% and TG ≥250 mg/dL
 
MMRM will be used to evaluate the REGN4461 effect for both between-group and within-group 
comparison, mean, SE, and 95% confidence interval at week 8 will be provided.  
More details of the analysis plan will be described in the SAP. 
11.4.4. 
Safety Analysis 
11.4.4.1. Adverse Events 
Definitions 
For safety variables, 7 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The blinded treatment period 1 is defined as the day from first dose of study drug to 
 
• The blinded treatment period 2 is defined as the time from 
 
 
• The blinded treatment period 3 is defined as the time from 
 
  
• The Open-Label Treatment Period 4 is defined as 
 
 
• The Open-Label Treatment Period 5 is defined as 
 
 
• Combined OLTP (period 4 + period 5)  
• The posttreatment period is defined as the time after the last dose of study drug. 
• The all-treatment period is defined as the day from the first dose of the study drug to 
EOT.  
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the all-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level terms. The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include:  
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• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.5.1), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
11.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) and weight will be 
summarized by baseline and change from baseline to each scheduled assessment time with 
descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-laboratory-range values.  
Electrocardiogram 
Electrocardiogram parameters, including QTc, will be summarized over time. Abnormal ECG 
status will be summarized.  
Number and percentage of patients with a PCSV for vital signs or ECG parameters, at any 
post-randomization time point, will be summarized. The PCSV criteria will be defined before 
database lock. 
11.4.4.3. Treatment Exposure 
Treatment exposure during the study will be summarized by treatment arm. Details will be 
provided in the SAP. 
11.4.4.4. Treatment Compliance 
Treatment compliance will be summarized. Details will be provided in the SAP. 
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11.4.5. 
Pharmacokinetics 
11.4.5.1. Analysis of Drug Concentration Data 
Descriptive statistics of REGN4461 and sLEPR serum concentrations will be presented at each 
sampling time point. Plots of individual serum concentrations will be presented by actual time 
point. Plots of summary statistics of individual serum concentrations will be presented by nominal 
time point. No formal statistical analysis will be performed. 
11.4.5.2. Analysis of Pharmacokinetic Parameters 
Pharmacokinetic parameters may include, but are not limited to, the following:  
• Cmax – serum peak concentration 
• Ctrough – serum trough concentrations both prior to and at steady state 
Parameters will be summarized by standard descriptive statistics and may be suitably normalized 
by dose and/or body weight. 
11.4.6. 
Analysis of Anti-Drug Antibody Data 
Immunogenicity will be characterized by the ADA response observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 9-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative  
− The treatment-emergent responses will be further characterized as persistent, 
indeterminate, or transient.  
o Persistent Response – Treatment-emergent ADA positive response with 2 
or more consecutive ADA positive sampling time points, separated by at 
least 16-week period (based on nominal sampling time), with no ADA 
negative samples in between, regardless of any missing samples.  
o Indeterminate Response – Treatment-emergent ADA positive response with 
only the last collected sample positive in the ADA assay, regardless of any 
missing samples.  
o Transient Response –Treatment-emergent ADA positive response that is 
not considered persistent or indeterminate, regardless of any missing 
samples.  
• Treatment boosted ADA 
 
 when baseline is positive in the ADA 
assay 
• Maximum ADA Titer values 
− Low (titer <1,000) 
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− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000) 
Listings of ADA positivity, treatment-emergent ADA, and titers presented by patient, time point, 
and dose tier will be provided. Prevalence of treatment-emergent ADA will be assessed as absolute 
occurrence (N) and percent of patients (%), grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
evaluated. Assessment of impact of ADA on safety and efficacy may be provided. 
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
11.5. 
Interim Analysis 
No formal IA is planned. Details of other analyses are described in Section 6.2. An unblinded team 
within Regeneron will review PK, PD, efficacy, and safety data to confirm the adequacy of the 
dose.  
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of the Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 17.1. 
12. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
12.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history) will be done using internationally 
recognized and accepted dictionaries. 
The case report form (CRF) data for this study will be collected with an electronic data capture 
(EDC) tool, Medidata Rave. 
12.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following:  
• IWRS system – randomization, study drug supply 
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• EDC system – data capture: Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
13. 
STUDY MONITORING 
13.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-based quality monitoring methodology focuses on employing a fit-for-purpose monitoring 
strategy, supported either directly by Regeneron as sponsor, or via our CRO partners. Risk-based 
quality monitoring strategies include: reduced source data verification, targeted source data 
review, the use of off-site/remote and triggered on-site monitoring visits, and centralized 
monitoring to identify site level risks and study level trends. The investigator must allow study-
related monitoring activities to occur. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
13.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
13.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (eCRFs) within the EDC system by trained site personnel. All required CRFs must be 
completed for each and every patient enrolled in the study. After review of the clinical data for 
each patient, the investigator must provide an electronic signature. A copy of each patient CRF 
casebook is to be retained by the investigator as part of the study record and must be available at 
all times for inspection by authorized representatives of the sponsor and regulatory authorities. 
14. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for:  
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• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator’s institution. 
In all instances, the confidentiality of the data must be respected. 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS  
15.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
Informed Consent 
ADULT PATIENTS:  
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient.  
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF 
read to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
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The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately. All study patients must be informed of the new information 
and provide their written consent if they wish to continue in the study. The original, signed revised 
ICF must be maintained in the patient’s study record and a copy must be given to the patient. 
PEDIATRIC PATIENTS:  
The principles of informed consent are described in ICH guidelines for Good Clinical Practice. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient and his/her parent(s) or legal guardian(s) prior to the 
patient’s participation in the study and after the aims, methods, objectives, and potential hazards 
of the study have been explained to the fullest possible extent in language that the patient and the 
parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the patient’s 
parent(s) or legal guardian(s) and the same investigator or designee who explained the ICF. 
Local law must be observed in deciding whether 1 or both parents’/guardians’ consent is required. 
If only 1 parent or guardian signs the consent form, the investigator must document the reason the 
other parent or guardian did not sign. The patient may also be required to sign and date the ICF, 
as determined by the IRB/EC and in accordance with the local regulations and requirements. 
• Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient’s parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately. All study patients and their parent(s) or legal guardian(s) 
must be informed of the new information and provide their written consent if they wish the patient 
to continue in the study. The original, signed revised ICF must be maintained in the patient’s study 
record and a copy must be given to the patient’s parent(s) or legal guardian(s). 
15.2. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
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The patient’s and investigator’s personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
15.3. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve:  
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB approval letter with a current list of the IRB members and their functions must 
be received by the sponsor prior to shipment of drug supplies to the investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
16. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment. Depending on local legislation, regulatory authority approval may also be 
required. 
17. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
17.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
17.2. 
Close-Out of a Site 
The sponsor and the investigator have the right to close out a site prematurely. 
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Investigator’s Decision 
The investigator must notify the sponsor of a desire to close out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close out a study site in writing. Reasons 
may include the following, among others:  
• The investigator has received all items and information necessary to perform the study 
but has not enrolled any patient within a reasonable period of time. 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines.  
• The total number of patients required for the study are enrolled earlier than expected. 
In all cases, the appropriate IRB, EC and health authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
18. 
STUDY DOCUMENTATION 
18.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRFs that will be provided to the sponsor. 
18.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator’s personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination. \ 
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19. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 12.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 13.1, Section 13.2, and Section 14).  
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current, approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 13.1).  
All patient data collected during the study will be recorded on paper or electronic CRF unless the 
data are transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for affirming that data entries in the CRF are accurate and correct by electronically 
signing a declaration that accompanies each set of patient final CRFs (Section 13.3 and 
Section 18.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 13.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 18.2).  
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20. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
21. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
22. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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23. 
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Brown RJ, Meehan CA, Cochran E, Rother KI, Kleiner DE, Walter M, et al. Effects of Metreleptin 
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mediated improvements in insulin sensitivity are independent of food intake in humans with 
lipodystrophy. J Clin Invest 2018; 128(8):3504-3516. 
 
Chiquette E, Oral EA, Garg A, Araújo-Vilar D,Dhankhar P. Estimating the prevalence of 
generalized and partial lipodystrophy: findings and challenges. Diabetes Metab Syndr Obes 2017; 
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Dayakar A, Chandrasekaran S, Veronica J,Maurya R. Leptin induces the phagocytosis and 
protective immune response in Leishmania donovani infected THP-1 cell line and human PBMCs. 
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Desai AD, Zhou C, Stanford S, Haaland W, Varni JW,Mangione-Smith RM. Validity and 
responsiveness of the pediatric quality of life inventory (PedsQL) 4.0 generic core scales in the 
pediatric inpatient setting. JAMA Pediatr 2014; 168(12):1114-1121. 
 
Diker-Cohen T, Cochran E, Gorden P,Brown RJ. Partial and generalized lipodystrophy: 
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Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N, et al. Efficacy and 
safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with 
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FDA. Briefing Document: BLA 125390, Myalept (metreleptin for injection).  2013;  Research 
CfDEa, editorFDA Maryland. 
 
Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, et al. Leptin reverses 
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Keller SD, Bayliss MS, Ware JE, Jr., Hsu MA, Damiano AM,Goss TF. Comparison of responses 
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Muniyappa R, Abel BS, Asthana A, Walter MF, Cochran EK, Remaley AT, et al. Metreleptin 
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Clin Lipidol 2017; 11(2):543-550. 
 
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recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in 
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Nidhina Haridas PA, Soronen J, Sadevirta S, Mysore R, Quagliarini F, Pasternack A, et al. 
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2015; 100(10):E1299-1307. 
 
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for lipodystrophy. N Engl J Med 2002; 346(8):570-578. 
 
Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance 
and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109(10):1345-1350. 
 
Safar Zadeh E, Lungu AO, Cochran EK, Brown RJ, Ghany MG, Heller T, et al. The liver diseases 
of lipodystrophy: the long-term effect of leptin treatment. J Hepatol 2013; 59(1):131-137. 
 
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symposium. J Allergy Clin Immunol 2006; 117(2):391-397. 
 
Shimomura I, Hammer RE, Ikemoto S, Brown MS,Goldstein JL. Leptin reverses insulin resistance 
and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999; 401(6748):73-76. 
 
Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, et al. Evidence 
of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-
term fasting. J Clin Invest 1996; 98(6):1277-1282. 
 
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2016; 52(2):187-193. 
 
Varni JW, Burwinkle TM, Seid M,Skarr D. The PedsQL 4.0 as a pediatric population health 
measure: feasibility, reliability, and validity. Ambul Pediatr 2003; 3(6):329-341. 
 
Varni JW, Seid M,Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life 
Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 2001; 
39(8):800-812. 
 
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inventory. Med Care 1999; 37(2):126-139. 
 
Varni JW, Seid M, Smith Knight T, Burwinkle T, Brown J,Szer IS. The PedsQL in pediatric 
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Generic Core Scales and Rheumatology Module. Arthritis Rheum 2002; 46(3):714-725. 
 
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24. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized, Double-Blind, Placebo-Controlled Study of 
REGN4461, A Leptin Receptor Agonist Antibody, in Patients with Generalized Lipodystrophy 
and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
 A Randomized, Double-Blind, Placebo-Controlled Study of REGN4461, A Leptin 
Receptor Agonist Antibody, in Patients with Generalized Lipodystrophy 
Protocol Number: 
R4461-GLD-1875 
Protocol Version: 
R4461-GLD-1875 Amendment 4 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 2
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
OF REGN4461, A LEPTIN RECEPTOR AGONIST ANTIBODY, IN 
PATIENTS WITH GENERALIZED LIPODYSTROPHY  
Compound 
REGN4461 
Protocol Number 
R4461-GLD-1875 
Clinical Phase 
Phase 2 
Sponsor 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician 
 
Project Biostatistician 
 
Clinical Trial Manager 
 
Study Medical Director 
 
Version / Date 
V 2.0 / August 22, 2022 
VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00
NCT04159415


Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
 
Regeneron Pharmaceuticals, Inc. 
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CONFIDENTIAL 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
Study Biostatistician  (
) 
 
 
See appended electronic signature page 
Study Clinical Pharmacologist (
) 
 
 
See appended electronic signature page 
Study Bioanalytical Sciences (
) 
 
 
See appended electronic signature page 
Study Director (
) 
 
 
See appended electronic signature page 
Study Global Patient Safety (
) 
 
 
See appended electronic signature page 
Project Biostatistician (
) 
 
 
See appended electronic signature page 
Head of BDM or designee (
) 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


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Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................8 
1. 
OVERVIEW ...............................................................................................................11 
1.1. 
Background/Rationale ................................................................................................11 
1.2. 
Study Objectives .........................................................................................................12 
1.2.1. 
Primary Objectives .....................................................................................................12 
1.2.2. 
Secondary Objectives .................................................................................................12 
1.2.3. 
Exploratory Objectives ...............................................................................................12 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................13 
1.2.5. 
Revision History for Statistical Analysis Plan Version 2 ...........................................13 
2. 
INVESTIGATION PLAN ..........................................................................................14 
2.1. 
Study Design and Randomization ..............................................................................14 
2.2. 
Sample Size and Power Considerations .....................................................................14 
2.3. 
Study Plan ...................................................................................................................17 
2.3.1. 
Sub-studies ..................................................................................................................18 
3. 
ANALYSIS POPULATIONS ....................................................................................18 
3.1. 
Efficacy Analysis Set ..................................................................................................19 
3.1.1. 
Full Analysis Set (FAS) ..............................................................................................19 
3.2. 
Double-blind Safety Analysis Set ...............................................................................19 
3.3. 
OLTP Safety Analysis Set ..........................................................................................19 
3.4. 
Pharmacokinetic (PK) Analysis Set............................................................................19 
3.5. 
The Immunogenicity Analysis Set..............................................................................19 
3.6. 
Glycemic Analysis Set ................................................................................................20 
3.7. 
Triglyceride Analysis Set ...........................................................................................20 
3.8. 
MRI Analysis Set ........................................................................................................20 
3.9. 
Clamp Analysis Set .....................................................................................................20 
3.10. 
Clamp Glycemic Analysis Set ....................................................................................20 
3.11. 
Insulin-Tolerance Test Analysis Set ...........................................................................20 
3.12. 
Insulin-Tolerance Test Glycemic Analysis Set ..........................................................20 
3.13. 
Quality-of-life Analysis Set ........................................................................................21 
3.14. 
Clinical Outcome Assessment ....................................................................................21 
3.15. 
 ..........................................................................................21 
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4. 
ANALYSIS VARIABLES .........................................................................................21 
4.1. 
Demographic and Baseline Characteristics ................................................................21 
4.2. 
Medical History ..........................................................................................................22 
4.3. 
Prior and Concomitant Medications ...........................................................................23 
4.4. 
Prohibited Medications and Procedures During Study ...............................................24 
4.5. 
Patient Disposition ......................................................................................................24 
4.6. 
Study Treatment Exposure and Compliance Variables ..............................................26 
4.7. 
Efficacy Variable ........................................................................................................29 
4.7.1. 
Primary Efficacy Variable (s) .....................................................................................29 
4.7.2. 
Secondary Efficacy Variable(s) ..................................................................................29 
4.8. 
Safety Variables ..........................................................................................................30 
4.8.1. 
Adverse Events Variables ...........................................................................................30 
4.8.1.1. 
Adverse Events and Serious Adverse Events .............................................................31 
4.8.1.2. 
Adverse Events of Special Interest .............................................................................31 
4.8.1.3. 
Adverse Events of Interest ..........................................................................................32 
4.8.1.4. 
Events Causing Death .................................................................................................32 
4.8.2. 
Laboratory Safety Variables .......................................................................................32 
4.8.3. 
Vital Signs ..................................................................................................................33 
4.8.4. 
12-Lead Electrocardiography (ECG) ..........................................................................33 
4.8.5. 
Tanner stages ..............................................................................................................33 
4.8.6. 
Physical Examination Variables .................................................................................33 
4.9. 
Other Variables ...........................................................................................................33 
4.10. 
Pharmacokinetic Variables .........................................................................................34 
4.11. 
Immunogenicity Variables ..........................................................................................34 
4.12. 
Quality of Life ............................................................................................................34 
4.13. 
Clinical Outcomes Assessment ...................................................................................35 
5. 
STATISTICAL METHODS .......................................................................................36 
5.1. 
Demographics and Baseline Characteristics ...............................................................36 
5.2. 
Medical History ..........................................................................................................37 
5.3. 
Prior and Concomitant Medications ...........................................................................37 
5.4. 
Prohibited Medications ...............................................................................................38 
5.5. 
Patient Disposition ......................................................................................................38 
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5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................38 
5.6.1. 
Exposure to Investigational Product ...........................................................................38 
5.6.2. 
Study Treatment Compliance .....................................................................................38 
5.7. 
Analyses of Efficacy Variables ..................................................................................39 
5.7.1. 
Analysis of Primary Efficacy Variables .....................................................................39 
5.7.1.1. 
Analysis of the Primary Endpoints: Change in Fasting Glucose and HbA1C 
from Baseline ..............................................................................................................39 
5.7.1.2. 
Analysis of the Primary Endpoint: Change in WMG from Baseline .........................40 
5.7.1.3. 
Analysis of the Primary Endpoint: Percent Change in TG from Baseline .................40 
5.7.1.4. 
Analysis of Primary Efficacy Endpoints: Subgroup Analyses ...................................41 
5.7.1.5. 
Supplemental Analyses of Primary Efficacy Endpoints .............................................41 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................42 
5.8. 
Analysis of Safety Data ..............................................................................................42 
5.8.1. 
Adverse Events ...........................................................................................................44 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................45 
5.8.3. 
Adverse Events of Interest ..........................................................................................45 
5.8.4. 
Clinical Laboratory Measurements.............................................................................45 
5.8.5. 
Analysis of Vital Signs ...............................................................................................46 
5.8.6. 
Analysis of 12-Lead ECG ...........................................................................................46 
5.8.7. 
Tanner Stages ..............................................................................................................47 
5.8.8. 
Physical Exams ...........................................................................................................47 
5.9. 
Analysis of Other Variables ........................................................................................47 
5.10. 
Analysis of Pharmacokinetic Variables ......................................................................48 
5.11. 
Analysis of Immunogenicity Data ..............................................................................48 
5.11.1. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................49 
5.11.1.1. 
Immunogenicity and Exposure ...................................................................................49 
5.11.1.2. 
Immunogenicity and Safety and Efficacy ...................................................................49 
5.12. 
Analysis of Quality of Life Variables .........................................................................50 
5.13. 
Analysis of Clinical Outcome Assessment .................................................................50 
6. 
DATA CONVENTIONS ............................................................................................51 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................51 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................51 
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CONFIDENTIAL 
6.3. 
Data Handling Convention for Missing Data .............................................................51 
6.4. 
Visit Windows ............................................................................................................52 
6.5. 
Unscheduled Assessments ..........................................................................................52 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................52 
6.7. 
Statistical Technical Issues .........................................................................................52 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................52 
7.1. 
Interim Analysis: PK and Safety Analysis for Part A ................................................52 
7.2. 
Timing of Planned Analyses .......................................................................................53 
7.3. 
Fifth Step and Final Analysis .....................................................................................53 
7.4. 
Additional Rules .........................................................................................................53 
8. 
SOFTWARE ...............................................................................................................54 
9. 
REFERENCES ...........................................................................................................55 
10. 
APPENDIX.................................................................................................................56 
10.1. 
Summary of Statistical Analyses ................................................................................56 
10.2. 
Windows for Analysis Time Points ............................................................................57 
10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ ..............................64 
10.4. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................65 
10.5. 
NMR Lipoprotein analysis .........................................................................................71 
10.6. 
DXA Variable List ......................................................................................................76 
10.7. 
Calculation for Efficacy Variables .............................................................................79 
10.8. 
Detailed Description of the Multiple Imputation Procedure ......................................82 
10.9. 
Schedule of Time and Events .....................................................................................83 
10.9.1. 
Footnotes for the Schedule of Events Table 3: Screening and Placebo Run-In .........86 
10.9.2. 
Footnotes for the Schedule of Events Table 4: Double-Blind Treatment 
Period 1 .......................................................................................................................92 
10.9.3. 
Footnotes for the Schedule of Events Table 5: Double-Blind Treatment 
Periods 2 and 3 ............................................................................................................99 
10.9.4. 
Footnotes for the Schedule of Events Table 6: Open-Label Treatment Period 
4 ................................................................................................................................105 
10.9.5. 
Footnotes for the Schedule of Events Table 7: Open-Label Treatment Period 
5 ................................................................................................................................113 
 
