Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the long-term safety, tolerability, and effect on intravascular hemolysis of REGN3918 in patients with paroxysmal nocturnal hemoglobinuria (PNH).

The secondary objectives of the study are:

* To evaluate the long-term effect of REGN3918 on intravascular hemolysis
* To assess the concentrations of total REGN3918 in serum
* To evaluate the occurrence of the immunogenicity of REGN3918

Detailed description:

Arms:
arm 1: Participants who have completed 1 of the 2 parent studies (R3918-PNH-1852 \[NCT03946748\] or R3918-PNH-1853)

Interventions: intervention 1: REGN3918
Intervention descriptions: intervention 1: Subcutaneous (SC) every week (QW) over the treatment period

Protocol document:
Prot_000.pdf: 
EudraCT: 2019-000130-20 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
AN OPEN-LABEL EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY, TOLERABILITY, AND EFFICACY OF 
REGN3918 IN PATIENTS WITH PAROXYSMAL NOCTURNAL 
HEMOGLOBINURIA 
Compound: 
REGN3918 
Clinical Phase: 
3 
Protocol Number: 
R3918-PNH-1868 
Protocol Version: 
R3918-PNH-1868 Original 
Date of Issue: 
See appended electronic signature page 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
Title 
An open-label extension study to evaluate the long-term safety, tolerability, 
and efficacy of REGN3918 in patients with paroxysmal nocturnal 
hemoglobinuria  
Site Locations 
 
Principal Investigator 
Multiple global sites 
Anita Hill, MBChB (Hons), MRCP, FRCPath, Ph.D 
Objectives 
The primary objective of the study is to evaluate the long-term safety, 
tolerability, and effect on intravascular hemolysis (ie, proportion of patients 
achieving lactate dehydrogenase (LDH) ≤ 1.5× upper limit of normal (ULN) 
over 26 weeks) of REGN3918 in patients with paroxysmal nocturnal 
hemoglobinuria (PNH).   
The secondary objectives of the study are: 
 
To evaluate the long-term effect of REGN3918 on intravascular 
hemolysis. 
 
To assess the concentrations of total REGN3918 in serum. 
 
To evaluate the occurrence of the immunogenicity of REGN3918. 
Study Design 
This study is an open-label, single-arm study with REGN3918.  Patients 
who have completed 1 of the 2 parent studies (ie, either R3918-PNH-1852 
) will be eligible for screening for this 2-year open-
label extension (OLE) study.   
This study contains 2 study periods: the 2-year open-labeltreatment period 
and the optional post-end-of-treatment (EOT) period (ie, after completion of 
the 2-year open-label treatment period). 
The transition of treatment with REGN3918 from the parent study to the 
OLE study is planned to be uninterrupted.  Therefore, the day 1 visit of the 
2-year open-label treatment period will occur on the same visit as the EOT 
study visit in the parent study and overlapping assessments do not need to 
be repeated in this OLE study.  Patients will continue their dose of up to 800 
mg once weekly (QW) from the parent study starting at day 1 in the OLE 
study with a potential change in dose/dosing interval (on day 1 or 
subsequently) only for patients in cohort A of the parent study R3918-PNH-
1852, if applicable.  As part of risk mitigation for this study, it is 
recommended for patients to receive updated meningococcal vaccination, 
daily oral antibiotic prophylaxis, and counselling regarding risk of Neisseria 
gonorrhea, as applicable.  In addition, blood transfusions should proceed 
according to a protocol-defined algorithm. 
Patients who do not enter into the optional post-EOT period should be 
followed for 21 weeks after the end of the 2-year open-label treatment 
period.  Patients should return for monthly visits with assessments 
corresponding to the week 104 (EOT) visit. 
The optional post-EOT period includes continued REGN3918 treatment of 
variable duration.  Patients may continue REGN3918 treatment after they 
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have completed the 2-year open-label treatment period and if they derive 
clinical benefit and have potential risk associated with the discontinuation 
of REGN3918.  Eligible patients will be asked to provide separate consent 
for continuing onto the optional post-EOT period.  The optional post-EOT 
period ends when 1 of the following is met: 
 
Clinical development of REGN3918 is terminated. 
 