 
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Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
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CONFIDENTIAL 
LIST OF TABLES 
Table 1: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG Separately (N=20, 10 Treated vs. 10 Placebo, Assuming 
Approximately 20% Dropout Rate from 26 Patients) ................................................16 
Table 2: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG Separately (N=20, 10 Treated vs. 10 Placebo, Assuming 
Approximately 20% Dropout Rate from 26 Patients) ................................................17 
Table 3: 
Screening and Placebo Run-In Schedule of Events ....................................................83 
Table 4: 
Double-Blind Treatment Period 1 Schedule of Events ...............................................88 
Table 5: 
Double-Blind Treatment Periods 2 and 3 Schedule of Events ...................................95 
Table 6: 
Open-Label Treatment Period 4 (OLTP 4) Schedule of Events ...............................102 
Table 7: 
Open-Label Treatment Period 5 (OLTP 5) Schedule of Events ...............................108 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................18 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
ARH 
Autoregressive heterogeneous 
ALT 
Alanine aminotransferase 
ANGPTL3 
Angiopoietin-like 3 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC 
Area under the curve 
CI 
Confidence interval 
CMQ 
Company MedDRA queries 
CRF 
Case report form (electronic or paper) 
CV 
Cardiovascular 
DBTP 
Double-blind treatment period 
ECG 
Electrocardiogram 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GLD 
Generalized lipodystrophy 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HLGT 
High level group term 
HLT 
High level term 
HRQoL 
health-related quality of life  
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IV 
Intravenously 
ITT 
Insulin-tolerance test 
IVRS 
Interactive voice response system 
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Protocol: R4461-GLD-1875 
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LSM 
Least squares mean 
LDL-C 
Low-density lipoprotein cholesterol 
MCS 
Mental component summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model with repeated measures 
MMTT 
Mixed meal tolerance test 
MRI 
Magnetic resonance imaging 
NAS 
Non-alcoholic fatty liver disease activity score 
OLTP 
Open label treatment period 
PCS 
Physical component summary 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PDFF 
Proton Density Fat Fraction 
PedsQLTM 
The Pediatric Quality of Life Inventory  
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PRO 
Patient reported outcomes 
PT 
Preferred term 
QW 
Every week 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SF-36 
Short Form-36 survey 
SMT 
Safety Monitoring Team 
SMQ 
Standard MedDRA queries 
SOC 
System organ class 
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CONFIDENTIAL 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO-DD 
WHO Drug dictionary 
 
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Protocol: R4461-GLD-1875 
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Date: August 22, 2022 
 
 
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CONFIDENTIAL 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) Version 2 is to ensure the credibility of the 
study results by pre-specifying the statistical approaches for the analysis of study data prior to 
database lock. The SAP is intended to be a comprehensive and detailed description of the 
strategy and statistical methods to be used in the analysis of data for R4461-GLD-1875 study. 
The content of this SAP is inclusive of all analyses, specifically the interim, first-step and final 
analyses. 
This plan may be revised during the study to accommodate protocol amendments and adapt to 
unexpected issues in study execution that may affect planned analyses. These revisions will be 
based on blinded data review, and a final plan will be issued prior to the first database lock.  
1.1. 
Background/Rationale 
REGN4461, a leptin receptor (LEPR) agonist, is a fully human monoclonal antibody (mAb) that 
is being investigated for the treatment of conditions associated with leptin deficiency, including 
lipodystrophy. Generalized lipodystrophy (GLD) is an ultra-rare condition characterized by near-
complete loss of adipose tissue (lipoatrophy). Adipose tissue functions to store energy and signal 
the status of energy stores by secreting hormones (adipokines) such as leptin, which regulates 
energy intake, energy expenditure, and reproductive function. Severe lipoatrophy and leptin 
deficiency in GLD manifest as hyperphagia, insulin resistance, diabetes, hypertriglyceridemia, 
pancreatitis, infertility, and hepatic steatosis (progressing to non-alcoholic steatohepatitis 
[NASH] and advanced liver disease). 
REGN4461 binds and activates leptin receptors (LEPR) signaling. REGN4461 is not related to 
endogenous leptin, and therefore should not have elevated risks of anti-drug antibodies cross-
reacting with endogenous leptin. Once-weekly administration of REGN4461 improved glycemic 
control, insulin sensitivity, hypertriglyceridemia, food intake, body weight, hepatic mass, and 
steatosis in lipodystrophic humanized LEPR mice. In toxicology studies (a non-GLP single- and 
repeated-dose pilot study and a GLP 13-week toxicology study in monkeys), REGN4461 
administration resulted in either reduction in body weight gain or body weight loss. These effects 
are consistent with a role of leptin in regulation of body weight. No adverse reactions of 
treatment have been identified to date. A first-in-human (FIH), double-blind, placebo-controlled 
study of REGN4461 in healthy volunteers (R4461-HV-1794) is completed. 
 
 
 
 
 
 
 
 
 There were no safety signals identified from the TEAEs observed in the REGN4461-
treated groups compared to placebo group in either part of the study. 
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CONFIDENTIAL 
The primary purpose of this current study is to demonstrate the efficacy, safety, and tolerability 
of REGN4461 in patients with GLD. Additional background information on the study drug and 
development program can be found in the Investigator’s Brochure. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objectives of the study are to: 
• Estimate the effects of REGN4461 on glycemic parameters in the subset of patients 
with elevated baseline hemoglobin A1c levels (HbA1c ≥7%) 
• Estimate the effects of REGN4461 on fasting triglyceride levels in the subset of 
patients with elevated baseline fasting triglycerides (TG ≥250 mg/dL) 
1.2.2. 
Secondary Objectives 
The secondary objectives are to: 
• Estimate the effects of REGN4461 on a composite endpoint of changes in either 
HbA1c or fasting TG for all patients 
• Estimate the effects of 3 dose levels of REGN4461 on glycemic parameters and 
fasting TG  
• Estimate the effects of REGN4461 on insulin sensitivity 
• Evaluate the safety and tolerability of REGN4461 
• Evaluate the pharmacokinetics (PK) and immunogenicity of REGN4461 
1.2.3. 
Exploratory Objectives 
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CONFIDENTIAL 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The content of this SAP reflects the content of the statistical section of Protocol R4461-GLD-
1875 Amendment 3 with the following exceptions: 
• In general, nominal p-values will not be provided unless otherwise specified in 
Section 5.7. 
• The FAS analysis set definition has been updated to “The full analysis set (FAS) 
includes all randomized patients who received any study drug.” The change to this 
definition is the deletion of the criteria “have at least 1 post-baseline assessment”, so 
as to bring the FAS definition into alignment with regulatory guidance. 
• The following analysis will not be performed since the non-informative prior will not 
provide additional information than is already planned for the primary analysis: “In 
addition, posterior probability that the improvement in each of the primary endpoints 
is greater than zero will be computed at week 8 separately for patients receiving 
REGN4461. Non-informative prior will be used for the posterior probability. The 
posterior probability will also be used to assess the treatment effect of REGN4461”. 
• For the primary efficacy analysis of Fasting TG, the statistical method of MMRM 
planned in the protocol will be replaced with a robust regression analysis. The robust 
regression method will be able to better address the lack of normality in the TG 
distribution. 
1.2.5. 
Revision History for Statistical Analysis Plan Version 2 
This is the second version of Statistical Analysis Plan (SAP). The following changes have been 
made to the SAP since Version 1.  
• Addition of descriptive statistical analyses for OLTP 5, per Protocol R4461-GLD-
1875 Amendment 3. 
• Section 4.8.1. Adverse Events Variables – the post-treatment period definition has 
been clarified. 
• Section 4.9 and 5.9. Other variables – total sLEPR has been moved from the PK 
section. 
• Section 4.9. Other variables – DXA analysis variables are not limited to the Appendix 
10.6. 
• Appendix 10.7. Calculation for efficacy variables – calculated total glucose infusion 
rate formula has been updated to “(M * 20) / (body mass * 6)” in step 2, correcting a 
typo. 
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Date: August 22, 2022 
 
 
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CONFIDENTIAL 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 2, randomized, double-blind, placebo-controlled study of the efficacy and safety 
of REGN4461 in patients with GLD who are not receiving recombinant methionyl human leptin 
(rhLeptin, metreleptin) therapy. 
After a screening period of up to 4 weeks, eligible patients will begin the single-blind placebo 
run-in period. After baseline testing, patients will be centrally randomized via interactive voice 
response system (IVRS) in a 1:1 ratio to Treatment Arm A or Treatment Arm B and treated 
double-blind for 24 weeks to receive:  
Treatment Arm A:  
Treatment Arm B: 
 
 
 
  
 
 
Subjects will be stratified based on screening HbA1c (HbA1c
8% or HbA1c >8%) to ensure 
equal representation of patients with very elevated HbA1c in each study arm. 
2.2. 
Sample Size and Power Considerations 
The size of the study is determined by feasibility assessments. Due to the limited number of 
GLD patients not being treated with metreleptin in the world, up to 26 patients will be enrolled 
for the study, with approximately a 20% dropout rate. The primary objective is estimating the 
treatment effect of REGN4461 on glycemic and lipids parameters.  
Metreleptin demonstrated a 2% absolute drop in HbA1c (standard deviation [SD]=1.5%) and a 
50% relative drop in fasting TG (SD=40%) from baseline to month 4 (Myalepta, 2018) 
(FDA, 2013). As a conservative treatment effect estimation for 8 weeks, the anticipated drop in 
HbA1c is 1.5%, because HbA1C will not have fully re-equilibrated by week 8; full equilibration 
would be expected at approximately 12 weeks. The change in fasting TG is expected to be the 
same at week 8 as at week 16. With 20 patients completing the study (10 patients per study arm, 
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CONFIDENTIAL 
assuming approximately a 20% dropout rate from 26 patients), the minimal detectable change 
(MDC) and power for the study are provided in Table 1 as below, for a 2-sided alpha of 0.05 test.  
Note: Ultimately, study enrollment was terminated on December 2, 2021, with a total of 16 
patients randomized and treated. 
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CONFIDENTIAL 
Table 1: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG Separately (N=20, 10 Treated vs. 10 Placebo, Assuming 
Approximately 20% Dropout Rate from 26 Patients)  
 
Number of 
Treated 
Patients 
Within-
Group 
Between-
Group 
Within-Group 
Between-Group 
 
 
MDC (half of the confidence 
interval), alpha=0.05 
Power for a 1.5% reduction in 
HbA1c, 60 mg/dL reduction in 
fasting glucose/MWG, and 50% 
reduction in fasting TG  
HbA1c* 
10 
1% 
1.4% 
80% 
56% 
Fasting 
Glucose* 
10 
53 mg/dL 
70 mg/dL 
60% 
38% 
WMG& 
10 
40 mg/dL 
53 mg/dL 
84% 
60% 
Fasting 
TG* 
10 
28% 
37% 
93% 
75% 
*Assuming SD for HbA1c is 1.5%, fasting glucose is 76 mg/dL, and fasting TG is 40% (FDA, 2013).  
& SD for WMG is 75% of SD for fasting glucose (57 mg/dL).  
A total of 16 patients were randomized and treated.  
If the glycemic and lipid subsets for the primary analysis have fewer patients with abnormal TGs 
or fasting glucose values, the table below (Table 2) provides minimal detectable change and 
power for the subset analysis. 
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CONFIDENTIAL 
Table 2: 
Minimal Detectable Change and Power for HbA1c, Fasting Glucose, WMG, 
and Fasting TG Separately (N=20, 10 Treated vs. 10 Placebo, Assuming 
Approximately 20% Dropout Rate from 26 Patients)  
  
Number of 
Treated 
Patients in the 
Subset* 
Within-
Group 
Between-
Group 
Within-
Group 
Between-
Group 
  
MDC (half of the confidence 
interval), alpha=0.05 
Power for a 1.5% reduction in 
HbA1c, 60 mg/dL reduction in 
fasting glucose/WMG and 50% 
reduction in fasting TG 
HbA1c$ 
5 
1.7% 
2.1% 
40% 
28% 
Fasting 
Glucose$ 
5 
88 mg/dL 
107 mg/dL 
27% 
19% 
WMG$ 
5 
66 mg/dL 
80 mg/dL 
43% 
31% 
Fasting TG$ 
9 
30% 
39% 
90% 
70% 
*Assuming 50% of the patients have elevated baseline HbA1c and 90% of the patients have elevated baseline TG. 
$Assuming SD for HbA1c is 1.5%, fasting glucose is 76 mg/dL, and fasting TG is 40% (FDA, 2013). SD for WMG 
is 75% of SD for fasting glucose (57 mg/dL). 
A total of 16 patients were randomized and treated. 
2.3. 
Study Plan 
The study comprises a 4-week screening period, 
 
 
 
  
Patients who are ≥12 years of age, (or lower limit of age approved by Health Authority, EC, and 
IRB) at the screening visit with a clinical diagnosis of GLD, will undergo screening, including 
measurement of HbA1c and fasting TG. Eligible patients will then begin the single-blind placebo 
run-in period within 4-weeks of screening. The 
 consists of two study treatment 
sequence arms, with each sequence containing three treatment periods (see diagram Figure 1 
below). 
As described in Protocol R4461-GLD-1875 Section 6.1, Study Description and Duration, the 
following DBTP R4461 IV loading doses and SC weekly doses are defined. 
• IV 
 
• REGN4461 low-dose: 
 
• REGN4461 high-dose: 
 
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The detailed dosing schedule for each treatment arm sequence (Treatment Arm A and Treatment 
Arm B) and body weight are provided in the Protocol Section 8.1, Table 2. 
 
 
  
 
 
 
Figure 1: 
Study Flow Diagram 
2.3.1. 
Sub-studies 
 
 
  
3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), below are the patient populations defined 
for statistical analysis. The primary efficacy analysis population is the FAS for the subgroup of 
patients with a baseline HbA1C ≥ 7% (glycemic analysis set) and the subgroup of patients with a 
baseline TG ≥ 250 mg/dL (triglyceride analysis set).  Additional patient populations included for 
safety are anti-drug (REGN4461) anti-body (ADA), pharmacokinetic (PK), quality of life and 
, etc. For the purposes of the definitions below, a patient is considered randomized to 
study treatment when they have been screened and received a randomization number and 
recorded in the IVRS/IWRS database. 
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3.1. 
Efficacy Analysis Set 
3.1.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients in the DBTP who received any study 
drug. Patients in the FAS population will be analyzed according to the treatment group allocated 
by randomization (i.e., as-randomized group). Efficacy endpoints will be analyzed using the 
FAS.  
3.2. 
Double-blind Safety Analysis Set 
The double-blind safety analysis set (SAF) includes all randomized patients who received any 
double-blind study drug. Patients will be analyzed according to the treatment received. 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
double-blind SAF. 
In addition:   
• Randomized patients for whom it is unclear whether they took the study drug will be 
included in the double-blind SAF as randomized. 
• For randomized patients receiving both REGN4461 and placebo study treatment in 
the DBTP1, the treatment group allocation for as-treated analysis will be REGN4461. 
• For randomized patients receiving both low-dose REGN4461 and high-dose 
REGN4461 study treatment in the DBTP2, the treatment group allocation for as-
treated analysis will be the most frequently administered REGN4461 dose.  
3.3. 
OLTP Safety Analysis Set 
The OLTP safety analysis set for Period 4 (OLTP 4 SAF) will be the randomized patients who 
received any open-label treatment period 4 study drug.  
The OLTP safety analysis set for Period 5 (OLTP 5 SAF) will be the randomized patients who 
received any open-label treatment period 5 study drug.  
The OLTP pooled safety analysis set (OLTP Pooled SAF) will be the randomized patients who 
received any open-label treatment period 4 study drug.  
 
3.4. 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set is defined as all randomized patients who received any study drug and have 
at least 1 non-missing post-baseline measurement of mibavademab concentration.  Treatment 
assignments for the DBTP are based on the treatment received (placebo or mibavademab). 
3.5. 
The Immunogenicity Analysis Set 
The ADA analysis set (AAS) includes all treated patients who received any amount of study 
drug (active or placebo [safety analysis set]) and had at least one non-missing anti-drug antibody 
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result following the first dose of study drug or placebo. The ADA analysis set is based on the 
actual treatment received (as treated) rather than as randomized. 
3.6. 
Glycemic Analysis Set 
The glycemic analysis set includes all patients who are in the FAS and have elevated baseline 
HbA1c (HbA1c ≥7%). Primary efficacy endpoints for glycemic parameters will be analyzed 
using the glycemic analysis set. Patients will be analyzed according to the treatment group 
allocated by randomization (i.e., as-randomized group). 
3.7. 
Triglyceride Analysis Set 
The triglyceride analysis set includes all patients who are in the FAS and have elevated baseline 
fasting TG (TG ≥250 mg/dL). Primary efficacy endpoints for triglycerides will be analyzed using 
the triglyceride analysis set. Patients will be analyzed according to the treatment group allocated 
by randomization (i.e., as-randomized group). 
3.8. 
MRI Analysis Set 
The MRI analysis set includes all patients who are in the FAS and eligible for the MRI test 
(some patients are not eligible for the MRI due to MRI contraindications or some sites do not 
have the technical capability to perform liver MRI). Patients will be analyzed according to the 
treatment group allocated by randomization (i.e., as-randomized group). 
3.9. 
Clamp Analysis Set 
The clamp analysis set includes all patients who are in the FAS and eligible for the clamp test 
(some patients are at the sites where there is no clamp capability). Patients will be analyzed 
according to the treatment group allocated by randomization (i.e., as-randomized group). 
3.10. 
Clamp Glycemic Analysis Set 
The clamp glycemic analysis set includes all patients who are in the clamp analysis set and have 
elevated baseline HbA1c (HbA1c ≥7%).  
3.11. 
Insulin-Tolerance Test Analysis Set 
The insulin-tolerance test analysis test includes all patients who are in the FAS, are not eligible 
for the clamp test, and are eligible for the qualified insulin-tolerance test (some patients are at the 
sites without clamp capability, but which have qualified insulin-tolerance test). Patients will be 
analyzed according to the treatment group allocated by randomization (i.e., as-randomized 
group). 
3.12. 
Insulin-Tolerance Test Glycemic Analysis Set 
The insulin-tolerance test glycemic analysis set includes all patients who are in the insulin-
tolerance test analysis set and have elevated baseline HbA1c (HbA1c ≥7%). Patients will be 
analyzed according to the treatment group allocated by randomization (i.e., as-randomized 
group). 
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3.13. 
Quality-of-life Analysis Set  
The analyses for quality of life will be performed on all patients in the FAS. Further for the SF-
36 and the PedsQL: 
• For Short-Form (SF-36) analysis set: patients will be included when a baseline and at 
least 1 matching post-baseline component summary score (physical or mental) are 
available. 
• For Pediatric Quality of Life Inventory (PedsQL) analysis set: patients will be 
included when a baseline and at least one post-baseline total scale score are available. 
3.14. 
Clinical Outcome Assessment 
The analyses for Clinical Outcome Assessments will be performed on all patients in the FAS. 
Further for each scale: 
• For the hunger and eating behaviors questionnaire, patients will be included when a 
baseline and at least one-week post-baseline scores are available. 
• For the sensation of Body Temperature PRO, patients will be included when a 
baseline and at least one post-baseline score is available. 
3.15. 
 
 
  
4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
For each patient, demographic and baseline characteristics will be obtained from the last 
available value up to the date of the first double blind study treatment administration (i.e. 
baseline definition). For patients randomized and not treated in R4461-GLD-1875, the baseline 
value is defined as the last available measurement prior to the date of randomization. 
The following variables will be summarized: 
Demographic Characteristics 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other, Pacific Islander, Not Reported, Other) 
• Age in years (quantitative and qualitative variable: ≥12 to <18, ≥18 to <45, ≥45 to 
<65, ≥65 to <75, and ≥75 years) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
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Baseline Characteristics 
• Baseline Weight (kg)  
• Baseline Height (cm) 
• Baseline Body mass index (BMI) in kg/m² (quantitative and qualitative variable 
defined as <30, ≥30) 
• Randomization strata as reported in the IVRS  
− HbA1c (≤8% or >8%) 
• Randomization strata as reported in the clinical database. 
− HbA1c (≤8% or >8%) 
Baseline Disease Characteristics  
• Fasting glucose 
• HbA1C both quantitative variable and qualitative variable defined as: <7%, ≥7%  
• WMG 
• Glucose AUC0-4 during MMTT 
• Glucose infusion rate per Kg body mass 
• Glucose infusion rate normalized for fat free mass 
• Glucose clearance rate (kITT) during ITT 
• Fasting TG both quantitative variable and qualitative variable defined as: <250 mg/dL 
and ≥250 mg/dL  
• Low density lipoprotein cholesterol (LDL-C)  
• High-density lipoprotein cholesterol (HDL-C) 
• Total Cholesterol (TC) 
• NMR Lipoprotein analysis (Note: List of data fields reported in the Lipoprotein NMR 
are listed in Appendix 10.5.) 
• Apo-B 
• Leptin 
4.2. 
Medical History 
As applicable, patient medical history will be dictionary coded by primary system organ class 
and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA), 
specifically the latest MedDRA version at the time of the first database lock.  
GLD disease history will be assessed by the following variables:  
• Time from diagnosis to study treatment randomization (years) 
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• GLD type (genetic or acquired, per CRF) 
• Congenital Generalized Lipodystrophy Gene type (genetic) 
• Method of diagnosis of GLD (genetically, clinical diagnosis, imaging or other) 
• Frequency of hospitalization of acute pancreatitis in the last three months, 6 months, 
and 12 months. 
• Metreleptin taken less than 30 days prior to informed consent (Yes/No) 
− If no, select >1month, >3months, >1year 
4.3. 
Prior and Concomitant Medications 
All medications taken from the time of informed consent to the final study visit, including 
medications that were started before the study and are ongoing during the study, will be reported 
in Concomitant Medications CRF.  
All medications will be dictionary coded using the World Health Organization-Drug Dictionary 
(WHO-DD) to both an anatomic category and a therapeutic category, with the latest version at 
the time of the first database lock.  Drug names will be matched to respective Anatomical-
Therapeutic-Chemical (ATC) classification, although a drug can be matched to more than one 
ATC classification (i.e. patients can be counted in several categories for the same medication).   
Prior medications, concomitant medications, and post-treatment medications are defined below 
and will be applied in the respective treatment periods (DBTP and OLTP). 
• Prior medications are defined as medications for which the stop date is before the date 
of the first DBTP study treatment administration. 
• Concomitant medications are defined as medications that are administered to the 
patients during the respective double-blind and open-label study treatment periods. 
Specifically: 
− Start date of the concomitant medication is on or after the first study treatment 
administration in respective study treatment periods 
 
; or 
− Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods and is “Ongoing” during the 
treatment emergent period; or   
− Start date of the concomitant medication is before the first study treatment 
administration in respective study treatment periods, and the end date is on or 
after the first study treatment administration in respective study treatment periods 
.  
The concomitant medication treatment emergent periods are defined as:  
• For concomitant medications in the DBTP, the treatment emergent period is defined 
from the first day of double-blind study treatment administration to the last day of 
double blind study treatment + 112 days (for patients who do not continue into the 
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OLTP) or to the day before the first open-label study treatment administration (for 
patients who enter the OLTP). 
• For concomitant medications in the OLTP, the treatment emergent period is defined 
from the first day of open-label study treatment administration to the last day of open-
label study treatment administration + 112 days.  
Note: In the case the start date is before first study treatment administration and both ongoing 
status and stop date are missing, the medication will be assumed to be concomitant. 
• Post-treatment medications are defined as medications for which the start date is after 
last date of study treatment administration + 112 days (≥ last study treatment +112 
days).   
4.4. 
Prohibited Medications and Procedures During Study 
The definitions of prohibited medications and procedures are described in the section 8.7.1 of the 
protocol. They will be reviewed and identified by the study clinician and reported in protocol 
deviations.   
4.5. 
Patient Disposition 
Patient disposition will include the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations.   
For patient study status, patient milestone categories for the DBTP are defined below.  As 
applicable, percentages will be calculated using the number of randomized patients in the 
denominator, with two exceptions.  Specifically, the two exceptions will be for the screened and 
non-randomized categories, which will not have associated percentages shown.  
• The total number of screened patients defined as who have signed ICF.  
• The total number of screen failure (SF) patients. 
• The total number of randomized patients, defined as all screened patients with a 
double-blind treatment kit number allocated and recorded in the IVRS database, 
regardless of whether the treatment kit was used. 
• The total number of patients randomized but not receiving study treatment. 
• The total number of patients randomized and receiving study treatment. 
• The total number of patients who completed the DBTP, defined as at least 23 weeks 
of study treatment administration and week 24 visit performed. 
• The total number of patients ongoing in DBTP (interim analysis). 
• The total number of patients who prematurely discontinued study treatment during 
the DBTP and the reasons for discontinuation collected on the study completion 
eCRF.  
• The total number of patients who do not proceed into OLTP and complete the last 
study follow-up visit (i.e. 16-week follow-up period). 
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Patient OLTP milestone categories are defined below.  As applicable, percentages will be 
calculated using a denominator of the number of patients administered open-label study 
treatment.  
• The total number of patients receiving study treatment in open-label treatment period 
4. 
• The total number of patients ongoing in OLTP 4 (applicable for interim analysis) 
• The total number of patients who completed the OLTP 4, 
 
 
• The number of patients who received 
 of treatment. 
• The total number of patients who prematurely discontinued study treatment during 
the OLTP 4, and the reasons for discontinuation collected on the study completion 
eCRF. 
• The total number of patients receiving study treatment in open-label treatment period 
5. 
• The total number of patients ongoing in OLTP 5. 
• The total number of patients who completed the OLTP 5, defined as at least OLTP 5 
 
• The total number of patients who prematurely discontinued study treatment during 
the OLTP 5, and the reasons for discontinuation collected on the study completion 
eCRF. 
• The total number of patients from OLTP 5 who complete the last study follow-up 
visit (i.e. 16-week follow-up period). 
The following patient populations for analyses are defined below: 
• Efficacy population: Full analysis set (FAS) 
• Safety analysis set (Double-blind SAF, OLTP 4 SAF, OLTP 5 SAF, Pooled OLTP 
SAF) 
• Glycemic analysis set 
• Triglyceride analysis set 
• MRI analysis set 
• Clamp analysis set 
• Insulin–Tolerance Test analysis set 
The following patient listings will provide the details from the patient disposition table. 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
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• A listing of patient prematurely discontinued from treatment, along with reasons for 
discontinuation 
4.6. 
Study Treatment Exposure and Compliance Variables 
Study treatment exposure variables for study drug administered during the DBTP1 are listed 
below with associated definitions: 
• Patient duration of DBTP1 SC study treatment exposure in weeks defined as: (last 
double-blind study treatment administration date in DBTP1 – first double-blind SC 
study treatment administration date in DBTP1 + 7)/7. Values will be rounded to one 
decimal place. 
• The total number of DBTP1 SC study treatment administrations by patient.  
• The following categories will be used for DBTP1 SC treatment exposure at 1 week 
intervals: ≥1 day and <1 week, ≥1 weeks and <2 weeks, ≥2 weeks and <3 weeks, ≥3 
weeks and <4 weeks, ≥4 weeks and <5 weeks, ≥5 weeks and <6, ≥6 weeks and <7, 
≥7weeks. 
• The total number of DBTP1 IV study treatment administrations by patient.  
Study treatment exposure variables for study drug administered during the DBTP2 are listed 
below with associated definitions: 
• Patient duration of DBTP2 SC study treatment exposure in weeks defined as: (last 
double-blind study treatment administration date in DBTP2 – first double-blind SC 
study treatment administration date in DBTP2 + 7)/7. Values will be rounded to one 
decimal place. 
• The total number of DBTP2 SC study treatment administrations by patient.  
• The following categories will be used for DBTP2 SC treatment exposure at 1 week 
intervals: ≥1 day and <1 week, ≥1 weeks and <2 weeks, ≥2 weeks and <3 weeks, ≥3 
weeks and <4 weeks, ≥4 weeks and <5 weeks, ≥5 weeks and <6, ≥6 weeks and <7, 
≥7weeks and <8 weeks and ≥8 weeks. 
• The total number of DBTP2 IV study treatment administrations by patient.  
Study treatment exposure variables for study drug administered during the DBTP3 are listed 
below with associated definitions: 
• Patient duration of DBTP3 SC study treatment exposure in weeks defined as: (last 
double-blind study treatment administration date in DBTP3 – first double-blind study 
treatment administration date in DBTP3 + 7)/7. Values will be rounded to one 
decimal place. 
• The total number of DBTP3 SC study treatment administrations by patient.  
• The following categories will be used for DBTP3 SC treatment exposure at 1week 
intervals: ≥1 day and <1 week, ≥1 week and <2 weeks, ≥2 weeks and <3 weeks, ≥3 
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weeks and <4 weeks, ≥4 weeks and <5 weeks, ≥5 weeks and <6, ≥6 weeks and <7, 
≥7weeks and <8 weeks and ≥8 weeks. 
Study treatment exposure variables for study drug administered during all DBTP are listed below 
with associated definitions: 
• Patient duration of all DBTP SC study treatment exposure in weeks defined as: (last 
double-blind study treatment administration date– first double-blind SC study 
treatment administration date + 7)/7. Values will be rounded to one decimal place. 
• The total number of DBTP SC study treatment administration by patient.  
• The following categories will be used for DBTP SC treatment exposure at 1 week 
intervals: ≥1 day and <1 weeks, ≥1 weeks and <2 weeks, ≥2 weeks and <3 weeks, ≥3 
weeks and <4 weeks, ≥4 weeks and <5 weeks, ≥5 weeks and <6, ≥6 weeks and <7, 
≥7weeks and <8 weeks, ≥8 weeks and <9,  ≥9 weeks and <10,  ≥10weeks and <11,  
≥11 weeks and <12 weeks,  ≥12 weeks and <13 weeks,  ≥13 weeks and <14 weeks,  
≥14 weeks and <15 weeks,  ≥15 weeks and <16 weeks, ≥16 weeks and <17 weeks, 
≥17weeks and <18 weeks, ≥18 weeks and <19 weeks,  ≥19 weeks and <20 weeks,  
≥20weeks and <21 weeks, ≥21 weeks and <22 weeks, ≥22 weeks and <23 weeks, ≥23 
weeks and <24 weeks and ≥24 weeks.  
REGN4461 treatment exposure variables for study drug administered during the OLTP 4 are 
listed below with associated definitions: 
• Patient duration of OLTP 4 SC study treatment exposure in weeks defined as: (the 
last OLTP 4 REGN4461 treatment administration date – first OLTP 4 REGN4461 
treatment administration date + 7)/7. Values will be rounded to one decimal place. 
• The total number of OLTP 4 REGN4461 treatment SC injections by patient.  
• The following categories will be used for OLTP 4 REGN4461 SC treatment exposure 
at 1 week intervals: ≥1 day and <1 weeks, ≥1 weeks and <2 weeks, ≥2 weeks and <3 
weeks, ≥3 weeks and <4 weeks, ≥4 weeks and <5 weeks, ≥5 weeks and <6, ≥6 weeks 
and <7, ≥7weeks and <8 weeks, ≥8 weeks and <9,  ≥9 weeks and <10,  ≥10weeks and 
<11,  ≥11 weeks and <12 weeks,  ≥12 weeks and <13 weeks,  ≥13 weeks and <14 
weeks,  ≥14 weeks and <15 weeks,  ≥15 weeks and <16 weeks, ≥16 weeks and <17 
weeks, ≥17weeks and <18 weeks, ≥18 weeks and <19 weeks,  ≥19 weeks and <20 
weeks,  ≥20weeks and <21 weeks, ≥21 weeks and <22 weeks, ≥22 weeks and <23 
weeks, ≥23 weeks and <24 weeks,  ≥24 weeks and <25 weeks, ≥25 weeks and <26, 
≥26 weeks and <27, ≥27weeks and <28 weeks, ≥28 weeks. 
REGN4461 treatment exposure variables for study drug administered during the OLTP 5 are 
listed below with associated definitions: 
• Patient duration of OLTP 5 SC study treatment exposure in weeks defined as: (last 
OLTP 5 REGN4461 treatment administration date – first OLTP 5 REGN4461 
treatment administration date + 7)/7. Values will be rounded to one decimal place. 
• The total number of OLTP 5 REGN4461 treatment SC injections by patient.  
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• The following categories will be used for OLTP 5 REGN461 SC treatment exposure 
at 1 week intervals, e.g.  ≥1 day and <1 weeks, ≥1 weeks and <2 weeks, ≥2 weeks 
and <3 weeks,  ≥51weeks and <52 weeks, ≥52 weeks. 
Cumulative OLTP REGN4461 exposure variables combining the 2 open label treatment periods 
(ie. OLTP 4 + OLTP 5) regardless of REGN4461 dose are listed below: 
• Cumulative OLTP patient duration of SC REGN4461 exposure in weeks defined as: 
Treatment arm A: OLTP 4 exposure + OLTP 5 treatment exposure.  Treatment arm 
B: OLTP 4 + OLTP 5 treatment exposure 
• Cumulative total number of OLTP REGN4461 SC treatment administration by 
patient defined as: Treatment arm A: OLTP 4 + OLTP 5 treatment injections.  
Treatment arm B: OLTP 4 + OLTP 5 treatment injections.  
• The following categories will be used for cumulative OLTP patient REGN4461 
treatment exposure at 4 week intervals, e.g.  ≥1 day and <1 weeks, ≥1 weeks and <2 
weeks, ≥2 weeks and <3 weeks, ≥3 weeks and <4 weeks, ≥4 weeks and <5 weeks, ≥5 
weeks and <6, ≥6 weeks and <7, ≥7weeks and <8 weeks … ≥79 weeks and <80 
weeks, ≥80. 
Cumulative REGN4461 total trial exposure variables combining DBTP and OLTP (regardless of 
treatment dose) are listed below: 
• Cumulative patient duration of SC REGN4461 study exposure in weeks defined as: 
Treatment arm A: DBTP2 treatment exposure + DBTP3 treatment exposure + OLTP 
4 exposure + OLTP 5 treatment exposure.  Treatment arm B: DBTP1 treatment 
exposure + DBTP2 treatment exposure + DBTP3 treatment exposure + OLTP 4 
treatment exposure + OLTP 5 treatment exposure. 
• Cumulative total number in study of REGN4461 SC treatment administration by 
patient defined as: Treatment arm A: 
 
 
 
 
• The following categories will be used for cumulative patient REGN4461 treatment 
exposure in the study at 4 week intervals, e.g.  ≥1 day and <1 weeks, ≥1 weeks and 
<2 weeks, ≥2 weeks and <3 weeks, ≥3 weeks and <4 weeks, ≥4 weeks and <5 weeks, 
≥5 weeks and <6, ≥6 weeks and <7, ≥7weeks and <8 weeks… ≥103 weeks and <104 
weeks, ≥104  
With respect to patient treatment administration compliance in the DBTP, the study treatment is 
administered during the investigative site visits or by a visiting nurse. Therefore, study 
compliance will be accessed by frequency for SC study drug administration for respective 
treatment periods, specifically: 
• The mean frequency for SC study treatment administration will be defined for each 
patient as the average number of days between 2 consecutive study drug 
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administration: (last double-blind dose date – first double-blind dose date) / (number 
of injections in DBTP), for patients receiving at least 2 injections. 
In the DBTP, all important and minor protocol deviations potentially impacting efficacy 
analyses, randomization and drug-dispensing irregularities, as well as other deviations, will be 
collected and reviewed on an ongoing basis throughout the study as described in the Protocol 
Deviation Plan (PDP).  Both monitoring collected and programmatically derived deviations are 
listed and defined in the PDP.  
4.7. 
Efficacy Variable 
Efficacy will be assessed through the following parameters: HbA1c, fasting glucose, WMG, 
fasting TG, glucose AUC0-4h from MMTT, glucose infusion rate per kg body mass from clamp, 
and glucose clearance rate (kITT) from Insulin-tolerance Test, liver volume as measured by MRI, 
and liver fat content as measured by MRI-PDFF. All parameters will be collected over the course 
of the study and sent for centralized evaluation, including scheduled and unscheduled blood 
draws.  
All efficacy assessment values obtained during the study (scheduled or unscheduled), can be 
used to provide a value for the primary efficacy endpoints. 
All efficacy measurements will be assigned to efficacy analysis windows defined in 
Appendix 10.2 of this SAP, with the intent to provide an assessment for 24 weeks of DBTP 
timepoints, 24 weeks of OLTP 4 timepoint, and 52 weeks of OLTP 5 timepoints. For all time 
points post-baseline, the value used for the analyses at a given time point (e.g. at week 8) is the 
value obtained within the corresponding efficacy analysis window. Unless otherwise specified, 
the baseline value is defined as the last available measurement prior to the date of the first 
double-blind study treatment administration (applicable to measurement derivations during both 
DBTP and OLTP). For patients randomized and not treated, the baseline value is defined as the 
last available value prior to the date of randomization.  
4.7.1. 
Primary Efficacy Variable (s) 
The primary endpoints of the study are: 
• Change in HbA1C from baseline to week 8. 
• Change in fasting glucose from baseline to week 8. 
• Change in weighted mean glucose (WMG) from baseline to week 8. Note: 
Calculation for WMG is in Appendix 10.7. 
• Percent change in fasting TG from baseline to week 8. Note: For Fasting TG, baseline 
is defined as the average of the last two measurements prior to first study 
administration. Fasting TG at week 8 is defined as the average of raw scores at week 
7 and week 8.  
4.7.2. 
Secondary Efficacy Variable(s) 
The secondary endpoints of the study are: 
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• Change in HbA1C from baseline to 
 
 
• Change in fasting glucose from baseline to 
 
 
• Change in weighted mean glucose (WMG) from baseline to 
 
• Percent change in fasting TG from baseline to 
 
. Note: For Fasting TG, baseline is 
defined as the average of the last two measurements prior to first study 
administration. Fasting TG at week 8 is defined as the average of raw scores at week 
7 and week 8. 
• Change from baseline in glucose AUC0-4 during an MMTT at weeks 8, 16, and 24. 
Note: Calculation for glucose AUC0-4 is in Appendix 10.7. 
• Change from baseline in glucose infusion rate per kg body mass during 
hyperinsulinemia-euglycemic clamp at weeks 8 and 52. Note: Calculation for glucose 
infusion rate is in Appendix 10.7. 
• Change from baseline in glucose clearance rate (kITT) during Insulin-tolerance Test at 
weeks 8 and 52. Note: Calculation for glucose infusion rate is in Appendix 10.7. 
• Change from baseline to week 8 in composite endpoint comprising absolute change in 
either HbA1c or percent change in fasting TG. See composite endpoint details in the 
Protocol R4461-GLD-1875 section 11.4.3.2. Note: Fasting TG is defined as the 
average of the raw scores at 
 for each patient. 
4.8. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, physical examination, tanner stages and ECG. Unless otherwise 
noted, the baseline value is defined as the last available value before the first dose of double-
blind study treatment.        
4.8.1. 
Adverse Events Variables 
The period of safety observation starts from the time when the patient gives informed consent 
and continues into the following periods: 
• The pre-treatment period is defined from the day the ICF is signed to the day before 
the first dose of double-blind study treatment administration. 
• The double-blind treatment-emergent adverse event (TEAE) period is defined from 
the day of the first dose of double-blind study treatment administration to the day of 
the last dose of double-blind study treatment administration + 112 days (16 weeks) 
for those patients not proceeding into the OLTP 4 (i.e. patients who prematurely 
discontinue study treatment), or up to the day before the first dose of OLTP 4 study 
treatment administration for those patients proceeding into the OLTP 4. 
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• The OLTP 4 treatment-emergent adverse event (TEAE) period is defined from the 
day of the first OLTP 4 study treatment administration to the day of the last OLTP 4 
study treatment administration + 112 days (16 weeks) for those patients not 
proceeding into the OLTP 5 (i.e., patients who prematurely discontinue study 
treatment), or up to the day before the first dose of OLTP 5 study treatment 
administration for those patients proceeding into the OLTP 5.  
• The OLTP 5 treatment-emergent adverse event (TEAE) period is defined from the 
day of the first OLTP 5 study treatment administration to the day of the last OLTP 5 
study treatment administration + 112 days (16 weeks).  
• Adverse events reported after the end of the respective TEAE periods will be 
provided in a patient listing.   
4.8.1.1. 
Adverse Events and Serious Adverse Events 
Adverse events (including serious adverse events (SAE), AEs causing permanent treatment 
discontinuation, deaths, and AEs of special interest) are recorded from the time of signed 
informed consent until the end of study. All AEs diagnosed by the Investigator will be reported 
and described. 
All AEs will be dictionary coded by “lowest level term (LLT)”, “preferred term (PT)”, “high 
level term (HLT)”, “high level group term (HLGT)” and associated primary “system organ class 
(SOC)” using the latest version of MedDRA at the time of the first database lock. 
Adverse Event Observation Period  
• Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
• TEAEs are AEs that developed or worsened or became serious during the respective 
TEAE period.  
• Post-treatment AEs are AEs that developed or worsened or became serious after the 
end of the respective TEAE periods. 
4.8.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner. AESIs will be recorded on the 
adverse event e-CRF using dedicated tick boxes, and/or identified using standard MedDRA 
queries (SMQ), company MedDRA queries (CMQ), MedDRA terms, and/or applicable 
laboratory assessments. Appendix 10.3 contains the definitions used to identify AESIs: 
The AESIs include: 
• Hypoglycemia, defined as blood glucose <54 mg/dL (eCRF, lab data) 
• New onset diabetes mellitus (NODM) (eCRF, lab data) 
• Hyperglycemia requiring treatment: this is defined as: (eCRF, lab, concomitant 
medication) 
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• Development of new or worsening of autoimmune disease (eCRF) 
• Hypersensitivity reactions (CMQ, eCRF [moderate and severe only]) 
4.8.1.3. 
Adverse Events of Interest 
Adverse events of interest are AE’s for which additional documentation is collected. Adverse 
events of interest include: 
• Injection site reaction, collected from the eCRF  
• Infusion reaction collected from the eCRF 
4.8.1.4. 
Events Causing Death 
The observation periods for patient deaths are per the observation periods defined above.  
• Death on-treatment:  deaths occurring during the respective TEAE period, 
• Death post-treatment:  deaths occurring during the post-treatment period. 
4.8.2. 
Laboratory Safety Variables 
Clinical laboratory tests will consist of blood analyses (including hematology, clinical chemistry 
and other) and urinalysis. Clinical laboratory values will be converted and analyzed using the US 
conventional units, with associated normal ranges provided by the central laboratory. Both actual 
test values and “change from baseline” values (defined as the post-baseline value minus the 
baseline value) will be used in the result summaries.  Potentially clinically significant values 
(PCSV) ranges will be applied to the laboratory test values as applicable (see Appendix 10.4 for 
PCSV definitions). For those laboratory tests that do not have PCSV ranges, central laboratory 
normal ranges will be applied to identify out-of-range values.  All laboratory samples will be 
collected before study treatment administration during the protocol scheduled visits, unless 
otherwise indicated.  
Unless otherwise specified below, blood samples for clinical laboratories will be collected at the 
protocol scheduled visits. The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
Hematology: 
• Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, platelets 
count, red blood indices 
• White blood cells: white blood cells, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
Clinical chemistry: 
• Metabolism:  total protein, albumin, creatine phosphokinase 
• Electrolytes:  sodium, potassium, chloride, calcium, bicarbonate 
• Renal function:  creatinine, blood urea nitrogen (BUN), uric acid 
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• Liver function:  Alanine aminotransferase (ALT), aspartate aminotransferases (AST), 
alkaline phosphatase (ALP), total bilirubin, LDH 
Non-Efficacy Lipid Panel 
HDL-C, LDL-C, TC, Apo B, NMR lipoprotein analysis. 
Urinalysis 
Urinalysis will include the following parameters: color, clarity, pH, specific gravity, ketones, 
protein, glucose, blood, bilirubin, leukocyte esterase, nitrite, WBC, RBC, hyaline and other casts, 
bacteria, epithelial cells, crystals, and yeast. 
Other 
Sex hormones (luteinizing hormone, follicle stimulating hormone, estradiol, and total 
testosterone). 
4.8.3. 
Vital Signs 
Vital signs parameters will include weight (kg), height (cm), BMI (kg/m2), respiratory rate 
(breaths/min), temperature (C), systolic and diastolic blood pressure (mmHg) and pulse (bpm) 
after the patient has been sitting or in the supine position. Both actual values and “change from 
baseline” values (defined as the post-baseline value minus the baseline value) will be used in the 
result summaries. Potentially clinically significant values (PCSV) ranges will be applied to the 
vital sign parameter values as applicable (see Appendix 10.4 for PCSV definitions).   
4.8.4. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed at specified time points according to 
Appendix10.9.The ventricular rate, heart rate (bpm), PR or PQ, QRS, RR, QTcF, and QT 
intervals will be recorded.   Electrocardiogram assessments will be described as normal or 
abnormal. Potentially clinically significant values (PCSV) ranges will be applied to the selected 
ECG parameter values as applicable (see Appendix 10.4 for PCSV definitions).   
4.8.5. 
Tanner stages 
Tanner stage assessments will be performed at specified time points according to Appendix 10.9. 
Tanner stages (1, 2, 3, 4, 5) will be recorded based on sex. 
4.8.6. 
Physical Examination Variables 
Physical examination will be conducted at the protocol scheduled visits (See Appendix 10.9 for 
schedule of event). The result is an outcome of normal, abnormal, and if abnormal then clinically 
significant (Yes/No, not examined). 
4.9. 
Other Variables 
Other assessment endpoints are listed and defined below. Protocol schedule visits will be 
assigned to the Global Analysis Windows (See Appendix 10.2). 
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• Change from baseline in liver volume as measured by MRI at 
 