Risk-to-benefit profile of REGN3918 in this patient population is 
deemed unfavorable. 
 
REGN3918 is approved by the regulatory authority governing the 
location of the study site. 
Study Duration 
It is projected that the first patients enrolled and who continue into the 
optional post-EOT period will have a study duration of approximately 
4 years and last patients enrolled will have a study duration of at least 
2 years. 
End of Study Definition 
At a study level, the end of study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
Approximately up to 
 patients are expected to enroll in this study. 
 
Target Population: 
The study population will consist of adult male and female patients with 
confirmed diagnosis of PNH who have completed 1 of the 2 parent studies 
(R3918-PNH-1852 
). 
Treatment 
 
 
Study Drug 
 
Dose/Route/Schedule: 
REGN3918  
Patients will be given a dose no greater than 800 mg subcutaneous (SC) QW 
(±1 day) over the treatment period. 
The location and administration options for SC route of administration will 
depend on the preference of the investigator and patient (eg, abdomen, thigh, 
or upper arm), the availability of clinical supply, and the home healthcare 
visiting professional.  Clinic visits for SC administration may or may not be 
needed. 
Endpoints 
 
 
Primary: 
The primary safety endpoint is incidence and severity of treatment-emergent 
adverse events (TEAEs) and other safety variables during the 2-year open-
label treatment period of the study in patients treated with REGN3918.   
Adverse events (AEs), serious AEs (SAEs), and AEs of special interest 
(AESIs) will be analyzed over the 2-year open-label treatment period.  For 
other safety variables, including laboratory data, vital signs, and 
electrocardiograms (ECGs), analysis will be conducted in reference to the 
baseline of the parent study, as this is the time point prior to any exposure 
to REGN3918. 
The primary efficacy endpoint is the proportion of patients achieving LDH 
≤1.5×ULN over week 26, defined as LDH ≤1.5×ULN at every scheduled 
time point up to week 26 (inclusive).   
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The baseline for the primary analysis of the primary efficacy endpoint is the 
baseline of the OLE (ie, this study) as it is expected that at this time point 
the 2 different populations from the parent studies should converge with 
regard to their control of intravascular hemolysis. 
 
Secondary: 
Key secondary efficacy endpoints include: 
 
The proportion of patients with breakthrough hemolysis over 
week 26 
 
The rate and number of units of transfusion over week 26 
Procedures and Assessments 
Efficacy assessments in this study include concentration of LDH in serum, 
number of transfusions of red blood cells (RBC) and number of units of 
RBC per transfusion, concentration of RBC hemoglobin, and concentration 
of free hemoglobin.  Safety assessments include vital signs, physical 
examination, anthropometric measurement, ECG, and clinical laboratory 
testing. 
Pharmacokinetic assessments include concentration of total REGN3918 and 
total C5 in serum.  Biomarker testing include measurements of the total 
complement hemolytic activity assay (CH50), haptoglobin, reticulocyte 
count, and bilirubin.  Immunogenicity assessment include measurement of 
anti-REGN3918 antibodies. 
For patients who consent to optional study procedures, blood and serum 
samples may be collected and stored as part of optional pharmacogenomics 
analysis and/or future biomedical research. 
Statistical Plan 
Justifcation of sample size: As this study is a follow-on that plans to include 
patients from the parent studies, R3918-PNH-1852 
, 
no calculation for sample size was performed.  It is expected to enroll up to 
 patients with PNH based on the maximum number of patients who could 
complete the parent study in the selected/participating countries. 
Analysis sets: The full analysis set (FAS) includes all enrolled patients who 
received any study drug.  Efficacy endpoints will be analyzed using the FAS 
analysis set, unless otherwise specified. 
The safety analysis set (SAF) includes all enrolled patients who received 
any study drug.  Treatment compliance/administration and all clinical safety 
variables will be analyzed using the SAF. 
Efficacy analyses: The primary efficacy endpoint is the proportion of 
patients achieving LDH ≤1.5×ULN over week 26, defined as LDH 
≤1.5×ULN at every scheduled time point up to week 26 (inclusive).   
All other efficacy analyses of this study are secondary.   
For efficacy endpoints that are defined by dichotomy of multiple 
measurements of a variable through a period of time, including the 
proportions of patients achieving LDH ≤1.0×ULN and LDH ≤1.5×ULN 
over week 26, week 78, and week 104, the analysis set consists of all FAS 
patients.  For this category of efficacy endpoints, including the primary 
efficacy endpoint, patients who fulfill 1 or more of the following will be 
considered as not meeting the endpoint: 
 