(only at sites with requisite capability)  
• Change from baseline in hepatic fat content by MRI-PDFF at 
 
(only at sites with requisite capability) 
• Change from baseline in liver stiffness as assessed by VCTE at 
 (only at sites 
with VCTE capability).  
• 
 
 
• Change from baseline in body composition (including absolute and percent lean mass 
and fat mass) using DXA at 
 (only at sites with whole body DXA 
capability). DXA analysis will occur on variables included but not limited to those  
listed in SAP Appendix 10.6.  
• Change from baseline in total sLEPR at 
 
4.10. 
Pharmacokinetic Variables 
Pharmacokinetic (PK) variables include concentrations of total drug and time as specified in the 
protocol.  
4.11. 
Immunogenicity Variables  
The immunogenicity variables include anti-drug antibody (ADA) status, and titer at nominal 
sampling time/visit. Serum samples for ADA will be collected at the clinic visits specified in 
Appendix 10.9.  
4.12. 
Quality of Life 
• Change over time in patient-reported outcomes measuring quality of life (S F-36; 
PedsQLTM), impacts on hunger and eating behaviors, and impacts on sensation of 
body temperature  
The Short Form – 36 Survey (SF-36) is a 36-item self-administered PRO measure assessing 
health-related quality of life (HRQoL) concepts relevant across age, disease, and treatment 
group. The SF-36 will be completed by patients ages 18 years of age and older. The SF-36 
assesses physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, and mental health. Patients answer questions assessing these 
concepts over the previous week using 3-, 5-, or 6-point Likert scales; scores range from 0 to 
100, with higher scores indicating better health. These eight scales can be aggregated into two 
summary measures: Physical (PCS) and Mental (MCS) Component Summary scores. 
The SF-36 endpoints include change from baseline in PCS and MCS at weeks 8, 16 and 24. 
The Pediatric Quality of Life Inventory (PedsQL™) 4.0 Generic Core Scales is a measure 
assessing HRQoL in children and adolescents. The PedsQL™ will be used to measure HRQoL 
in patients ages 12 to 17. The PedsQL™ is a 23-item measure that assesses physical functioning, 
emotional functioning, social functioning, and school/work/studies functioning. The instructions 
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for PedsQL™ ask how much of a problem each item has been over the past 7 days on a 5-point 
response scale, ranging from never a problem (0) to almost always a problem (4). The measure 
will be a self-administered PRO for patients ages 13 to 17 years (teen report) and for patients 12 
years of age (child form). The items for each of the teen and child forms for patients are 
essentially identical, differing primarily in the use of developmentally appropriate language. 
Items are reverse-scored and linearly transformed to a 0 to 100 scale so that higher scores 
indicate better HRQoL. The total scale score is computed as the sum of all the items over the 
number of items answered on individual scales.  
The PedsQL endpoint include change from baseline in total scale score at weeks 8, 16 and 24. 
4.13. 
Clinical Outcomes Assessment 
Hunger and Eating Behaviors Questionnaire  
The hunger and eating behaviors questionnaire is a novel daily PRO that measures hunger related 
to lipodystrophy. The PRO contains 4 daily items:  highest level of hunger, lowest level of 
hunger, how much time felt hungry, and frequency of fullness after eating meals or snacks.   
Each item consists of 5 categories.  The hunger and eating behaviors questionnaire include the 
below endpoints summarized at the weekly level for each patient. 
For each item, a variable will be created for each response category representing the number of 
days in a week that a patient reports a response in that category and an additional variable will 
created for the number of days in a week with missing data. 
Percentage of days in a week out of the number of non-missing days that a patient reports the 
following categories for each item: 
·      Highest level of hunger: “Quite hungry” or “Extremely hungry” 
·      Lowest level of hunger: “Not hungry at all” or “A little hungry” 
·      How much time felt hungry: “None of the time” or “A little of the time” 
·      Frequency of fullness after eating meals or snacks: “Most of the time” or “Every time” 
 
In addition for each item of the hunger and eating behaviors questionnaire, weekly averages out 
of the number of non-missing will be calculated and change from baseline will be summarized at 
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each post-baseline week. Values will be assigned to each categorical response as follows: 
 
Sensation of Body Temperature 
The Sensation of Body Temperature PRO is a de novo PRO that measures aspects related to 
body temperature sensation, cold and hot. The PRO contains 2 items, each with 5 categories.  
The Sensation of Body Temperature PRO endpoints for each item consist of the number and 
percentage of responses for each category at baseline and weeks 8, 16 and 24 as well as 
categorical shift responses from baseline to week 8, 16, and 24. 
PGI-S Hunger endpoints consists of the number and percentage of responses for each category at 
baseline and weeks 8, 16 and 24 as well as categorical shift responses from baseline to week 8, 
16, and 24. 
PGI-C Hunger endpoints consists of the number and percentage of responses for each category at 
weeks 8, 16 and 24. 
5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following information: the 
number of patients reflected in the calculation (n), mean, median, SD, minimum, and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized three times, specifically by study 
treatment sequence in the DBTP, by double-blind treatment sequence and all patients in OLTP 4, 
and by all patients in OLTP 5, unless otherwise noted. Double-blind treatment period summaries 
will be presented containing all patients in the double-blind safety analysis set, and respective 
open-label treatment period summaries will be presented with patients from their respective 
open-label safety analysis set.   
Definitions 
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For the analysis of safety data, the following definitions will be used to summarize data:  
• Study treatment sequence A: Defined as patients receiving placebo followed by low-
dose, followed by high-dose (Periods 1, 2 and 3 respectively) 
• Study treatment sequence B: Defined as patients receiving low-dose, followed by 
high-dose followed by high-dose (Periods 1, 2 and 3 respectively) 
• Study treatment dose groups: Defined as patients receiving placebo, low-dose, high-
dose (all high dose periods, including study treatment sequence B Period 3), 
regardless of study treatment sequence.  
5.2. 
Medical History  
Medical history will be descriptively summarized by study treatment sequence in the DBTP for 
patients in the double-blind safety analysis set. All reported patient’s medical history will be 
presented by PT, primary SOC and HLT.  The tables will be presented by SOC sorted 
alphabetically and decreasing patient frequency of HLT based on the double-blind treatment 
incidence in the study.  
Patient disease characteristics as described in section 4.2 will be summarized in the double-blind 
safety analysis set.  
5.3. 
Prior and Concomitant Medications  
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized by study 
treatment sequence in the DBTP for patients in the double-blind safety analysis set. Summaries 
will present patient counts (and percentages) for all prior medications, by decreasing frequency 
of the overall incidence of ATC followed by therapeutic class.  In case of equal frequency across 
anatomic or therapeutic categories, alphabetical order will be used. Patients will be counted once 
in each ATC category (anatomic or therapeutic) linked to the medication but may be counted 
several times for the same medication.  
For patients in the safety analysis set, all concomitant medications during the DBTP, dictionary 
coded by WHO-DD, will be descriptively summarized by study treatment sequence in the DBTP 
for patients in the double-blind safety analysis set. Summaries will present patient counts (and 
percentages) for the concomitant medication groups described in Section 4.3 for all concomitant 
medications, by decreasing frequency of the incidence of ATC followed by therapeutic class.  In 
case of equal frequency across anatomic or therapeutic categories, alphabetical order will be 
used. Patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication, hence may be counted several times for the same medication.   
For the OLTP 4, concomitant medications will be dictionary coded by WHO-DD and will be 
descriptively summarized as described for the DBTP. For patient in the OLTP 4 safety analysis 
set, medications will be summarized by double-blind treatment sequence and all patients 
receiving open-label study treatment. 
For the OLTP 5, concomitant medications will be dictionary coded by WHO-DD and will be 
descriptively summarized in the OLTP 5 safety analysis set, for all patients receiving open-label 
study treatment. 
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5.4. 
Prohibited Medications  
Listing of prohibited medications will be provided for the patients in the safety analysis set for 
the DBTP and respective OLTP. Prohibited medications are listed in the protocol and identified 
through medical review. 
5.5. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in the 
study as described in section 4.5, as well as the patient analysis populations. Patient disposition 
and analysis populations will be summarized three times, specifically by study treatment 
sequence in the DBTP, in OLTP 4 by double-blind treatment sequence and all patients receiving 
open-label study treatment, and in OLTP 5 for all patients, unless otherwise noted. Exception 
listings will be generated for any patient treated but not randomized, randomized but not treated, 
and treated differently than randomized. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
Study treatment exposure will be summarized three times, specifically by study treatment 
sequence for period 1 and again by study treatment sequence for the whole DBTP, study 
treatment sequence by study treatment dose groups and combined doses (regardless of study 
treatment sequence) in the DBTP, in OLTP 4 by double-blind treatment sequence and all 
patients, and in OLTP 5 by all patients, unless otherwise noted. Double-blind treatment period 
safety summaries will be presented containing all patients in the double-blind safety analysis set, 
and open-label treatment period safety summaries will be presented with patients from the 
respective open-label safety analysis set.  
5.6.1. 
Exposure to Investigational Product 
Study treatment exposure in the respective treatment periods and for the overall DBTP will be 
descriptively summarized for SC treatment duration and total number of SC study drug 
administrations as described in Section 4.6. Treatment duration and total number of study drug 
administration will be summarized using the number of patients with data, mean, SD, etc.  
Study treatment frequency in DBTP1 and DBTP2 will be descriptively summarized for IV 
treatment study drug administrations, specifically the number of infusions per patient. 
REGN4461 dosing exposure will be summarized cumulatively for OLTP, combining OLTP 4 
and OLTP 5 for all patients. 
Additionally, REGN4461 dosing exposure will be summarized cumulatively across the study, 
combining DBTP and OLTP for patients who received REGN4461 in the DBTP regardless of 
dose. 
5.6.2. 
Study Treatment Compliance 
Descriptive statistics of the dosing intervals for SC study drug administration will be 
summarized. Further, study treatment infusion interruptions and incomplete infusions with 
reason will be provided in a patient listing for those patients with incomplete infusions.  
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Important protocol deviations will be summarized for the DBTP. Both monitored and derived 
protocol deviations will be summarized for important deviation categories by count (percentage), 
and again by type of important deviation (patient count and percentage).  
5.7. 
Analyses of Efficacy Variables 
Efficacy results will be summarized three times, specifically by study treatment sequence and 
visit in the DBTP, by study treatment dose groups and combined doses (regardless of study 
treatment sequence) in the DBTP, in OLTP 4 by double-blind treatment sequence and all 
patients, and in OLTP 5 by all patients, unless otherwise noted. Double-blind treatment period 
efficacy summaries will be presented containing all patients in the double-blind FAS analysis set, 
open-label treatment period efficacy summaries will be presented with patients from respective 
open-label safety analysis set.  
Note: Caution should be used when interpreting the results of the summary by study treatment 
dose groups and combined doses (regardless of study treatment sequence) in the DBTP. In this 
analysis the carry over effect from period to period is ignored since a washout period was not 
designed into this study between active study treatment periods. 
Definitions 
For the analysis of efficacy data, the following definitions will be used to summarize data:  
• Study treatment sequence A: Defined as patients receiving placebo followed by low-
dose, followed by high-dose (Periods 1, 2 and 3 respectively) 
• Study treatment sequence B: Defined as patients receiving low-dose, followed by 
high-dose followed by high-dose (Periods 1, 2 and 3 respectively) 
• Study treatment dose groups: Defined as patients receiving placebo, low-dose, high-
dose (all high dose periods, including study treatment sequence B Period 3), 
regardless of study treatment sequence.  
All efficacy endpoints will be analyzed using lab values in conventional units.  
Comparisons between study treatment groups and within active treatment group comparisons to 
baseline in the DBTP will be provided with nominal p-values as appropriate. There will be no 
statistical hypothesis testing, so multiplicity adjustments do not apply.  
5.7.1. 
Analysis of Primary Efficacy Variables  
5.7.1.1. 
Analysis of the Primary Endpoints: Change in Fasting Glucose and HbA1C 
from Baseline 
For primary glycemic endpoints, change from baseline to week 8 in fasting glucose and HbA1c, 
will be analyzed in the FAS population for the subgroup of patients with baseline HbA1C≥7% 
(Glycemic Analysis Set) using a mixed-effect model with repeated measures (MMRM) 
approach. All post-baseline data available within week 4 to week 8 efficacy analysis windows 
for HbA1C and within 
fficacy analysis windows for fasting glucose will be 
used and missing data are accounted for by the MMRM model. Each model will include the 
fixed categorical effects of treatment sequence group (group A versus group B), time point 
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, treatment-by-time point 
interaction, baseline value, and baseline by visit interaction. Contrast and estimate statements 
will be used to assess the treatment effects (LS means with confidence intervals) and R4461 
mean difference from placebo with nominal p-value. An unstructured covariance structure will 
be used (if that does not converge, then structured covariance structures such as autoregressive 
heterogeneous [ARH] will be assessed). Parameters will be estimated using restricted maximum 
likelihood method with the Newton-Raphson algorithm.  Denominator degrees of freedom will 
be estimated using Satterthwaite’s approximation.    
To support interpretation of the fasting glucose and HbA1C results at week 8, descriptive 
summaries will be provided at each visit in the DBTP1(collected up to the day of the last study 
treatment administration + 14 days). Mean changes (±SE) will be plotted over time by the 
treatment sequence group. A spaghetti plot will be provided for individual patient data over time 
by the treatment sequence group.  
5.7.1.2. 
Analysis of the Primary Endpoint: Change in WMG from Baseline 
For the DBTP1 primary comparison of the R4461 group to the placebo group, the change from 
baseline in WMG at week 8 will be analyzed in the FAS population for the subgroup of patients 
with baseline HbA1C≥7%. The analysis method is an analysis of covariance (ANCOVA) to 
compare study treatment group differences (R4461 versus Placebo). This model will include the 
fixed categorical effects of study treatment sequence (treatment sequence A versus treatment 
sequence B), and continuous fixed covariate baseline value. Missing data will be imputed using 
multiple imputation based on other observed measurements, assuming Missing At Random. 
Missing WMG values will be imputed 100 times to generate 100 complete data sets. The results 
from the 100 analyses using ANCOVA model will be combined using Rubin’s formulae. 
Summary statistics including LS means change from baseline, standard error (SE), and 
corresponding 95% confidence interval will be provided for each treatment group. Mean 
difference between treatments with associated 95% CI and nominal p-value will also be 
provided. 
To support interpretation of the WMG modelled results at week 8, a descriptive summary of raw 
data will be provided at week 8 (collected up to the day of the last study treatment administration 
+ 14 days).  
5.7.1.3. 
Analysis of the Primary Endpoint: Percent Change in TG from Baseline 
For the DBTP1 primary comparison of the R4461 group to the placebo group, the percent change 
from baseline in fasting TG at week 8 will be analyzed in the FAS population for the subgroup of 
patients with baseline TG ≥250 mg/dL (Triglyceride Analysis Set). The analysis method is a 
robust regression model (Mehrotra 2012) to compare study treatment group differences (R4461 
versus Placebo), with the endpoint as the response variable using M-estimation (using SAS 
ROBUSTREG procedure). A natural log transformation will be applied to the TG value prior to 
analysis, aiming to provide a relatively normal data distribution. This model will include the 
fixed categorical effects of study treatment sequence (treatment sequence A versus treatment 
sequence B), and continuous fixed covariate of log transformed baseline value. Missing data will 
be imputed using multiple imputation based on other observed measurements, assuming Missing 
At Random. Data will be log-transformed before imputation process and then back transformed 
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to create the imputed data sets using the TRANSFORM statement of SAS MI procedure. 
Missing triglyceride values will be imputed 100 times to generate 100 complete data sets. The 
results from the 100 analyses using ROBUSTREG model will be combined using Rubin’s 
formulae. Summary statistics including LS means percent change from baseline, standard error 
(SE), corresponding 95% confidence interval will be provided for each treatment group. Mean 
difference between treatment groups with associated 95% CI and nominal p-value will also be 
provided. 
To support interpretation of the fasting TG results at week 8, descriptive summaries will be 
provided at each visit in the DBTP1(collected up to the day of the last study treatment 
administration + 14 days). Median changes (Q1, Q3) will be plotted over time by the treatment 
sequence group. A spaghetti plot will be provided for individual patient data over time by the 
treatment sequence group.  
5.7.1.4. 
Analysis of Primary Efficacy Endpoints: Subgroup Analyses 
The following subgroup of interest will be evaluated. Given the small number of patients in at 
least one subgroup level, an interaction term of treatment by subgroup in period 1 will not be 
used. The patient subgroup of interest will be analyzed as described above for each primary 
efficacy endpoint.  
• Objective evidence of low total body fat mass (TOT_PFAT) as demonstrated by 
DXA, or of low leptin levels as defined below, assessed during the baseline 
assessment: 
          Less than 20% total body fat by DXA (females), or less than 14% total body fat. 
          (males) 
          OR 
          Leptin levels ≤8.0 ng/ml. 
5.7.1.5. 
Supplemental Analyses of Primary Efficacy Endpoints 
Change from week 8 to week 16 for patients in Treatment Arm A will be provided to estimate 
the treatment effect of the low dose. If the patients do not have a significant reduction in HbA1c 
or TG from baseline to week 8, defined as change in HbA1c (absolute value change is less than -
0.4%, change in TG [percent change] is less than -20%), then their data from week 8 to week 16, 
after they have switched to the low dose of REGN4461, will be pooled with data from baseline 
to week 8 for patients in Treatment Arm B, to evaluate the treatment effect of low dose on the 
primary efficacy endpoints. Similarly, if there is not a significant reduction from baseline to 
week 8 for patients in Treatment Arm A, data from patients in Treatment Arm A (change from 
week 16 to week 24) will be pooled together with data from patients in Treatment Arm B 
(change from week 8 to week 16) to estimate the treatment effect of increasing the dose from a 
low-dose regime to a high-dose regime. These supplemental efficacy endpoints will be analyzed 
as described above for each of the primary efficacy measures (with the single exception, nominal 
p-values will not be provided). 
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5.7.2. 
Analysis of Secondary Efficacy Variables  
The seven secondary efficacy endpoints will be descriptively summarized at baseline and each 
post baseline visit (collected up to the day of the last study treatment administration + 14 days). 
Efficacy endpoint data will be summarized by at least patient number, mean, median, 95% CI, 
SD, min and max. These tables will be provided twice, once for patients in the FAS population 
and again for the subgroup of patients as follows: 
• Patient subgroup HbA1c ≥ 7%: HbA1C (Periods 2 and 3 only), WMG (Periods 2 and 
3 only), fasting glucose (Periods 2 and 3 only), glucose infusion rate (insulin 
sensitivity-clamp), glucose clearance rate (KITT from insulin sensitivity-ITT, glucose 
AUC0-4 during MMTT 
• Patient subgroup TG ≥ 250mg/dL: fasting TG (Periods 2 and 3 only) 
Analysis of Primary Efficacy Measures at Week 16 and Week 24 
For the primary efficacy measures (HbA1C, fasting glucose, WMG, fasting TG) at week 16 and 
24, these secondary efficacy endpoints will be analyzed for within–patient changes to baseline. 
The method of analysis is as described above in section 5.7.1 (with the single exception, nominal 
p-values will not be provided). 
Supplemental Analysis of MMTT 
The secondary efficacy measure MMTT will also be analyzed as described above in SAP Section 
5.7.1.5 for the HbA1C measure. 
Efficacy Composite Endpoint HbA1C and TG 
For this composite endpoint, the method of analyses is a mixed-effect model with repeated 
measures (MMRM) approach at week 8 in the FAS population. The analyses details will include 
the fixed categorical effects of treatment sequence group (group A versus group B), time point 
(week 8), treatment-by-time point interaction. Contrast and estimate statements will be used to 
assess the treatment effects (LS means with 95% confidence intervals) and R4461 mean 
difference from placebo, with 95% CI. 
5.8. 
Analysis of Safety Data 
Safety results will be summarized four times, specifically by study treatment sequence within 
each cumulative period (specifically, period 1, period 1+2, and period 1 + 2 + 3) in the DBTP, by 
study treatment dose groups and combined doses (regardless of study treatment sequence) in the 
DBTP, and in the OLTP 4 by double-blind treatment sequence and all patients receiving open-
label study treatment, and in OLTP 5 for all patients, unless otherwise noted. Double-blind 
treatment period safety summaries will be presented containing all patients in the double-blind 
safety analysis set, open-label treatment period safety summaries will be presented with patients 
from respective open-label safety analysis set. No formal inferential testing will be performed for 
the DBTP or OLTP. Summaries will be descriptive in nature. 
Note: Caution should be used when interpreting the results of the summary by study treatment 
dose groups and combined doses (regardless of study treatment sequence) in the DBTP. In this 
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analysis the carry over effect from period to period is ignored since a washout period was not 
designed into this study between active study treatment periods.  
Definitions 
For the analysis of safety data, the following definitions will be used to summarize data:  
• Study treatment sequence A: Defined as patients receiving placebo followed by low-
dose, followed by high-dose (Periods 1, 2 and 3 respectively) 
• Study treatment sequence B: Defined as patients receiving low-dose, followed by 
high-dose followed by high-dose (Periods 1, 2 and 3 respectively) 
• Study treatment dose groups: Defined as patients receiving placebo, low-dose, high-
dose (all high dose periods, including study treatment sequence B Period 3), 
regardless of study treatment sequence.  
General common rules 
All safety analyses will be performed, unless otherwise specified, using the following common 
rules: 
• Safety data in patients who do not belong to the safety analysis sets (i.e., exposed but 
not randomized) will be listed separately. 
• PCSV values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and 
defined by the Sponsor for clinical laboratory tests, vital signs, ECG (PCSV version 
dated January 2009 [Appendix 10.4]).  
• PCSV criteria will determine which patients had at least 1 PCSV during the 
respective TEAE periods, taking into account all evaluations including unscheduled 
or repeated evaluations. 
• The treatment-emergent PCSV denominator for a given parameter will be based on 
the number of patients assessed for that given parameter at least once during the 
respective TEAE periods. 
• All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned 
to Global Analysis Windows defined in Appendix 10.2 in order to provide an 
assessment for the screening visit through follow-up visit time points. 
• For quantitative safety parameters including central laboratory measurements and 
vital sign scores, descriptive statistics will be used to summarize observed values and 
change from baseline values by visit.  
• Unless otherwise specified, in the case of multiple assessments within an analysis 
window, the assessment closest to the protocol planned visit study day will be used in 
analysis. 
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5.8.1. 
Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs summarized in respective TEAE 
periods (i.e. blinded treatment period 1, blinded treatment period 1 + 2, blinded treatment period 
1 +2 + 3) by DBTP study treatment sequence, by study treatment dose groups and combined 
doses (regardless of study treatment sequence) in the DBTP, in OLTP 4 by double-blind 
treatment sequence and all patients, and in OLTP 5 by all patients, and OLTP combined (OLTP 
4 + OLTP 5) for all patients, unless otherwise noted. If an AE onset date (occurrence, worsening, 
or becoming serious) is incomplete, an imputation algorithm will be used to classify the AE as 
pre-treatment, treatment-emergent, or post-treatment.  The algorithm for imputing date of onset 
will be conservative and will classify an AE as treatment-emergent unless there is definitive 
information to determine pre-treatment or post-treatment status.  Details on classification of AEs 
with missing or partial onset dates are provided in Section 6.3. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC and PT. In addition, incidence tables by SOC, HLGT, HLT, and PT 
will be provided for all TEAEs, serious TEAEs, and TEAE leading to permanent treatment 
discontinuation. Multiple occurrences of the same event in the same patient will be counted only 
once in a table. For tables presenting severity of events, the worst severity will be chosen for 
patients with multiple instances of the same event. The denominator for computation of 
percentages is the respective safety analysis set. 
AE incidence tables will present data by SOC sorted alphabetically and PT sorted by decreasing 
frequency and summarize the number (n) and percentage (%) of patients experiencing an AE. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
• Overview of TEAEs, summarizing number (%) of patients with any 
− TEAE; 
− Serious TEAE; 
− TEAE leading to death; 
− TEAE leading to permanent treatment discontinuation. 
• All TEAEs by primary SOC, HLGT, HLT, and PT 
• All TEAEs by primary SOC and PT 
• Number (%) of patients experiencing common TEAE(s) presented by primary SOC 
and PT (PT incidence ≥ 2 patients in any treatment group)  
• All TEAEs relationship (related/not related) to REGN4461 
• All TEAEs by maximum severity (i.e., mild, moderate, or severe) 
Analysis of all treatment emergent serious adverse event(s) 
• All Serious TEAEs by primary SOC, HLGT, HLT, and PT 
• All Serious TEAEs by primary SOC and PT 
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• All Serious TEAEs relationship (related/not related) to REGN4461 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to permanent treatment discontinuation, by primary SOC, HLGT, 
HLT, and PT 
• All TEAEs leading to permanent treatment discontinuation, by primary SOC and PT 
Patient Deaths 
The following summaries of deaths will be generated. 
• Number (%) of patients who died by study period (TEAE and post-treatment) and 
reason for death;  
• TEAEs leading to death (death as an outcome on the AE CRF page, as reported by 
the Investigator) by SOC and PT. 
5.8.2. 
Analysis of Adverse Events of Special Interest  
Treatment-emergent adverse events of special interest (AESI), as listed in Section 4.8.1.2, will be 
presented by SOC and PT as applicable.  AESI are defined by SMQ, CMQ, lab data, and/or 
dedicated e-CRF are summarized by frequency (%) as described in Appendix 10.3. 
5.8.3. 
Adverse Events of Interest 
Treatment emergent adverse events for infusion reactions and injection site reactions will be 
summarized by patient frequency (%) as defined in section 4.8.1.3. TEAE’s will be presented by 
SOC and PT. 
The following summaries will also be presented for infusion reactions TEAEs: 
• Intensity of the event (mild, moderate, or severe)  
• Number of infusion reactions in the DBTP per patient 
The following summaries will also be presented for injection site reactions TEAEs 
• Intensity of the event (mild, moderate, or severe) 
• Summary by preferred ISR term 
5.8.4. 
Clinical Laboratory Measurements  
General clinical laboratory parameter actual values (quantitative) and change from baseline 
values will be descriptively summarized at baseline and each post-baseline visit (collected up to 
the day of last dose of study treatment + 14 days). These parameters will be presented by the 
biological functions defined in Section 4.8.2.  
Individual patient laboratory parameter measurements will be additionally evaluated by PCSV 
criteria (See Appendix 10.4), specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the respective TEAE periods. These laboratory 
parameters will be presented by the biological functions defined in Section 4.8.2. The incidence 
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of PCSVs at any time during the respective TEAE periods will be summarized regardless of the 
baseline level, and again according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of laboratory measurements that meet PCSV criteria will be provided for the 
report appendix.  For those laboratory parameters that don’t have an associated PCSV criteria, 
similar summary tables can be provided based on measurements outside the central laboratory 
normal ranges, if applicable. 
Drug-induced liver injury 
For respective treatment period, an evaluation of drug-induced serious hepatotoxicity (eDISH) 
with the graph of distribution of peak values of ALT versus peak values of total bilirubin will 
also be presented using post-baseline values during respective TEAE periods. Note that the ALT 
and total bilirubin values are presented on a logarithmic scale.  
Patient listing of possible Hy’s law cases identified (i.e., patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin >2 x ULN, concomitantly or not) 
with ALT, AST, ALP, total bilirubin, and if available direct and indirect bilirubin will be 
provided. 
5.8.5. 
Analysis of Vital Signs 
The vital sign actual values and change from baseline values obtained will be descriptively 
summarized at baseline and each post-baseline visit (collected up to the day of last dose of study 
treatment + 14 days). 
Individual patient vital sign measurements (regardless of sitting position) will be additionally 
evaluated by PCSV criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSV criteria within the TEAE period.  The incidence of PCSVs at 
any time during the respective TEAE periods will be summarized regardless of the baseline 
level, and again according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of vital sign measurements that meet PCSV criteria will be provided for the 
report appendix.   
5.8.6. 
Analysis of 12-Lead ECG 
ECG results will be presented through an overall interpretation of ECG status and by ECG 
parameters (HR, PR, QRS, QT and QTcF), collected up until the day of the last dose of study 
treatment + 14 days.  
ECG parameters will be summarized through an overall interpretation of ECG status, specifically 
normal or abnormal (includes clinically significant (Yes/No)). The count and percentage of 
patients with at least 1 abnormal post-baseline ECG during the respective TEAE period will also 
be summarized according to the following baseline status categories:  
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• Normal/missing; 
• Abnormal 
Individual patient ECG measurements will be additionally evaluated by PCSV criteria, 
specifically identifying patients with at least one post-baseline measurement that meets the 
PCSV criteria within the TEAE period.  The incidence of PCSVs at any time during the 
respective TEAE periods will be summarized regardless of the baseline level, and again 
according to the following baseline categories: 
• Normal (according to PCSV criterion/criteria)/missing 
• Abnormal according to PCSV criterion or criteria 
Patient listings of ECG measurements that meet PCSV criteria will be provided for the report 
appendix.   
5.8.7. 
Tanner Stages 
Tanner stages (outcome categories of 1, 2, 3, 4, 5) will be summarized for adolescent patients 
(<18 years of age), by patient frequency and percentage at baseline and each post-baseline visit 
(collected up the day of the last dose of study treatment + 14 days). Post baseline Tanner stage 
categories will also be assessed by the patient’s Tanner stage at baseline.  
5.8.8. 
Physical Exams 
A list of patients with any clinically significant abnormality results will be generated. 
5.9. 
Analysis of Other Variables 
All measurements, scheduled or unscheduled, will be assigned to Global Analysis Windows 
(Appendix 10.2) in order to provide an assessment for all post-baseline visit.   
Change from baseline liver volume and hepatic fat content by MRI will be descriptively 
summarized by treatment group (treatment arm A, treatment arm B) at weeks 8, 24 and 52 for 
patient in the MRI analysis set. Mean difference between treatments with associated 95% CI will 
also be provided at week 8. 
 
 
 
Change from baseline in liver stiffness as assessed by VCTE at week 52 will be descriptively 
summarized by treatment group (treatment arm A, treatment arm B) in patients in FAS and have 
the week 52 assessment. 
Change from baseline in body composition (including lean mass and fat mass) using DXA at 
weeks 8, 24, and 52 will be descriptively summarized by treatment group (treatment arm A, 
treatment arm B) in patients in FAS and have at least one post-baseline assessment. 
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Change from baseline in total sLEPR at 
, will be 
descriptively summarized by treatment group (treatment arm A, treatment arm B) in patients in 
FAS and have at least one post-baseline assessment. 
Summary statistics will include the number of patients with data, mean, SD, median, minimum, 
maximum, Q1 and Q3. 
5.10. 
Analysis of Pharmacokinetic Variables  
Descriptive statistics for concentrations of total drug will be presented. Mean concentrations will 
be tabulated by visit and treatment group, with concentrations below the LLOQ set to zero. Plots 
of the mean concentrations (linear and log scales) will be presented by nominal sampling time. 
Plots of the individual concentrations (linear and log scales) will be presented by actual sampling 
time. In the linear-scaled plots, concentrations below the LLOQ will be set to zero; in the log-
scaled plots, concentrations below the LLOQ will be imputed as LLOQ/2. Where appropriate, 
relationship between concentrations of total drug and other pharmacodynamic biomarkers 
including, but not limited to, changes in endpoints of interest (e.g. HbA1c, glucose, WMG, and 
TG) may be evaluated descriptively.  
5.11. 
Analysis of Immunogenicity Data 
The immunogenicity variables described in Section 4.11 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA status, ADA category and maximum 
titer observed in patients in the ADA analysis set.  
The ADA status of each patient may be classified as one of the following:  
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 9-fold the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay. 
The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥9-fold the baseline titer value  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent 
will be further categorized as follows: 
Treatment-emergent is further sub-categorized as: 
− Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 16-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
− Transient - Not persistent or indeterminate, regardless of any missing samples 
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− Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
The maximum titer category of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
Samples that are positive in ADA assay may be assessed for the presence of neutralizing anti-
drug antibodies (NAb) when NAb assay is available.   
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative patients 
• Number (n) and percent (%) of patients with pre-existing ADA 
• Number (n) and percent (%) of treatment-emergent ADA positive patients 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-
emergent, and treatment-boosted ADA response. 
5.11.1. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.11.1.1. Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to REGN4461 will be 
explored by treatment groups. Plots of individual REGN4461 concentration time profiles may be 
provided to examine the potential impact of ADA by maximum titer on these profiles.  
5.11.1.2. Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety will be explored with a 
primary focus on adverse events during the TEAE period. 
• Injection site reaction (serious or severe and lasting 24 hours or longer)  
• Infusion reactions   
• Hypersensitivity (SMQ: Hypersensitivity [Narrow])  
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
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Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g., scatter plot or spaghetti plot). 
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
− ADA Positive 
• Treatment-emergent 
• Treatment-boosted 
− Maximum post-baseline titer category 
5.12. 
Analysis of Quality of Life Variables 
The summary of results for quality-of-life variables will be presented by treatment groups 
(treatment arm A, treatment arm B) containing patients from the full analysis set, unless 
otherwise specified.  
The baseline value is defined as the last available measurement prior to the date of the first 
double-blind study treatment administration. All measurements, scheduled or unscheduled, will 
be assigned to Global Analysis Windows (Appendix 10.2) in order to provide an assessment for 
all post-baseline visit.   
For the SF-36 and PedsQL, raw value and change from baseline will be summarized using mean, 
median, SD, min, max, Q1, Q3 for each post baseline visit among the SF-36 and PedsQL 
analysis set respectively. 
5.13. 
Analysis of Clinical Outcome Assessment 
The summary of results for clinical outcomes assessments will be presented by treatment groups 
(treatment arm A, treatment arm B) containing patients from the full analysis set, unless 
otherwise specified.  
For each item in the Hunger and Eating Behaviors questionnaire, the variables representing the 
number of days in a week that a patient reports a response in each category and the variable for 
the number of days in a week with missing data will be treated as continuous and summarized 
using descriptive statistics (mean, median, SD, min, max, Q1, Q3) for each week.  Similarly, for 
each item, the percentage of days in a week out of the number of non-missing days that a patient 
reports the pre-specified categories (Section 4.13) will be treated as continuous and summarized 
using descriptive statistics (mean, median, SD, min, max, Q1, Q3) for each week.  Additionally, 
the weekly average value and change from baseline will be summarized using mean, median, 
SD, min, max, Q1, Q3 for each post baseline visit.  
For categorical variables from the Sensation of Body Temperature PRO and the PGI-S Hunger, 
the frequency and percentage in each category will be displayed at baseline and weeks 8, 16 and 
24.  Shift tables from baseline will be conducted among those with a baseline value at weeks 8, 
16 and 24.  For the PGI-C Hunger, the frequency and percentage in each category will be 
displayed at weeks 8, 16 and 24.  
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment is programmatically defined as the last 
available measurement prior to the date of the first double-blind study treatment administration. 
For patients randomized and not treated, the baseline value is defined as the last available value 
prior to the date of randomization. 
6.2. 
Data Handling Convention for Efficacy Variables  
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 5.7.1 and Section 5.7.2. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings.  This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Date and Time of First/Last Study Treatment 
The date and time of study drug administration are filled in e-CRF. No missing data is expected. 
Date of first/last administration is the first/last start date of study drug provided in e-CRF. 
Adverse Event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
When the partial AE date/time information does not indicate that the AE started prior to study 
treatment or after the TEAE period, the AE will be classified as treatment-emergent. 
Medication/Procedure 
No imputation of medication/procedure start/end dates or times will be performed.  If a 
medication date or time is missing or partially missing and it cannot be determined whether it 
was taken prior or concomitantly or stopped prior to the first study treatment administration, it 
will be considered as concomitant medication/procedure. 
Potentially Clinically Significant Value (PCSV) 
If a patient has a missing baseline value, this patient will be grouped in the category 
“normal/missing at baseline.” 
For PCSVs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSV will be based 
only on the second condition. 
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For a PCSV defined on a threshold and/or a normal range, this PCSV will be derived using this 
threshold if the normal range is missing; e.g., for eosinophils the PCSV is >0.5 giga/L or >ULN 
if ULN ≥0.5 giga/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSVs. 
6.4. 
Visit Windows 
Visit windows will be programmatically imposed on those efficacy and safety measures 
repeatedly collected over the course of the study. These visit windows are derived from the 
number of days in study, specifically assigning day ranges to represent the study assessment 
schedule provided in the protocol.  Data analyzed by time point (including efficacy, laboratory 
safety data, vital signs, and ECG) will be summarized using the analysis windows given in 
Appendix 10.2 (i.e. efficacy analysis windows for Part B efficacy and global analysis windows 
for others). These analysis windows will be applicable for all efficacy and safety analyses, and 
they are defined to provide more homogeneous data for time point-specific analyses. If multiple 
valid values of a variable exist within an analysis window, the nearest from the targeted study 
day will be selected for analysis, unless otherwise specified. If the difference is a tie, the value 
after the targeted study day will be used. If multiple valid values of a variable exist within a same 
day, then the first value of the day will be selected when time is available, else the scheduled 
visit will be selected. 
6.5. 
Unscheduled Assessments 
For efficacy, safety laboratory data, vital signs, and ECG, unscheduled visit measurements may 
be used to provide a measurement for a time point, including baseline, if appropriate according 
to their definitions. The measurements may also be used to determine abnormal values, AESIs, 
and PCSVs. 
6.6. 
Pooling of Centers for Statistical Analyses 
Not applicable. 
6.7. 
Statistical Technical Issues 
Not applicable.  
7. 
TIMING OF STATISTICAL ANALYSES 
7.1. 
Interim Analysis: PK and Safety Analysis for Part A  
An interim analysis will be performed after at least 4 patients complete 
 