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 
Discontinue prematurely from study treatment  
 
Have ≥50% missing values of measurements of the analyzed 
variable during the assessed period.  Note: For the primary efficacy 
endpoint, it means having missing LDH value at week 13 or 
week 26. 
 
Have breakthrough hemolysis (as defined in the secondary 
endpoint and based on investigator judgment) while on treatment 
over the assessed period. 
Patients who do not fulfill the above criteria will be evaluated based on their 
non-missing measurements of the variable.   
For secondary endpoints that are defined by a change or percent change from 
baseline of the OLE study to a time point in a variable, the analysis set will 
consist of all FAS patients who have a non-missing baseline measurement 
of the variable.  This category of endpoints includes: 
 
Percent changes and changes from baseline of the OLE study in 
LDH levels to week 26, week 78, and week 104 
 
Changes from baseline of the OLE study RBC hemoglobin levels 
to week 26, week 78, and week 104 
 
Changes from baseline of the OLE study in free hemoglobin levels 
to week 26, week 78, and week 104 
For secondary endpoints that are defined by any occurrence of a defined 
event during a period, the analysis set will consist of all FAS patients.  This 
category of endpoints includes: 
 
The proportions of patients with breakthrough hemolysis over 
week 26, week 78, and week 104 
 
The proportions of patients who are transfusion-free (with RBCs) 
over week 26, week 78, and week 104  
For the rates and numbers of units of transfusion with RBCs over week 26, 
week 78, and week 104, the analysis set consists of all FAS patients.  The 
rate of units of transfusion for a patient will be calculated based on the 
duration of treatment exposure of the patient.   
For binary efficacy endpoints, means and 95% confidence intervals by 
approximation of a one-sample t-statistic as primary analysis and by exact 
methods as sensitivity analysis will be calculated for this category of 
efficacy endpoints.  Sensitivity analysis by multiple imputation of missing 
measurements of the analyzed variable may be performed. 
For continuous efficacy endpoints, means and 95% confidence intervals will 
be derived from one-sample t-test, analysis of covariance (ANCOVA) 
modeling, or MMRM (mixed-effect model for repeated measures) analysis. 
Safety analyses: Evaluation of long-term safety and tolerability of 
REGN3918 is part of the primary objective of the study.  Safety variables 
including AEs, laboratory test results, and vital signs will be descriptive 
based on the safety population, and no formal statistical testing will be 
performed.  Safety analysis will focus on the treatment period. 
For analyses of changes from baseline in laboratory and vital signs 
parameters, baseline of the parent study will be considered.  In addition, 
baseline of the current study may also be considered. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BID 
Twice a day 
CH50 
Total complement hemolytic activity assay 
CRF 
Case report form (electronic or paper) 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOT 
End of treatment 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GPI 
Glycophosphatidylinositol 
HSC 
Hematopoietic stem cells 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgG4p 
Human monoclonal immunoglobulin G4P 
Ig 
Immunoglobulin  
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification  
MAVE 
Major adverse vascular event 
MMRM 
Mixed-effect model for repeated measures 
NAb 
Neutralizing antibody 
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NOAEL 
No observable adverse effect level 
OLE 
Open-label extension 
PFS 
Pre-filled syringe 
PIGA 
Phosphatidylinositol glycan anchor biosynthesis class A 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PT 
Preferred term 
QW 
Once weekly 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WOCP 
Women of childbearing potential 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. 
INTRODUCTION ......................................................................................................14 
1.1. 
Background on Paroxysmal Nocturnal Hemoglobinuria ............................................14 
1.2. 
Background on REGN3918 ........................................................................................15 
2. 
STUDY OBJECTIVES ..............................................................................................17 
2.1. 
Primary Objective .......................................................................................................17 
2.2. 
Secondary Objectives .................................................................................................17 
2.3. 
Exploratory Objectives ...............................................................................................17 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................18 
3.1. 
Hypothesis ..................................................................................................................18 
3.2. 
Rationale .....................................................................................................................18 
3.2.1. 
Rationale for Study Design .........................................................................................18 
3.2.1.1. 
Rationale for the Primary Safety and Efficacy Endpoints ..........................................18 
3.2.1.2. 
Rationale for Secondary Efficacy Endpoints ..............................................................19 
3.2.2. 
Rationale for Dose Selection ......................................................................................20 
3.3. 
Benefit-Risk ................................................................................................................20 
4. 
ENDPOINTS ..............................................................................................................22 
4.1. 