 
 as of the cut-off date of Dec 1, 2021. The goal of the interim analysis is to assess 
whether the doses selected achieved the expected drug concentrations and PK profiles, and 
effects on glycemic and lipid parameters. 
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7.2. 
Timing of Planned Analyses  
The first-step analysis will be conducted as soon as all patients have been randomized and all 
data through week 36 has been entered, cleaned and locked. The first-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include the primary and secondary endpoints collected during the double-blind period, as well as 
the open-label week 36 visit in Period 4. 
The second-step analysis will be conducted as soon as all patients have been randomized and all 
data through week 56 has been entered, cleaned and locked. The second-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include pharmacokinetic and safety measures. 
The third-step analysis will be conducted as soon as all patients have been randomized and all 
data through week 64 has been entered, cleaned and locked. The third-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include efficacy, pharmacokinetic and safety measures. 
The fourth-step analysis will be conducted as soon as all patients have been randomized and all 
data through week 76 has been entered, cleaned and locked. The fourth-step analysis will be 
conducted on all randomized patients who receive study treatment. These statistical analyses will 
include efficacy, pharmacokinetic and safety measures. 
7.3. 
Fifth Step and Final Analysis 
The fifth-step and final analysis will be conducted at the end of the study, and will consist of the 
final analysis for efficacy, pharmacokinetic and safety measures. 
7.4. 
Additional Rules 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply for analyses performed at 
first through fourth step analyses: 
• Any lipid assessments within efficacy analysis windows up to the OLTP 5 week 52 
visit will be taken into account (may include few unscheduled lipid data soon after the 
cut-off date).  
• Patients without end of treatment visit performed at the time of the cut-off date will 
be considered as ongoing and exposed up to the cut-off date.  
• Patients who did not complete the respective treatment period nor prematurely 
discontinued the study treatment at cut-off date will be: 
− Analyzed as “ongoing” in the disposition summary. 
− Their TEAE period and treatment period will end at the respective data cut-off 
date. 
− Their treatment duration will be derived by considering date of cut-off as last 
administration date.  
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− Analyses of number of IP administrations, and mean IP administration frequency 
will be performed up to the last administration reported in the e-CRF up to the 
cut-off date.  
− AEs occurring, worsening or becoming serious after the cut-off date will not be 
included in the analyses. However, any available outcome before database lock, 
regardless of timing in relation to the cut-off date, of an adverse event starting 
prior to the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions and deaths occurring after the cut-off date will not 
be included in the analyses.  
− Post-treatment period, and post-study period are not applicable for ongoing 
patients. Analyses of post-study deaths and post-treatment medications will be 
performed for patients who either completed or prematurely discontinued the 
treatment before or at the data cut-off date. 
− Analysis of status at last study contact and proportion of patients with insufficient 
follow-up will be provided for patients who either completed or prematurely 
discontinued the treatment before or at the data cut-off date. 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. WHO Multicenter Growth Reference Study Group. WHO Child Growth Standards: 
Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body 
mass index-for-age: Methods and development. Geneva: World Health Organization; 
2006. 
3. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The 
prevention and treatment of missing data in clinical trials. N Engl J Med. 2012 Oct 
4;367(14):1355-60. doi: 10.1056/NEJMsr1203730. 
4. FDA. Briefing Document: BLA 125390, Myalept (metreleptin for injection).  2013;  
Research CfDEa, editorFDA Maryland. 
5. Myalepta. Myalepta [product label on the internet]. Windsor (UK): Aegerion 
Pharmaceuticals Ltd., 2018. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/004218/WC500253136.pdf 2018. 
6. Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data 
using multiple imputation in conjunction with robust regression. Biometrics. 2012 
Dec;68(4):1250-9. doi: 10.1111/j.1541-0420.2012.01780.x.
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Primary Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
In patients with elevated baseline 
HBA1c (HbA1c 
7%), absolute 
change from baseline to the end of the 
DBTP 1 in: 
− HbA1c (week 8) 
− Fasting glucose (week 
8) 
− WMG (week 8) 
In 
patients 
with 
elevated 
baseline fasting TG (fasting TG 
250 mg/dL), percent change 
from baseline to the end of the 
DBTP 1 in fasting TGs  
 
Glycemic Analysis 
Set  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Triglyceride 
Analysis Set 
MMRM 
 
No 
 
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10.2. 
Windows for Analysis Time Points 
Below are the definitions for the visit windows programmatically imposed on measures repeatedly collected over the course of the 
study.  These visit windows reflect the study schedule of assessments as described in the protocol.  
The visit windows are constructed using ranges applied to the number of days in study (study days) when the measure is collected. 
Below are the relevant definitions for the analysis visit windows:  
1. Study day is defined as the number of days since the first study treatment administration +1. The first study treatment occurs 
on Study Day 1. 
2. Open-label study day is defined as the number of days since the first open-label study treatment administration+1 
3. Since the protocol specifies that measurements be collected before study treatment is administered on a given day, it is 
appropriate that baseline include Day 1. 
4. For randomized but not treated patients, Day 1 is the day of randomization.   
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Table 1: 
General Global Analysis Windows  
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Table 2: 
Efficacy Analysis Windows  
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Table 3: 
Double-blind treatment period – Period Windows 
For those measurements that are collected cumulatively over time (example AE’s), analyses performed within the 8-week period 
windows will use the following definitions to bin observations. Observations will be binned based on the start date of the 
measurement.  
• The blinded treatment Period 1 is defined as the day from first dose of study drug to the day before study drug administered 
at the week 8 visit. 
• The blinded treatment Period 2 is defined as the time from the study drug administered at the week 8 visit to the day before 
study drug administered at the week 16 visit. 
• The blinded treatment Period 3 is defined as the time from the study drug administered at the week 16 visit to the week 24 
visit for those patients not proceeding into the OLTP. For those patients proceeding into the OLTP, Period 3 ends the day 
before first study drug administered in OLTP. 
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10.3. 
List of AESIs with Data Sources and Definitions of SMQ/CMQ 
Table 4 Summary of AESIs and the Methods of Data Collections and Derivations 
AESI 
Using an e-CRF specific tick box on 
AE page 
Using Standard MedDRA Query 
(SMQ)/company MedDRA Query (CMQ) or 
Laboratory data criteria 
Hypoglycemia 
Yes 
• Blood glucose <54 mg/dL 
New onset diabetes mellitus (NODM) 
Yes 
For patients with no diabetes at baseline: 
• Two values of fasting (≥8 hr) plasma glucose 
≥126 mg/dL (7.0 mmol) during treatment 
period 
OR 
• Two values of HbA1c ≥6.5% (48 mmol/mol) 
during treatment period 
Note: Patients who meet either of these criteria 
during the PBO run-in period will be considered 
to have diabetes at baseline. 
Hyperglycemia requiring treatment 
Yes  
N/A 
Development of new or worsening of 
autoimmune disease 
Yes 
N/A 
Hypersensitivity reactions 
  
Yes 
• CMQ ‘Hypersensitivity, which is defined as 
Hypersensitivity SMQ (narrow) excluding the 
following PTs: 
o Injection site dermatitis,  
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o Injection site eczema, 
o  Injection site hypersensitivity, 
o  Injections site rash, 
o  injection site reaction,  
o Injection site recall reaction,  
o Injection site urticaria,  
o Injection site vasculitis 
^ dedicated CRF for ISR captures event PT and associated symptoms  
10.4. 
Criteria for Potentially Clinically Significant Values (PCSV)  
Parameter 
PCSV 
Comments 
Clinical chemistry 
ALT 
By distribution analysis: 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
 
AST 
By distribution analysis: 
>2 ULN and baseline ≤ 2 ULN 
>3 ULN and baseline ≤ 3 ULN 
>5 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
 
Alkaline Phosphatase 
> 1.5 ULN and baseline ≤ 1.5 ULN 
 
Total Bilirubin 
> 1.5 ULN and baseline ≤ 1.5 ULN 
> 2 ULN and baseline ≤ 2 ULN 
 
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Parameter 
PCSV 
Comments 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 ULN and baseline 
ALT≤3 ULN or Total bilirubin ≤ 2 ULN 
 
CPK 
> 3 ULN and ≤ 5 ULN and baseline ≤ 3ULN 
>5 ULN and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 ULN and baseline ≤ 10 ULN 
  
Creatinine 
 30% increase from baseline 
 60% increase from baseline 
 
Creatinine Clearance 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
 
 
Uric Acid 
Hyperuricemia 
 
>408 μmol/L 
 
 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
Hypochloremia: 
Hyperchloremia: 
 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
129 mmol/L  
 150 mmol/L  
Must also be outside the normal range. 
 
Potassium 
< 3  mmol/L 
 5.5 mmol/L  
Must also be outside the normal range. 
 
Total Cholesterol 
>6.20 mmol/L (Under 18 yrs) 
>7.74 mmol/L (18 yrs +) 
Must also be outside the normal range. 
 
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Parameter 
PCSV 
Comments 
Triglycerides 
> 5.6 mmol/L if baseline < 5.6 mmol/L 
or 
>50% from baseline 
Must also be outside the normal range. 
Glucose 
  
  
Hypoglycemia <3.9 mmol/L or 70 mg/dL  
 
Hyperglycemia  
Fasting glucose ≥250 mg/dL or 13.9mmol/L 
and 
Increase in fasting glucose >50 mg/dL or 2.8mmol/L above 
baseline 
Must also be outside the normal range. 
 
 
 
 
HbA1c  
HbA1c ≥10.5% AND increase in HbA1c of ≥1.5% from 
baseline value  
 
 
Albumin 
≤25 g/L 
 
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Parameter 
PCSV 
Comments 
Hematology 
WBC 
<4.5 GIGA/L or 4,500 /mm3 (12 to 17 yrs) 
>13.5 GIGA/L or 13,500 /mm3 (12 to 17 yrs) 
< 3.0 Giga/L (3000/mm3)  
≥ 16.0 Giga/L (18 yrs +) 
Must also be outside the normal range. 
 
Lymphocytes 
>4.0 Giga/L 
<0.6 Giga/L 
 
Neutrophils 
<1.2 GIGA/L or 1,200 /mm3 (2 to 17 yrs) 
> 1 ULN (2 to 17 yrs) 
< 1.5 Giga/L (1,500/mm3) 
Must also be outside the normal range. 
 
Eosinophils 
> 0.5 Giga/L (500/ mm3) 
or > ULN if ULN ≥ 0.5 Giga/L 
 
Monocytes 
>1.5 Giga/L 
 
Hemoglobin 
< 1.55 mmol/L or10.0 g/dL or any decrease > 0.31 mmol/L or 
2 g/dL (2 to 17 yrs) 
≤115 g/L (Male 18 yrs +) 
≤95 g/L (Female 18 yrs +) 
≥185 g/L (Male 18 yrs +) 
≥165 g/L (Female 18 yrs +) 
Decrease from Baseline ≥20 g/L (18 yrs +) 
Must also be outside the normal range. 
 
Platelets 
< 100 Giga/L (100,000/mm3) 
> 700 Giga/L (100,000/mm3) 
Must also be outside the normal range. 
 
Hematocrit  
 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
 
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Parameter 
PCSV 
Comments 
Vital Signs 
HR 
≤45 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
 
SBP 
≤90 mmHg and decrease from baseline ≥20 mmHg (12 to 17 
yrs) 
≥130 mmHg and increase from baseline ≥20 mmHg (12 to 17 
yrs) 
 90 mmHg and decrease from baseline  20 mmHg (18 yrs +) 
 160 mmHg and increase from baseline  20 mmHg (18 yrs 
+) 
 
DBP 
≤54 mmHg and decrease from baseline ≥10 mmHg (12 to 17 
yrs) 
≥78 mmHg and increase from baseline ≥10 mmHg (12 to 17 
yrs) 
 45 mmHg and decrease from baseline  10 mmHg (18 yrs +) 
 110 mmHg and increase from baseline  10 mmHg (18 yrs 
+) 
 
 
Weight 
 10% decrease versus baseline 
 
ECG parameters 
  
HR 
≤45 bpm and decrease from baseline ≥20 bpm (12 to 17) 
≥120 bpm and increase from baseline ≥20 bpm (12 to 17) 
≤45 bpm and decrease from baseline ≥20 bpm (18 yrs +) 
≥120 bpm and increase from baseline≥20 bpm (18 yrs +) 
 
PR 
 180 ms (12 to 17 yrs) 
>220 ms and increase from baseline ≥20 ms (18 yrs +) 
 
 
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Parameter 
PCSV 
Comments 
QRS 
 110 ms (12 to 17 yrs) 
>110 ms and increase from baseline ≥20% (18 yrs +) 
>120 ms and increase from baseline ≥20% (18 yrs +) 
 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms)  
Borderline:  
431-450 ms (Boys, Male) 
451-470 ms (Girls, Female) 
 
Prolonged*:  
>450 ms (Boys, Male) 
> 470 ms (Girls, Female) 
QTc ≥500 ms 
 
Increase versus baseline (Males and Females) 
Borderline 30-60 ms 
Prolonged*: >60 ms  
 
To be applied to QTcF correction formulas  
 
 
 
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10.5. 
NMR Lipoprotein analysis 
The following data fields are reported in the Lipoprotien NMR. The data are analyzed by two separate algorithms (denoted 3 and 4 
respectively). Therefore, names have a 3 or 4 at the end of the data field label. For example, VLDLCP3 is the VLDL & chylomicron 
particles (total) using algorithm 3 and VLDLCP4 is the VLDL & chylomicron particles (total) using algorithm 4. Some of the 
variables are measured identically regardless of which algorithm is used, for example ELP_TC which is the total cholesterol. 
VLDL & 
Chylomicron 
Particles 
(total) 
nmol/L 
VLDLCP3 
Large VLDL 
& 
Chylomicron 
Particles 
nmol/L 
VLCP3 
Medium 
VLDL 
Particles 
nmol/L 
VMP3 
Small VLDL 
Particles 
nmol/L 
VSP3 
LDL 
Particles 
(total) 
nmol/L 
LDLP3 
IDL Particles 
nmol/L 
IDLP3 
Large LDL 
Particles 
nmol/L 
LLP3 
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Small LDL 
Particles 
(total) 
nmol/L 
LSP3 
HDL 
Particles 
(total) 
µmol/L 
HDLP3 
Large HDL 
Particles 
µmol/L 
HLP3 
Medium HDL 
Particles 
µmol/L 
HMP3 
Small HDL 
Particles 
µmol/L 
HSP3 
VLDL Size 
nm 
VZ3 
LDL Size 
nm 
LZ3 
HDL Size 
nm 
HZ3 
Non-gender 
specific 
  
LPIR 
Total 
Cholesterol 
mg/dL 
ELP_TC 
HDL 
Cholesterol 
mg/dL 
ELP_HDLC 
Triglycerides 
mg/dL 
ELP_TG 
ApoB 
mg/dL 
ELP_APOB 
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              AND 
               
VLDL & 
Chylomicron 
Particles 
(total) 
nmol/L 
VLDLCP4 
Large VLDL 
& 
Chylomicron 
Particles 
nmol/L 
VLCP4 
Medium 
VLDL 
Particles 
nmol/L 
VMP4 
Small VLDL 
Particles 
nmol/L 
VSP4 
LDL 
Particles 
(total) 
nmol/L 
LDLP4 
IDL Particles 
nmol/L 
IDLP4 
Large LDL 
Particles 
nmol/L 
LLP4 
Small LDL 
Particles 
(total) 
nmol/L 
LSP4 
LDL 
Cholesterol 
mg/dL 
ELP_LDLC 
VLDL 
Cholesterol 
mg/dL 
ELP_VLDLC 
Non HDL 
Cholesterol 
mg/dL 
ELP_NONHDLC 
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HDL 
Particles 
(total) 
µmol/L 
HDLP4 
Large HDL 
Particles 
µmol/L 
HLP4 
Medium HDL 
Particles 
µmol/L 
HMP4 
Small HDL 
Particles 
µmol/L 
HSP4 
VLDL Size 
nm 
VZ4 
LDL Size 
nm 
LZ4 
HDL Size 
nm 
HZ4 
Non-gender 
specific 
  
LPIR 
Total 
Cholesterol 
mg/dL 
ELP_TC 
HDL 
Cholesterol 
mg/dL 
ELP_HDLC 
Triglycerides 
mg/dL 
ELP_TG 
ApoB 
mg/dL 
ELP_APOB 
LDL 
Cholesterol 
mg/dL 
ELP_LDLC 
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VLDL 
Cholesterol 
mg/dL 
ELP_VLDLC 
Non HDL 
Cholesterol 
mg/dL 
ELP_NONHDLC 
 
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10.6. 
DXA Variable List 
LARM_AREA 
LARM_BMC 
LARM_BMD 
LARM_FAT 
LARM_LEAN 
LARM_CR 
RARM_AREA 
RARM_BMC 
RARM_BMD 
RARM_FAT 
RARM_LEAN 
RARM_CR 
LLEG_AREA 
LLEG_BMC 
LLEG_BMD 
LLEG_FAT 
LLEG_LEAN 
LLEG_CR 
RLEG_AREA 
RLEG_BMC 
RLEG_BMD 
RLEG_FAT 
RLEG_LEAN 
RLEG_CR 
TRUNK_FAT 
TRUNK_LEAN 
ANDRD_FAT 
ANDRD_LEAN 
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GYND_FAT 
GYND_LEAN 
HEAD_AREA 
HEAD_BMC 
HEAD_BMD 
HEAD_FAT 
HEAD_LEAN 
HEAD_CR 
LEG_AREA 
LEG_BMC 
LEG_BMD 
LEG_FAT 
LEG_LEAN 
LEG_CR 
ARM_AREA 
ARM_BMC 
ARM_BMD 
ARM_FAT 
ARM_LEAN 
ARM_CR 
TOT_AREA 
TOT_BMC 
TOT_BMD 
TOT_FAT 
TOT_LEAN 
TOT_PFAT 
TOT_CR 
TOT_ZSCORE 
TOT_ZSCORE_CR 
ADJTOT_AREA 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 78 of 114 
 
CONFIDENTIAL 
ADJTOT_BMC 
ADJTOT_BMD 
ADJTOT_FAT 
ADJTOT_LEAN 
ADJTOT_PFAT 
ADJTOT_CR 
ADJTOT_ZSCORE 
ADJTOT_ZSCORE_CR 
VATMASS 
VATVOL 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 79 of 114 
 
CONFIDENTIAL 
10.7. 
Calculation for Efficacy Variables 
Weighted Mean Glucose (WMG) 
(mg/dL) 
(Xt-15+ Xt0)*(t0 – t-15)  + (Xt0 + Xt1)*(t1 – t0)  + … (Xt10 + Xt11)*(t11 – t10)   
                2                                       2                               2 
                                                t11 – t-15 
Note: Xti is the value of glucose at time ti (actual time) 
t-15= -15 minutes (pre-meal) (MMTT CRF) 
t0= 0 minutes (pre-meal) (MMTT CRF) 
t1= 30 minutes (MMTT CRF) 
t2= 60 minutes (MMTT CRF) 
t3= 90 minutes (MMTT CRF) 
t4= 120 minutes (MMTT CRF) 
t5= 180 minutes (MMTT CRF) 
t6= <30 mins prior to lunch (WMG CRF) 
t7= 120 mins after lunch (WMG CRF) 
t8= <30 mins prior to dinner (WMG CRF) 
t9= 120 mins after dinner (WMG CRF) 
t10= 10 PM or Bedtime (WMG CRF) 
t11 = next morning fasting glucose measurement 
Glucose AUC0-4 during an MMTT 
(mg/dL*minutes) 
(Xt1+Xt0)*(t 1- t0)   + (Xt1 + Xt2)*(t2 - t1)  + …. (Xtn + Xt(n-1))*(tn – t(n-1))   
       2                                     2                                            2 
Note: Xti is the value of glucose at time ti 
t0= 0 minutes 
t1= 30 minutes 
t2= 60 minutes  
t3= 90 minutes  
t4= 120 minutes 
t5= 180 minutes 
Glucose infusion rate per kg body 
mass during hyperinsulinemia-
euglycemic clamp (mg/Kg/min) 
The following time points have been defined: 
t1= ‘Beginning of steady state sampling – Time 0’ 
t2 = ‘Steady state – 5 mins’ 
t3 = ‘Steady state – 10 mins’ 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 80 of 114 
 
CONFIDENTIAL 
t4 = ‘Steady state – 15 mins’ 
t5 = ‘Steady state – 20 mins’ 
t6 = ‘Steady state – 25 mins’ 
t7= ‘End of steady state – 30 mins’ 
INSBEDS = Bedside whole blood Glucose (Mean) 
Sample collection time = INSTIM 
Time of change in D20 infusion: INSTM 
Body mass (DXA) = TOT_FAT + TOT_LEAN + TOT_BMC 
Fat free mass (FFM) = TOT_LEAN + TOT_BMC 
Step 1: 
Calculate the Mean rate of D20 infused steady state (M): 
M=  
((INSTMt1 – INSTIMt1) * D20MLHRt1) + (INSTMt2 – INSTMt1) * D20MLHRt2) + (INSTMt3 
– INSTMt2) * D20MLHRt3) + …(INSTIMt7 – INSTMt6) * D20MLHRt7) ) 
                                             INSTIMt7 - INSTIMt1 
Step 2:  
Calculate Total Glucose Infusion Rate (GIR total) (mg/Kg/min) = 
(M * 20) / (body mass * 6) 
Step 3: 
Calculate Space correction (SC): 
INSBEDSt7 - INSBEDSt1 * 1.9)/ INSTIMt7 - INSTIMt1 
Step 4: 
MTOTAL (whole body glucose metabolism) = GIRtotal – SC  
Glucose infusion rate normalized for 
Fat free mass (mg/Kg/min) 
MFFM=MTOTAL * (Body mass/FFM) 
Glucose clearance rate (kITT) during 
Insulin-tolerance Test (% mg/dL/min) 
The following time points have been defined: 
t2 = ‘Post insulin administration – 5 mins’ 
t4 = ‘Post insulin administration – 15 mins’ 
 
KITT is the percent change in glucose over time. 
For KITT we are calculating the percent change in glucose from time t2 to t4. 
KITT = ((Bedside whole blood Glucose (Mean)t2 - Bedside whole blood Glucose (Mean)t4)/ 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 81 of 114 
 
CONFIDENTIAL 
(Bedside whole blood Glucose (Mean)t2))/(t4-t2) 
Calculate KITT for each visit to calculate change from BL. 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 82 of 114 
 
CONFIDENTIAL 
10.8. 
Detailed Description of the Multiple Imputation Procedure 
The following is a detailed description of the multiple imputation procedure which will be used for analysis of the secondary efficacy 
endpoints. 
In general, the missing pattern is anticipated to be not monotone, a two-step approach will be used: 
• Step 1:  the MCMC method will be used in conjunction with the IMPUTE=MONOTONE option to create an imputed data 
set with a monotone missing pattern. Set the SEED=17100 option in SAS MI procedure 
• Step 2:  Using the monotone data set from step 1, missing data will be imputed using the regression method. Set the 
SEED=34200 option in SAS MI procedure 
The imputation model for step 1 will include the values of the analyzed parameter at baseline and planned time-points up to week 24. 
The imputation model for step 2 will include the same variables as in step 1 with the following additional variables: 
• age, BMI, and gender (age and BMI included as continuous variables). 
Non-continuous variables included in the imputer’s model (i.e., gender) are not expected to be missing. 
In addition, for continuous efficacy variables anticipated to have a non-normal distribution (i.e. TG), data will be log-transformed 
before imputation process and then back-transformed to create the imputed data sets using the TRANSFORM statement of SAS MI 
procedure. 
For variables other than those continuous efficacy variables anticipated to have a non-normal distribution (i.e. TG), for each 
simulation leading to negative imputed value, another value will be redrawn using MINIMUM option of SAS MI procedure. 
The number of imputations (100) will be informally verified by replicating sets of 100 imputations and checking whether the 
combined results are stable. If not stable, the number of imputations will be increased and informally checked as above, and thus 
continued until stable estimates are obtained. 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 83 of 114 
 
CONFIDENTIAL 
10.9. 
Schedule of Time and Events 
Table 3: 
Screening and Placebo Run-In Schedule of Events 
Study Period 
Screening 
Placebo Run-In 
 
In-Clinic Outpatient 
Visit1,2 
In-Clinic Outpatient 
Visit2 
In-Clinic Outpatient Visit or Remote Visit3 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Screening/Baseline 
  
  
  
  
  
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
Medical History4 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
HIV Serology and Hepatitis Testing (HBsAg, HCV) 
X 
 
 
 
 
Treatment and Medications 
 
 
 
 
 
Safety6 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
Height7 
X 
 
 
 
 
Weight7 
X 
X 
 
 
 
Physical Examination8 
X 
X 
 
 
 
Tanner Staging  
X 
 
 
 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 84 of 114 
 
CONFIDENTIAL 
Study Period 
Screening 
Placebo Run-In 
 
In-Clinic Outpatient 
Visit1,2 
In-Clinic Outpatient 
Visit2 
In-Clinic Outpatient Visit or Remote Visit3 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Electrocardiogram9 
X 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
Menstrual History, Pregnancy Status Reporting, and 
Confirmation of Contraception10 
X 
X 
X 
X 
X 
Laboratory Testing11 
 
 
 
 
 
Hematology 
X 
X12 
 
 
 
Blood Chemistry 
X 
X12 
 
 
 
Pregnancy Test (WOCBP)10 
Serum 
Urine 
 
 
 
Urinalysis 
X 
 
 
 
 
Leptin 
 
X 
 
 
 
Efficacy11 
 
 
 
 
 
Fasting Triglycerides and Glucose2 
X2 
X2  
 
 
X 
HbA1c, Fructosamine 
X 
X 
 
 
Insulin/C-peptide2 
X2 
X2 
 
 
 
Urine Protein, Creatinine, Albumin 
 
X 
 
 
 
COA Training13 
 
X 
 
 
 
Daily Appetite Hunger and Eating Behavior PRO13 
 
X 
X 
Sensation of Body Temperature PRO 
 
X 
 
 
 
SF-36 Questionnaire/PedsQLTM 14 
 
X 
 
 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 85 of 114 
 
CONFIDENTIAL 
Study Period 
Screening 
Placebo Run-In 
 
In-Clinic Outpatient 
Visit1,2 
In-Clinic Outpatient 
Visit2 
In-Clinic Outpatient Visit or Remote Visit3 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Global Impression of Severity 
 
X 
 
 
 
Liver MRI (volume/fat content)15 
 
X 
VCTE15 
 
X 
Whole body DXA15 
 
X 
PK/Biomarkers Procedure/Samples16 
  
  
  
  
  
Endocrine Hormones17  
 
X 
 
 
X 
ANGPTL3, PCSK9, sLEPR 
 
X 
 
 
X 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 86 of 114 
 
CONFIDENTIAL 
10.9.1. 
Footnotes for the Schedule of Events Table 3: Screening and Placebo Run-In 
1. Patients may be re-screened if they fail the screening for reasons related to incidental or 
transitory conditions (eg, medication use, concomitant illness, medical condition). If 
patients are re-screened within the original 4-week screening period, only screening 
test(s) (eg, an out-of-range lab value) that resulted in initial screen failure should be 
repeated. 
2. Procedures may be conducted on different days during the screening/baseline period, if 
needed. Blood draws for laboratory testing at the screening visit and visit 2 will be 
collected in a fasted state (after at least approximately a 12-hour fast). The duration of 
fasting may be shortened for patients with a documented clinical contraindication to 
fasting. 
3. Procedures may be conducted by trained study staff at a remote location (ie, at home 
visits, work, and/or school). 
4. Medical history should include detailed lipodystrophy history including prior 
medication/investigational products, genetic diagnosis (if known), imaging results, leptin 
levels (if known) and results of any previous anti-metreleptin antibody testing (if 
applicable). 
5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
7. Body weight should be measured after voiding (empty bladder) using a calibrated scale. 
Patients should empty pockets and remove shoes, belts, outer-layer clothing, or any other 
heavy wearable prior to being weighed. In individuals under 18 years of age, standing 
height should be recorded at least every 3 months using a stadiometer. Patients should be 
instructed to remove footwear and stand upright with their heels together. Tanner staging 
for pubertal development should be performed at least every 3 months until patient 
reaches Tanner stage 5. 
8. Complete physical examination will be performed at screening (visit 1) and includes skin, 
head, eyes, nose, throat, neck, joints, lungs, heart, pulse, abdomen (including liver and 
spleen), lymph nodes, and extremities. A brief neurologic examination should also be 
performed. Limited physical examination will be performed on all remaining visits and 
includes lungs, heart, abdomen, and skin. 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 87 of 114 
 
CONFIDENTIAL 
9. The electrocardiogram (ECG) can be performed up to 24 hours prior to study drug 
administration. 
10. Menstrual events and pregnancy status of WOCBP will be monitored throughout the 
study. A serum pregnancy test will be performed at screening, and a urine pregnancy test 
will be performed locally (eg, point-of-care) at subsequent visits. A positive urine 
pregnancy test should be confirmed with a serum test. 
11. Study assessments should be performed, and blood samples are to be collected before 
study drug administration, unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
12. Samples for hematology and blood chemistry analysis do not need to be collected at 
visit 2 if visits 1 and 2 occur within 48 hours of each other. 
13. Patients must receive eCOA training at the time they receive the eCOA device. 
Additionally, patients must be trained on the Daily Appetite Hunger and Eating Behavior 
PRO prior to completion of PRO assessments. Patients will be instructed to fill out the 
Daily Appetite Hunger and Eating Behavior PRO on a daily basis. The site will check the 
patient’s adherence to completion of all study questionnaires at each designated visit.  
14. SF-36 is to be completed by patients 18 years or older, and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a PRO for patients ages 13 to 17 
years (teen report) and for patients 12 years of age (child form). 
15. Liver fat content and liver volume MRI scans, VCTE, and whole body DXA will be 
performed only at sites where these techniques are available. Liver MRI scans, VCTE, 
and whole body DXA can be performed from day -28 to day 1 prior to dosing of study 
drug. 
16.  Biomarker blood draw samples will be collected pre-dose.  
17. Endocrine hormones include but are not limited to luteinizing hormone, follicle-
stimulating hormone, estradiol, and testosterone (Protocol Section 9.2.7.1). 
18. DNA can be collected at any visit after obtaining consent. 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 88 of 114 
 
CONFIDENTIAL 
Table 4: 
Double-Blind Treatment Period 1 Schedule of Events 
Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Disposition 
  
  
  
  
  
  
  
  
  
  
  
Clinic Admission 
X 
 
 
 
 
 
 
 
 
 
 
Clinic Discharge 
 
 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X3 
 
 
 
 
 
 
 
 
Treatment and medications 
 
 
 
 
 
 
 
 
 
 
 
Safety5 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
Height7 
 
 
X 
 
 
 
 
 
 
 
 
Weight7 
 
 
X8 
 
X 
X 
 
X 
 
X 
 
Tanner Staging7 
 
 
X 
 
 
 
 
 
 
 
 
Physical Examination22 
 
 
X 
 
 
 
 
 
 
 
 
Electrocardiogram9 
 
X 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 89 of 114 
 
CONFIDENTIAL 
Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Menstrual History, Pregnancy 
Status Reporting, and 
Confirmation of 
Contraception10 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing11 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
X 
 
 
X 
 
X 
 
 
X 
Blood Chemistry 
 
 
X 
 
 
X 
 
X 
 
 
X 
INR/PTT, Platelets (Local Lab) 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (WOCBP)10 
 
X 
 
 
 
 
 
X 
 
 
 
Urinalysis 
 
 
X 
 
 
X 
 
X 
 
 
X 
Leptin12 
 
 
X12 
 
 
 
 
 
 
 
 
Efficacy11 
 
 
 
 
 
 
 
 
 
 
 
Fasting Triglycerides and 
Glucose12 
 
 
X12 
 
 
 
 
 
 
 
X12 
HbA1c 
 
 
X 
 
 
 
 
X 
 
 
 
Fructosamine 
 
 
X 
 
 
 
 
X 
 
 
 
Insulin/C-peptide12 
 
 
X12 
 
 
 
 
 
 
 
 
Lipid Panel 12 
 
 
X12 
 
 
 
 
 
 
 
 
Urine Protein, Creatinine, 
Albumin 
 
 
X 
 
 
 
 
 
 
 
 
Insulin Sensitivity 
Measurement 13, 14 
 
 
X 
 
 
 
 
 
 
 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 90 of 114 
 
CONFIDENTIAL 
Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
MMTT15 
 
X 
 
 
 
 
 
 
 
 
 
Weighted Mean Glucose 
Assessment16 
 
X 
 
 
 
 
 
 
 
 
 
COA Training17 
X 
 
 
 
 
 
 
 
 
 
 
Daily Appetite Hunger and 
Eating Behavior PRO17 
X 
 
 
 
 
 
 
 
 
X 
Sensation of Body Temperature 
PRO 
X 
 
 
 
 
 
 
 
 
 
SF-36 Questionnaire/ 
PedsQLTM 18 
X 
 
 
 
 
 
 
 
 
 
Patient Global Impression of 
Severity 
X 
 
 
 
 
 
 
 
 
 
PK/Biomarker/Drug 
Concentration and ADA 
Samples19 
 
 
 
 
 
 
 
 
 
 
 
REGN4461 Concentration 
Blood Sample 
 
 
X 
 
X 
X 
 
 
 
 
 
ADA Sample 
 
 
X 
 
 
 
 
 
 
 
 
Endocrine Hormones20  
 
 
X 
 
 
 
 
X 
 
 
 
ANGPTL3, PCSK9, sLEPR 
 
 
X 
 
X 
X 
 
 
 
 
 
Immunophenotyping 
 
 
X 
 
 
 
 
 
 
 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 91 of 114 
 
CONFIDENTIAL 
Study Period 
Baseline Assessment 
Double-Blind Treatment Period 1 
  
In-Clinic Stay1 
In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 92 of 114 
 
CONFIDENTIAL 
10.9.2. 
Footnotes for the Schedule of Events Table 4: Double-Blind Treatment Period 1 
1. 
 
 All other patients 
may choose to be admitted on day -1. Patients will have the option to leave on the same 
day of study drug administration after being observed for at least 4 hours, provided all 
required assessments and procedures have been completed on that day.  
2. Assessments/procedures other than those occurring during in-clinic stays may be 
conducted by trained study staff at a remote location (ie, at home visits, work, and/or 
school).  
3. Randomization can occur within 24 hours prior to day 1 study drug administration if 
necessary. 
4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
6. Vital signs should be recorded 
 
  
7. In individuals under 18 years of age, standing height should be recorded at least every 
3 months using a stadiometer. Patients should be instructed to remove footwear and stand 
upright with their heels together. Body weight must be measured after voiding (empty 
bladder) using a dedicated, calibrated scale. Patients should empty pockets and remove 
shoes, belts, outer-layer clothing, or any other heavy wearable prior to being weighed. 
Tanner staging for pubertal development should be performed at least every 3 months 
until patient reaches Tanner stage 5. 
8. This body weight will be used for dose tier determination. Body weight may be measured 
up to 24 hours prior to day 1 study drug administration and must be measured prior to 
randomization. 
9. The ECG can be performed up to 24 hours prior to study drug administration. 
10. Menstrual events and pregnancy status of WOCBP will be monitored throughout the 
study. A urine pregnancy test will be performed locally (eg, point-of-care). A positive 
urine pregnancy test should be confirmed with a serum test. 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 93 of 114 
 
CONFIDENTIAL 
11. Study assessments should be performed, and blood samples are to be collected before 
study drug administration unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
12. Patients must be in a fasted state (after at least approximately a 12-hour fast). The 
duration of fasting may be shortened for patients with a documented clinical 
contraindication to fasting. 
13. Patients must be in a fasted state (after at least approximately a 12-hour fast) for insulin 
sensitivity assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Insulin sensitivity will be measured by 
clamp at sites where a qualified and experienced facility and staff are available. Blood 
samples for the clamp will be collected for the analysis of glucose, insulin, C-peptide at 
following times: 2 baseline samples within 30 minutes before starting insulin infusion 
and up to 4 samples during the 30 minutes steady state. Additional samples will be 
analyzed for point of care glucose measures during insulin infusion, as outlined in the 
study manual. 
 
 
  
For sites that do not have the ability to perform a clamp study but do have a qualified and 
experienced ITT facility and staff, patients will undergo an ITT. Patients with a history of 
seizure disorder should not undergo ITT. Blood samples will be collected for the analysis 
of glucose, insulin, C-peptide timed as follows: 2 baseline samples before starting insulin 
administration and at 5, 10, 15, 20 and 30 minutes after starting the insulin 
administration. 
 
 
  
14. Patients presenting to sites without qualified and experienced facility and staff to perform 
a clamp or ITT will not undergo clamp or ITT evaluation. This procedure can be done 
within 3 days prior to day 1. 
15. Patients must be in a fasted state (after at least approximately a 12-hour fast) prior to 
MMTT assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Blood samples will be collected on the 
days of the MMTT for the analysis of glucose, insulin, C-peptide, and TGs. Sampling 
times are as follows:  
• For glucose analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For insulin analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For C-peptide analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For TG analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
This procedure can be done within 3 days prior to day 1. 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 94 of 114 
 
CONFIDENTIAL 
16. Additional blood samples will be collected on the days of WMG assessments, timed as 
follows: (1) less than 30 minutes prior to lunch, (2) 120±10 minutes after lunch, (3) less 
than 30 minutes prior to dinner, (4) 120±10 minutes after dinner, and (5) 10 PM or 
bedtime. This procedure must be done on the same day as MMTT. Blood samples will be 
analyzed for glucose, insulin and for C-peptide.  
17. Patients must receive eCOA training at the time they receive the eCOA device. 
Additionally, patients must be trained on the Daily Appetite Hunger and Eating Behavior 
PRO prior to completion of PRO assessments. If the patient was previously trained on 
both the eCOA and the PRO assessments, no additional training is required at this time. 
Patients will be instructed to fill out the Daily Appetite Hunger and Eating Behavior PRO 
on a daily basis. The site will check the patient’s adherence to completion of all study 
questionnaires at each designated visit.  
18. SF-36 is to be completed by patients 18 years or older, and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a self-administered PRO for 
patients ages 13 to 17 years (teen report) and for patients 12 years of age (child form). 
19. Collection 
of 
blood 
samples 
for 
drug 
concentration 
on 
day 
1 
will 
be 
pre-infusion/injection and at the end of infusion ±15 mins. On other visits, drug 
concentration and biomarker samples will be collected pre-dose. Samples for sLEPR, 
ANGPTL3, and PCSK9 should be collected at the time points that drug concentration is 
measured. On all visits ADA and drug concentration samples should be collected prior to 
administration of drug. 
20. Endocrine 
hormones 
include 
but 
are 
not 
limited 
to 
luteinizing 
hormone, 
follicle-stimulating hormone, estradiol, and testosterone. 
21. 
 
 
 
 
 
22. Complete physical examination will be performed on day 1 (visit 8) and includes skin, 
head, eyes, nose, throat, neck, joints, lungs, heart, pulse, abdomen (including liver and 
spleen), lymph nodes, and extremities. A brief neurologic examination should also be 
performed. Limited physical examination will be performed on all remaining visits and 
includes lungs, heart, abdomen, and skin. 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 95 of 114 
 
CONFIDENTIAL 
Table 5: 
Double-Blind Treatment Periods 2 and 3 Schedule of Events 
Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Admission 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Clinic Discharge 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Treatment and 
Medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height6 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Weight6 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
Tanner Staging6 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
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Date: August 22, 2022 
 
 
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CONFIDENTIAL 
Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Physical 
Examination21 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Electrocardiogram7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Menstrual History, 
Pregnancy Status 
Reporting, and 
Confirmation of 
Contraception8 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Blood Chemistry 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Pregnancy Test 
(WOCBP)8 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Leptin10 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Triglycerides 
and Glucose10 
 
X10 
 
 
 
 
 
 
 
X10 
 
X10 
 
 
 
 
 
 
X10 
HbA1c 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Fructosamine 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Insulin/C-peptide10 
 
X10 
 
 
 
 
 
 
 
 
 
X10 
 
 
 
 
 
 
 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 97 of 114 
 
CONFIDENTIAL 
Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Lipid Panel10 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine Protein, 
Creatinine, Albumin 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Insulin Sensitivity 
Measurement11,12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMTT13 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Weighted Mean 
Glucose Assessment14 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
COA Training15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily Appetite 
Hunger and Eating 
Behavior PRO15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Sensation of Body 
Temperature PRO 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
SF-36 Questionnaire/ 
PedsQLTM 16 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Patient Global 
Impression of 
Severity 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Patient Global 
Impression of Change 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Exit Interview 
X17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 98 of 114 
 
CONFIDENTIAL 
Study 
Period 
Double-Blind Treatment Period 2 
Double-Blind Treatment Period 3 
  
In-Clinic Stay1 
 In-Clinic Outpatient Visit or Remote Visit 2 
In-Clinic 
Stay1 
 In-Clinic Outpatient Visit or Remote Visit2 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Liver MRI 
(volume/fat 
content) 18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole body DXA18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Biomarker/Drug 
Concentration and 
ADA Samples 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
REGN4461 
Concentration Blood 
Sample 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
ADA Sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunophenotyping 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Endocrine 
Hormones20 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
ANGPTL3, PCSK9, 
sLEPR 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
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Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 99 of 114 
 
CONFIDENTIAL 
10.9.3. 
Footnotes for the Schedule of Events Table 5: Double-Blind Treatment Periods 2 
and 3  
1. In-clinic stay may begin within a ±2-day window. Patients will have the option to leave 
on the same day of study drug administration after being observed for at least 4 hours, 
provided all required assessments and procedures on that day have been completed. 
2. Assessments/procedures other than those occurring during in-clinic stays may be 
conducted by trained study staff at a remote location (ie, at home visits, work, and/or 
school). However, during the 
 
  
3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
5. Vital signs should be recorded prior to 
 
  
6. In individuals under 18 years of age, standing height should be recorded at least every 
3 months using a stadiometer. Patients should be instructed to remove footwear and stand 
upright with their heels together. Body weight must be measured after voiding (empty 
bladder) using a dedicated, calibrated scale. Patients should empty pockets and remove 
shoes, belts, outer-layer clothing, or any other heavy wearable prior to being weighed. 
Tanner staging for pubertal development should be performed at least every 3 months 
until patient reaches Tanner stage 5. 
7. The ECG can be performed up to 24 hours prior to study drug administration. 
8. Menstrual events and pregnancy status of WOCBP will be monitored throughout the 
study. A serum pregnancy test will be performed at the screening and EOS visit and urine 
pregnancy test performed locally (eg, point-of-care) at subsequent visits. A positive urine 
pregnancy test should be confirmed with a serum test. 
9. Study assessments should be performed, and blood samples are to be collected before 
study drug administration unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
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Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
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Page 100 of 114 
 
CONFIDENTIAL 
10. Patients must be in a fasted state (after at least approximately a 12-hour fast). The 
duration of fasting may be shortened for patients with a documented clinical 
contraindication to fasting. 
11. Patients must be in a fasted state (after at least approximately a 12-hour fast) for insulin 
sensitivity assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Insulin sensitivity will be measured by 
clamp at sites where a qualified and experienced facility and staff are available. Blood 
samples for the clamp will be collected for the analysis of glucose, insulin, C-peptide at 
following times: 2 baseline samples within 30 minutes before starting insulin infusion 
and up to 4 samples during the 30 minutes long steady state. Additional samples will be 
analyzed for point of care glucose measures during insulin infusion, as outlined in the 
study manual. 
 