Primary and Secondary Endpoints..............................................................................22 
4.1.1. 
Primary Safety Endpoint .............................................................................................22 
4.1.2. 
Primary Efficacy Endpoint .........................................................................................22 
4.1.3. 
Key Secondary Efficacy Endpoints ............................................................................22 
4.1.4. 
Other Secondary Endpoints ........................................................................................22 
4.2. 
Exploratory Endpoints ................................................................................................23 
5. 
STUDY VARIABLES................................................................................................24 
5.1. 
Demographic and Baseline Characteristics ................................................................24 
5.2. 
Efficacy Variables ......................................................................................................24 
5.2.1. 
Laboratory Variables for the Assessment of Efficacy ................................................24 
5.2.2. 
Transfusion Record .....................................................................................................24 
5.3. 
Safety Variables ..........................................................................................................24 
5.4. 
Pharmacokinetic Variables .........................................................................................24 
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5.5. 
Immunogenicity Variables ..........................................................................................24 
6. 
STUDY DESIGN .......................................................................................................25 
6.1. 
Study Description and Duration .................................................................................25 
6.1.1. 
Study Periods ..............................................................................................................27 
6.1.1.1. 
Two-year Open-Label Treatment Period with REGN3918 ........................................27 
6.1.1.2. 
Optional Post-End-of-Treatment Period .....................................................................27 
6.1.1.3. 
Duration of Study .......................................................................................................27 
6.1.2. 
End of Study Definition ..............................................................................................28 
6.2. 
Planned Interim Analysis ............................................................................................28 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............29 
7.1. 
Number of Patients Planned .......................................................................................29 
7.2. 
Study Population .........................................................................................................29 
7.2.1. 
Inclusion Criteria ........................................................................................................29 
7.2.2. 
Exclusion Criteria .......................................................................................................29 
7.3. 
Premature Withdrawal from the Study .......................................................................30 
7.4. 
Replacement of Patients .............................................................................................30 
8. 
STUDY TREATMENTS............................................................................................30 
8.1. 
Investigational Treatments ..........................................................................................30 
8.2. 
Drug Administration ...................................................................................................31 
8.3. 
Transfusion Algorithm ................................................................................................31 
8.4. 
Pretreatments ..............................................................................................................32 
8.4.1. 
Meningococcal Vaccinations ......................................................................................32 
8.4.2. 
Oral Antibiotics ..........................................................................................................32 
8.5. 
Dose Modification and Study Treatment Discontinuation Rules ...............................32 
8.5.1. 
Study Drug Discontinuation .......................................................................................32 
8.5.1.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................32 
8.5.1.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................33 
8.6. 
Management of Acute Reactions ................................................................................33 
8.6.1. 
Acute Injection Reactions ...........................................................................................33 
8.6.1.1. 
Systemic Injection Reactions ......................................................................................33 
8.6.1.2. 
Local Injection Site Reactions ....................................................................................33 
8.7. 
Risk Management of Neisseria Gonorrhea .................................................................33 
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8.8. 
Dose Modification ......................................................................................................34 
8.9. 
Method of Treatment Assignment ..............................................................................34 
8.9.1. 
Blinding ......................................................................................................................34 
8.10. 