 
 
Patients will undergo an ITT at sites where a qualified and experienced ITT facility and 
staff are available. Patients with a history of seizure disorder should not undergo ITT. 
Blood samples will be collected for the analysis of glucose, insulin and C-peptide timed 
as follows: two baseline samples before starting insulin administration and at 5, 10, 15, 
20 and 30 minutes after starting the insulin administration. 
 
 
  
12. Patients presenting to sites without qualified and experienced facility and staff to perform 
a clamp or ITT will not undergo clamp or ITT evaluation. This procedure can be done 
within 3 days prior to day 57. 
13. Patients must be in a fasted state (after at least approximately a 12-hour fast) prior to 
MMTT assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting. Blood samples will be collected on the 
days of the MMTT for the analysis of glucose, insulin, C-peptide, and TGs. Sampling 
times are as follows: 
• For glucose analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For insulin analysis, -15,0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For C-peptide analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For TG analysis: -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
This procedure can be done within 3 days prior to day 56 and 112. 
14. Additional blood samples will be collected on the days of WMG assessments, timed as 
follows: (1) less than 30 minutes prior to lunch, (2) 120±10 minutes after lunch, (3) less 
than 30 minutes prior to dinner, (4) 120±10 minutes after dinner, and (5) 10 PM or 
bedtime. For patients who are discharged prior to completion of WMG blood draw 
assessments, the after-dinner and prior-to-bedtime assessments will not be required. This 
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Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
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Page 101 of 114 
 
CONFIDENTIAL 
procedure must be done on the same day as MMTT. Blood samples will be analyzed for 
glucose, insulin and for C-peptide. 
15. Patients must receive eCOA training at the time they receive the eCOA device. 
Additionally, patients must be trained on the Daily Appetite Hunger and Eating Behavior 
PRO prior to completion of PRO assessments. If the patient was previously trained on 
both the eCOA and the PRO assessments, no additional training is required at this time. 
Patients will be instructed to fill out the Daily Appetite Hunger and Eating Behavior PRO 
daily through week 24. The site will check the patient’s adherence to completion of all 
study questionnaires at each designated visit.  
16. SF-36 is to be completed by patients 18 years or older and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a self-administered PRO for 
patients ages 13 to 17 years (teen report) and for patients 12 years of age (child form). 
17. Exit interviews will be conducted either during in-clinic stay for DBTP2 or between 
 
18. Liver volume and fat content MRI and whole body DXA scans may be performed up to 
14 days prior to visit 17. These tests will only be performed at sites where these 
techniques are available. Patients may be required to fast at least 5 hours prior to an MRI 
scan. 
19. Collection of blood samples for drug concentration on 
 will be pre-infusion and at 
the end of infusion ±15 mins. On other visits, drug concentration and biomarker samples 
will be collected pre-dose. Samples for sLEPR, ANGPTL3, and PCSK9 will be collected 
at the time points that drug concentration is measured. On all visits ADA and drug 
concentration samples should be collected prior to administration of drug. 
20. Endocrine 
hormones 
include 
but 
are 
not 
limited 
to 
luteinizing 
hormone, 
follicle-stimulating hormone, estradiol, and testosterone. 
21. Complete physical examination will be performed at the EOT and EOS visits and 
includes skin, head, eyes, nose, throat, neck, joints, lungs, heart, pulse, abdomen 
(including liver and spleen), lymph nodes, and extremities. A brief neurologic 
examination should also be performed. Limited physical examination will be performed 
on all remaining visits and includes lungs, heart, abdomen, and skin.  
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 102 of 114 
 
CONFIDENTIAL 
Table 6: 
Open-Label Treatment Period 4 (OLTP 4) Schedule of Events 
Study Period 
 
Treatment Period 41 
  
In-Clinic2 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
 In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
 In-Clinic 
Outpatient 
Visit 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Disposition 
 
 
 
 
 
 
 
 
Clinic Admission 
X 
 
 
 
 
 
 
 
Clinic Discharge 
 
X 
 
 
 
 
 
 
Treatment and 
Medications 
 
 
 
 
 
 
 
 
Safety6 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
Height7 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
X 
 
X 
Tanner Staging7 
 
X 
 
X 
 
X 
 
X 
Physical Examination 
 
X 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Menstrual History, 
Pregnancy Status 
Reporting, and 
Confirmation of 
Contraception8 
 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 103 of 114 
 
CONFIDENTIAL 
Study Period 
 
Treatment Period 41 
  
In-Clinic2 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
 In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
 In-Clinic 
Outpatient 
Visit 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Laboratory Testing9 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
X 
 
X 
 
X 
Blood Chemistry 
 
X 
 
X 
 
X 
 
X 
INR/PTT, Platelets 
(Local Lab) 
 
 
 
 
 
 
 
X 
Pregnancy Test 
(WOCBP)8 
 
X 
 
X 
 
X 
 
X 
Urinalysis 
 
X 
 
X 
 
X 
 
X 
Efficacy9 
 
 
 
 
 
 
 
 
Fasting Triglycerides 
and Glucose10 
 
X 
 
X 
 
X 
 
X 
HbA1c 
 
X 
 
X 
 
X 
 
X 
Fructosamine 
 
X 
 
X 
 
X 
 
X 
Insulin/C-peptide10 
 
X 
 
X 
 
X 
 
X 
Lipid Panel10 
 
X 
 
X 
 
X 
 
X 
Urine Protein, 
Creatinine, Albumin 
 
X 
 
X 
 
X 
 
X 
Insulin Sensitivity 
Measurement 11,12 
 
 
 
 
 
 
 
X 
MMTT13 
X 
 
 
 
 
 
 
 
Weighted Mean 
Glucose Assessment14 
X 
 
 
 
 
 
 
 
Daily Appetite Hunger 
and Eating Behavior 
PRO 
X 
 
 
 
 
 
 
 
Sensation of Body 
Temperature PRO 
X 
 
 
 
 
 
 
 
SF-36 Questionnaire/ 
PEDs QOL15 
X 
 
 
 
 
 
 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 104 of 114 
 
CONFIDENTIAL 
Study Period 
 
Treatment Period 41 
  
In-Clinic2 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
 In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
In-Clinic 
Outpatient 
Visit 
In-Clinic 
Outpatient 
Visit or 
Remote 
Visit 
 In-Clinic 
Outpatient 
Visit 
Visit Number: 
Day: 
±Visit Window (d): 
Week: 
Patient Global 
Impression of Severity 
X 
 
 
 
 
 
 
 
Patient Global 
Impression of Change 
X 
 
 
 
 
 
 
 
Exit Interview 
 
 
 
 
 
 
 
X20 
Liver MRI (volume/fat 
content)16 
X 
 
 
 
 
 
 
X 
Whole body DXA16 
X 
 
 
 
 
 
 
X 
VCTE 
 
 
 
 
 
 
 
X16 
PK/Biomarker/Drug 
Concentration and 
ADA Samples9 
 
 
 
 
 
 
 
 
REGN4461 
Concentration Blood 
Sample 
 
X 
 
X 
 
X 
 
X 
ADA Sample 
 
X 
 
X 
 
 
 
X 
Endocrine Hormones19 
 
X 
 
X 
 
X 
 
X 
ANGPTL3, PCSK9, 
sLEPR 
 
X 
 
X 
 
X 
 
X 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 105 of 114 
 
CONFIDENTIAL 
 
10.9.4. 
Footnotes for the Schedule of Events Table 6: Open-Label Treatment Period 4 
1. During the Open-Label Treatment Period, patients will be treated with study drug 
weekly. Study drug can be administered at the clinical site, by the site personnel or 
another healthcare professional at a remote location (eg, the patient’s home, school, or 
place of work), or self-administered/administered by a designated person.  
a. If medication is administered by site personnel or another healthcare professional, 
study personnel will monitor AEs, concomitant medications, menstrual 
history/pregnancy status reporting/confirmation of contraception weekly. Diabetes 
and lipid medication adjustments must occur at least once monthly (see footnote 5). 
b. If patients are self-administering study drug or the study drug is being administered 
by a designated person, site personnel must assess the patient for AEs, concomitant 
medications, menstrual history/pregnancy status reporting/confirmation of 
contraception, and diabetes and lipid medications adjustments must occur at least 
once monthly. These assessments may occur via telephone contact or in-site 
assessments, at the discretion of the investigator. 
2. In-clinic stay can begin within a ±2-day window. Patients will have the option to leave on 
the same day of study drug administration after being observed for at least 4 hours, 
provided no other procedures are required on that day. 
3. Training for study drug administration must be performed and documented for all 
patients who choose to self-administer REGN4461 during OLTP 4. Training is not 
required for patients who choose to not self-administer study drug. Training may occur at 
any time during OLTP 4 prior to first self-administration. If an appropriate designee 
(eg, parent or caregiver) will administer study drug to the patient during OLTP 4, this 
individual will undergo training as above.  
4. A medication administration diary will be provided to the patient/designee prior to 
initiation of self-administration or administration by a designated person such as a parent 
or caregiver. The diary must be completed upon each study drug administration. Training 
on the diary will be provided only to patients which will self-administer REGN4461. 
5. 
 
 
 
 
 
 
 
 
 
 
 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 106 of 114 
 
CONFIDENTIAL 
6. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated.  
7. In individuals under 18 years of age, standing height should be recorded at least 
approximately every 3 months. Tanner staging for pubertal development should be 
performed at least approximately every 3 months until patient reaches Tanner stage 5. 
8. Menstrual events and pregnancy status of WOCBP will be monitored through the EOS 
visit. A urine pregnancy test will be performed locally (eg, point-of-care). A positive 
urine pregnancy test should be confirmed with a serum test. 
9. Study assessments should be performed, and blood samples are to be collected before 
study drug administration, unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. At all visits, PK, ADA, and ANGPTL3/PCSK9/sLEPR samples should be 
collected prior to the administration of drug. 
10. Patients must be in a fasted state (after at least approximately a 12-hour fast). The 
duration of fasting may be shortened for patients with a documented clinical 
contraindication to fasting. 
11. Patients must be in a fasted state (after at least approximately a 12-hour fast) for insulin 
sensitivity assessments. The duration of fasting may be shortened for patients with a 
documented clinical contraindication to fasting.  
12. Insulin sensitivity will be measured by clamp at sites where a qualified and experienced 
facility and staff are available. Blood samples for the clamp will be collected for the 
analysis of glucose, insulin, C-peptide at following times: 2 baseline samples within 
30 minutes before starting insulin infusion and up to 4 samples during the 30 minutes 
long steady state. Additional samples will be analyzed for point of care glucose measures 
during insulin infusion, as outlined in the study manual. 
 
 
  
13. Patients will undergo an ITT at sites where a qualified and experienced ITT facility and 
staff are available. Patients with a history of seizure disorder should not undergo ITT.  
Blood samples will be collected for the analysis of glucose, insulin and C-peptide timed 
as follows: two baseline samples before starting insulin administration and at 5, 10, 15, 
20 and 30 minutes after starting the insulin administration. 
 
 
. 
14. Patients presenting to sites without qualified and experienced facility and staff to perform 
a clamp or ITT will not undergo clamp or ITT evaluation. This procedure can be done 
within 3 days prior to day 365. 
15. Patients must be in a fasted state (after at least approximately a 12-hour fast) prior to 
MMTT assessments. The duration of fasting may be shortened for patients with a 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 107 of 114 
 
CONFIDENTIAL 
documented clinical contraindication to fasting. Blood samples will be collected on the 
days of the MMTT for the analysis of glucose, insulin, C-peptide, and TGs. Sampling 
times are as follows: 
• For glucose analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For insulin analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For C-peptide analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
• For TG analysis, -15, 0 (premeal), 30, 60, 90, 120, and 180 minutes 
This procedure can be done within 3 days 
. 
16. Additional blood samples will be collected on the days of WMG assessments, timed as 
follows: (1) less than 30 minutes prior to lunch, (2) 120±10 minutes after lunch, (3) less 
than 30 minutes prior to dinner, (4) 120±10 minutes after dinner, and (5) 10 PM or 
bedtime. For patients who are discharged prior to completion of WMG blood draw 
assessments, the after-dinner and prior-to-bedtime assessments will not be required. This 
procedure must be done on the same day as MMTT. Blood samples will be analyzed for 
glucose, insulin and for C-peptide. 
17. SF-36 is to be completed by patients 18 years or older and PedsQLTM is to be completed 
by patients 12 to 17 years of age. The PedsQLTM will be a self-administered PRO for 
patients ages 13 to 17 years (teen report) and for patients 12 years of age (child form). 
18. Liver volume and fat content MRI, whole body DXA may be performed up to 14 days 
prior to visit 37 and visit 65. VCTE may be performed up to 14 days prior to visit 65. 
These tests will only be performed at sites where these techniques are available. Patients 
may be required to fast at least 5 hours prior to an MRI scan. 
19. 
 
 
 
 
 
20. Endocrine hormones include but are not limited to luteinizing hormone, follicle-
stimulating hormone, estradiol, and testosterone (Protocol Section 9.2.7.1). 
21. In the event that a patient has an early termination visit that occurs before week 8, the exit 
interview will be conducted during this visit. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 Page 108 of 114 
 
CONFIDENTIAL 
Table 7: 
Open-Label Treatment Period 5 (OLTP 5) Schedule of Events 
  
Open-Label Period1 
Off-Drug Follow-up 
Period 
  
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Treatment and 
Medications 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 Page 109 of 114 
 
CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period 
  
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Safety5 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs6 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
Height7 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
Weight 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
Tanner Staging7 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Physical 
Examination 
X 
  
  
  
X 
  
X 
  
  
  
X12 
  
  
  
X12 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 Page 110 of 114 
 
CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period 
  
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Menstrual 
History, 
Pregnancy 
Status 
Reporting, and 
Confirmation of 
Contraception8 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Laboratory 
Testing9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology 
X 
  
 X 
  
X 
  
X 
  
X 
  
X 
X 
X 
 
X 
Blood Chemistry 
X 
  
 X 
  
X 
  
X 
  
X 
  
X 
X 
X 
 
X 
Pregnancy Test 
(WOCBP)8 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
Serum 
Urinalysis 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 Page 111 of 114 
 
CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period 
  
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
Efficacy9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Fasting 
Triglycerides 
and Glucose10 
X 
  
X  
  
X 
  
X 
  
X 
  
X 
X 
X 
 
X 
HbA1c 
X 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Lipid Panel10 
X 
  
  
  
X 
  
X 
  
X 
  
  
  
  
  
X 
Urine Protein, 
Creatinine, 
Albumin 
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
Liver MRI 
(volume/fat 
content)11 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Whole body 
DXA11 
 X 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
VCTE11 
 X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 Page 112 of 114 
 
CONFIDENTIAL 
  
Open-Label Period1 
Off-Drug Follow-up 
Period 
  
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-
Clinic 
Outpati
ent Visit 
or 
Remote 
Visit1 
In-
Clinic 
Outpati
ent Visit 
In-Clinic 
Outpatient 
Visit or 
Remote Visit 
In-
Clinic 
Outpati
ent Visit 
  
  
  
  
  
  
  
  
  
  
  
 EOT 
  
  
  
EOS 
Visit Number: 
Day of OLTP 5: 
±Visit Window 
(d): 
Week of 
OLTP 5: 
PK/Biomarker/
Drug 
Concentration 
and ADA 
Samples9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
REGN4461 
Concentration 
Blood Sample 
X 
  
X 
  
X 
  
X 
  
X  
  
X 
 
 
 
X 
ADA Sample 
X 
  
  
 
  
  
X 
  
  
  
X 
  
  
  
X 
ANGPTL3, 
PCSK9, sLEPR 
X 
  
X 
  
X 
  
X 
  
  
  
X 
 
 
 
X 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 113 of 114 
 
CONFIDENTIAL 
10.9.5. 
Footnotes for the Schedule of Events Table 7: Open-Label Treatment Period 5 
1. During the open-label period, patients will be treated with study drug weekly. Study drug 
can be administered at the clinical site, by the site personnel or another healthcare 
professional at a remote location (eg, the patient’s home, school, or place of work), or 
self-administered/administered by a designated person. 
a. If medication is administered by site personnel or another healthcare professional, 
study personnel will monitor AEs, concomitant medications, menstrual 
history/pregnancy status reporting/confirmation of contraception weekly. Diabetes 
and lipid medication adjustments must occur at least once monthly (see footnote 4). 
b. If patients are self-administering study drug or the study drug is being administered 
by a designated person, site personnel must assess the patient for AEs, concomitant 
medications, menstrual history/pregnancy status reporting/confirmation of 
contraception, and diabetes and lipid medications adjustments must occur at least 
once monthly. These assessments may occur via telephone contact or in-site 
assessments, at the discretion of the investigator. 
2. Training for study drug administration must be performed and documented for all 
patients who choose to self-administer REGN4461 during OLTP 5. Training is not 
required for patients who choose to not self-administer study drug. Training may occur at 
any time during OLTP 5 prior to first self-administration. If an appropriate designee (eg, 
parent or caregiver) will administer study drug to the patient during OLTP 5, this 
individual will undergo training as above. 
3. A medication administration diary will be provided to the patient/designee prior to 
initiation of self-administration or administration by a designated person such as a parent 
or caregiver. The diary must be completed upon each study drug administration. Training 
on the diary will be provided only to patients which will self-administer REGN4461. 
4. 
 
 
 
 
 
 
 
 
 
 
 
5. All safety assessments should be performed before study drug administration, if possible, 
unless otherwise indicated. 
6. Vital signs should be recorded 
 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R4461-GLD-1875 
Statistical Analysis Plan V2 
 
Date: August 22, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
Page 114 of 114 
 
CONFIDENTIAL 
7. In individuals under 18 years of age, standing height should be recorded at least 
approximately every 3 months. Tanner staging for pubertal development should be 
performed at least every 3 months until patient reaches Tanner stage 5. 
8. Menstrual events and pregnancy status of WOCBP will be monitored through the EOS 
visit. A serum pregnancy test will be performed at the EOS visit a urine pregnancy test 
will be performed locally (e.g, point-of-care). A positive urine pregnancy test should be 
confirmed with a serum test. 
9. Study assessments should be performed, and blood samples are to be collected before 
study drug administration, unless otherwise indicated. For patients undergoing apheresis, 
study assessments are to be performed and blood samples are to be collected immediately 
before the lipid-apheresis procedure. Study drug will be administered after the apheresis 
procedure. 
10. Patients must be in a fasted state (after at least approximately a 12-hour fast). The 
duration of fasting may be shortened for patients with a documented clinical 
contraindication to fasting. 
11. Liver volume and fat content MRI and VCTE may be performed up to 14 days prior to 
. Whole body DXA may be performed up to 14 days prior to 
 
. If the patient had their 
 whole body DXA and/or 
liver MRI within 28 days prior to 
 the applicable procedure does not need to be 
repeated at 
 These tests will only be performed at sites where these techniques are 
available. Patients may be required to fast at least 5 hours prior to an MRI scan.  
12. Complete physical examination will be performed at the EOT and EOS visits and 
includes skin, head, eyes, nose, throat, neck, joints, lungs, heart, pulse, abdomen 
(including liver and spleen), lymph nodes, and extremities. A brief neurologic 
examination should also be performed. Limited physical examination will be performed 
on all remaining visits and includes lungs, heart, abdomen, and skin. 
 
                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


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                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00


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                                        VV-RIM-00208339-1.0 Approved - 24 Aug 2022 GMT-5:00