Treatment Logistics and Accountability .....................................................................34 
8.10.1. 
Packaging, Labeling, and Storage ..............................................................................34 
8.10.2. 
Supply and Disposition of Treatments .......................................................................34 
8.10.3. 
Treatment Accountability ...........................................................................................34 
8.10.4. 
Treatment Compliance ................................................................................................35 
8.11. 
Concomitant Medications ...........................................................................................35 
8.11.1. 
Prohibited Medications ...............................................................................................35 
8.11.2. 
Permitted Medications ................................................................................................35 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................36 
9.1. 
Schedule of Events .....................................................................................................36 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................39 
9.1.2. 
Early Termination Visit ..............................................................................................40 
9.1.3. 
Unscheduled Visits .....................................................................................................40 
9.2. 
Study Procedures ........................................................................................................41 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................41 
9.2.2. 
Study Drug Administration.........................................................................................41 
9.2.3. 
Efficacy Procedures ....................................................................................................41 
9.2.3.1. 
Serum Lactate Dehydrogenase ...................................................................................41 
9.2.3.2. 
Transfusion Record Update ........................................................................................41 
9.2.3.3. 
Red Blood Cell Hemoglobin ......................................................................................41 
9.2.3.4. 
Free Hemoglobin ........................................................................................................42 
9.2.4. 
Safety Procedures .......................................................................................................42 
9.2.4.1. 
Concomitant Medications ...........................................................................................42 
9.2.4.2. 
Vital Signs ..................................................................................................................42 
9.2.4.3. 
Physical Examination and Body Weight ....................................................................42 
9.2.4.4. 
Electrocardiogram .......................................................................................................42 
9.2.4.5. 
Laboratory Testing ......................................................................................................42 
9.2.5. 
Drug Concentration and Total C5 Measurements ......................................................44 
9.2.6. 
Immunogenicity Measurements and Samples ............................................................44 
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9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................44 
9.2.8. 
Future Biomedical Research (Optional) .....................................................................45 
9.2.8.1. 
Pharmacogenomic Analysis (Optional) ......................................................................45 
10. 
SAFETY EVALUATION AND REPORTING .........................................................46 
10.1. 
Recording and Reporting Adverse Events ..................................................................46 
10.1.1. 
General Guidelines .....................................................................................................46 
10.1.2. 
Data Collection Period ................................................................................................47 
10.1.3. 
Reporting Procedure ...................................................................................................47 
10.1.4. 
Events that Require Expedited Reporting to Sponsor ................................................47 
10.2. 
Definitions ..................................................................................................................48 
10.2.1. 
Adverse Event .............................................................................................................48 
10.2.2. 
Serious Adverse Event ................................................................................................48 
10.2.3. 
Adverse Events of Special Interest .............................................................................48 
10.2.4. 
Severity .......................................................................................................................49 
10.2.5. 
Causality .....................................................................................................................49 
10.3. 
Safety Monitoring .......................................................................................................50 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................51 
11. 
STATISTICAL PLAN................................................................................................51 
11.1. 
Statistical Hypothesis ..................................................................................................51 
11.2. 
Justification of Sample Size........................................................................................51 
11.3. 
Analysis Sets ...............................................................................................................51 
11.3.1. 
Efficacy Analysis Sets ................................................................................................51 
11.3.2. 
Safety Analysis Set .....................................................................................................52 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................52 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................52 
11.3.5. 
Exploratory Analysis Sets ...........................................................................................52 
11.3.5.1. 
Exploratory Biomarker Endpoint Analysis Set ..........................................................52 
11.4. 
Statistical Methods ......................................................................................................52 
11.4.1. 
Patient Disposition ......................................................................................................52 
11.4.2. 
Demography and Baseline Characteristics .................................................................53 
11.4.3. 
Efficacy Analyses .......................................................................................................53 
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11.4.4. 
Safety Analysis ...........................................................................................................54 
11.4.4.1. 
Adverse Events ...........................................................................................................54 
11.4.4.2. 
Other Safety ................................................................................................................55 
11.4.4.3. 
Treatment Exposure ....................................................................................................55 
11.4.4.4. 
Treatment Compliance ................................................................................................55 
11.4.5. 
Pharmacokinetics ........................................................................................................55 
11.4.5.1. 
Analysis of Drug Concentration Data .........................................................................55 
11.4.6. 
Analysis of Immunogenicity Data ..............................................................................56 
11.4.7. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data ..............................56 
11.5. 
Additional Statistical Data Handling Conventions .....................................................56 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........57 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................58 
12.1. 
Data Management and Electronic Systems ................................................................58 
12.1.1. 
Data Management .......................................................................................................58 
12.1.2. 
Electronic Systems ......................................................................................................58 
12.2. 
Study Monitoring ........................................................................................................58 
12.2.1. 
Monitoring of Study Sites ...........................................................................................58 
12.2.2. 
Source Document Requirements ................................................................................59 
12.2.3. 
Case Report Form Requirements ................................................................................59 
12.3. 
Audits and Inspections ................................................................................................59 
12.4. 
Study Documentation .................................................................................................60 
12.4.1. 
Certification of Accuracy of Data ...............................................................................60 
12.4.2. 
Retention of Records ..................................................................................................60 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................61 
13.1. 
Good Clinical Practice Statement ...............................................................................61 
13.2. 
Informed Consent .......................................................................................................61 
13.3. 
Patients Confidentiality and Data Protection ..............................................................61 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................62 
13.5. 
Clinical Study Data Transparency ..............................................................................62 
14. 
PROTOCOL AMENDMENTS ..................................................................................62 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................62 
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15.1. 
Premature Termination of the Study ...........................................................................62 
15.2. 
Close-out of a Site ......................................................................................................63 
16. 
CONFIDENTIALITY ................................................................................................63 
17. 
FINANCING AND INSURANCE .............................................................................63 
18. 
PUBLICATION POLICY ..........................................................................................63 
19. 
REFERENCES ...........................................................................................................64 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................66 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................67 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................37 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................26 
 
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1. 
INTRODUCTION  
1.1. 
Background on Paroxysmal Nocturnal Hemoglobinuria  
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, life-threatening, and rare 
multisystem disease.  It is characterized by uncontrolled complement activation on red blood cells 
(RBCs), resulting in intravascular hemolysis (Sahin, 2016), and on white blood cells and platelets, 
resulting in an increased risk of thrombosis.  The estimated incidence of PNH is 1.3 cases per 
million individuals per year, and the estimated prevalence is 15.9 cases per million individuals per 
year (Preis, 2014).   
Paroxysmal nocturnal hemoglobinuria originates from a multipotent, hematopoietic stem cell 
(HSC) that acquires a mutation of the phosphatidylinositol glycan anchor biosynthesis class A 
(PIGA) gene.  The PIGA gene product is required for the biosynthesis of the 
glycophosphatidylinositol (GPI) anchor, a glycolipid moiety that attaches dozens of proteins to the 
plasma membrane of cells.  Consequently, the PNH stem cell and all of its progeny have a 
reduction or absence of GPI-anchored proteins.  The mature blood cells derived from the 
hematopoietic clone can have a complete deficiency (type III) or a partial deficiency (type II) of 
GPI-linked proteins (Hillmen, 2004).  Two of the proteins that are affected by the absence of GPI 
anchors are CD55 and CD59, complement regulatory proteins.  CD55 regulates complement 
activation by inhibiting complement component 3 (C3) convertases, whereas CD59 inhibits the 
assembly of the membrane-attack complex (MAC) C5b–C9 by interacting with C8 and C9 
(Brodsky, 2009).  Their absence renders PNH erythrocytes susceptible to complement-mediated 
intravascular hemolysis.  This intravascular hemolysis in patients with PNH causes anemia 
(frequently requiring blood transfusion) and hemoglobinuria.  Complications of PNH include 
thrombosis, abdominal pain, dysphagia, erectile dysfunction, and pulmonary hypertension 
(Hillmen, 2006).  Thromboembolism is the most common cause of mortality in patients with PNH 
and accounts for approximately 40% to 67% of attributable deaths.  Potential mechanisms for 
thromboembolism include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, 
absence of other GPI-linked proteins, and endothelial dysfunction (Hill, 2013).  Paroxysmal 
nocturnal hemoglobinuria frequently occurs with autoimmune aplastic anemia (Luzzatto, 2018).  
Evidence suggests that loss of PIGA provides protection for the PNH clone against HSC loss (by 
removing a putative GPI-anchored autoantigen serving as a target for an autoimmune response 
against the HSC). 
The diagnosis of PNH is established using the internationally accepted definition of presence of 
PNH granulocyte clone size of >10% measured in peripheral blood by flow cytometry.  An 
accepted definition of active disease is the presence of 1 or more of the following PNH-related 
signs or symptoms within 3 months: fatigue, hemoglobinuria, abdominal pain, shortness of breath 
(dyspnea), anemia (hemoglobin <10 g/dL), history of a major adverse vascular event (MAVE; 
including thrombosis), dysphagia, or erectile dysfunction.  Alternatively, activity can be 
established by a history of RBC transfusion due to PNH within 3 months.   
Eculizumab, approved for the treatment of PNH in many countries worldwide, including the 
United States (US) and European Union (EU) member states, is a humanized monoclonal antibody 
directed against the terminal complement protein C5.  It blocks the formation of the MAC C5b-9, 
thus protecting PNH RBCs from complement-mediated intravascular hemolysis.  The basis for 
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approval of eculizumab has been its effectiveness in PNH, as evidenced by the initial reduction of 
lactate dehydrogenase (LDH) levels and by the long-term reduction in the need for blood 
transfusions; decrease in the incidence of thrombosis; improvement in anemia; and improvement 
in quality of life (Griffin, 2017).   
However, not all patients receive optimal therapeutic benefit.  For example, 25% of patients still 
need recurrent, albeit less frequent, blood transfusions.  Up to 20% of patients on eculizumab 
therapy require significant increases in dose or dose frequency due to breakthrough hemolysis 
secondary to incomplete inhibition of C5 (Nakayama, 2016) (Hill, 2013) (Peffault de Latour, 
2015).  While the regulatory approval of ravulizumab (UltomirisTM) in the US in December 2018 
has improved convenience with a dosing frequency of every 8 weeks, it is not available in most of 
the world and patients still experience some hemolytic breakthrough.  In addition, it does not offer 
the significant convenience and reduced burden of subcutaneous (SC) self-administration.  In rare 
instances, eculizumab, and presumably ravulizumab, is ineffective due to polymorphic variation 
in the gene encoding C5 such that the protein is not recognized by eculizumab (Nishimura, 2014).  
The heterogeneity in these hematological responses may be related to underlying aplastic anemia, 
C3b-mediated extravascular hemolysis, or incomplete pharmacologic blockade of C5, and rare 
polymorphisms in the gene coding for C5 (Al-Ani, 2016).   
Thus, unmet needs for patients include better control of breakthrough hemolysis by providing 
maximal and durable inhibition of C5 throughout the dosing interval, improving the dosing 
regimen, binding to the polymorphic variant C5 protein which renders eculizumab ineffective, and 
development of a convenient SC formulation.   
1.2. 
Background on REGN3918 
REGN3918 is a fully human monoclonal immunoglobulin G4P (IgG4P) antibody directed against 
the terminal complement protein C5, which inhibits terminal complement activation by preventing 
C5 cleavage by C5 convertase into C5a (anaphylatoxin) and C5b, thereby blocking the formation 
of the MAC C5b-9, a structure mediating cell lysis.  REGN3918 is being developed for the 
treatment of PNH and other diseases in which tissue damage is mediated by terminal complement 
pathway activity.  REGN3918 can be administered by intravenous (IV) or SC administration.  
Additionally, REGN3918 binds to polymorphic variations in C5 that are not recognized by 
eculizumab. 
REGN3918 was well-tolerated in a toxicology study in cynomolgus monkeys at doses up to 
 following IV administration for 26 weeks, with a 13-week recovery period.  The 
no observable adverse effect level (NOAEL) based on the results of this toxicology study was 
determined to be 
, the highest dose tested.  REGN3918 was demonstrated to have low 
potential for cytokine release in cell-based, in vitro experiments.  Complexes of REGN3918 and 
C5 did not result in the formation of immune complexes capable of binding to complement C1q. 
REGN3918 has been evaluated in a randomized, placebo-controlled, double-blind study 
(R3918-HV-1659) in 56 healthy subjects 
in 
7 dose cohorts (N=8, randomized 
6:2 REGN3918:placebo for each cohort).  REGN3918 was found to be generally well tolerated in 
ascending single-doses of 1, 3, 10, 30 mg/kg IV, and 300 and 600 mg SC.  The seventh cohort, a 
multiple-dose cohort of 4 weekly (QW) SC doses of 400 mg following a 15 mg/kg IV loading 
dose, resulted in 1 resolved serious adverse event (SAE) in the study, an episode of salpingitis of 
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undetermined etiology.  Utilizing the gold standard sheep RBC hemolysis assay (sRBC total 
complement hemolytic activity assay [CH50]), dose-dependent, complete complement inhibition 
was demonstrated for the single-dose cohorts.  The multiple-dose cohort demonstrated complete 
complement inhibition throughout the dosing period.   
Two studies, R3918-PNH-1852 
, will be conducted in PNH patients.  
R3918-PNH-1852 includes patients who are treatment-naïve to complement inhibitor or have not 
recently received complement inhibitor therapy.  
 includes patients who have 
been treated with eculizumab for at least 26 weeks and will switch to REGN3918.  Both studies 
will evaluate REGN3918 administered over 26 weeks in a single-arm open-label design.  Both 
studies will be referred to as the parent studies. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety, tolerability, and effect on 
intravascular hemolysis (ie, proportion of patients achieving LDH ≤1.5× upper limit of normal 
[ULN] over 26 weeks) of REGN3918 in patients with PNH.   
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the long-term effect of REGN3918 on intravascular hemolysis 
 To assess the concentrations of total REGN3918 in serum 
 To evaluate the immunogenicity of REGN3918 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
 To explore the long-term effect on clinical thrombotic events 
 To explore the long-term effect on renal function  
 To explore the long-term effect of REGN3918 on complement activation and 
intravascular hemolysis relevant to PNH and other related diseases 
 To explore the long-term effect of REGN3918 on the concentrations of total C5 
protein 
 To collect future biomedical research samples from consented patients in order to 
study REGN3918 mechanism of action (including relationship to safety and efficacy), 
complement pathway biology, PNH, and related complement-mediated diseases 
 To collect whole blood DNA and RNA from consented patients in order to explore 
whether potential differences in patient efficacy and safety are associated with 
genotype and gene expression, and to further study C5, PNH, or other conditions 
associated with complement-mediated injury 
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3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
No formal statistical hypothesis will be tested.   
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
The current clinical trial (R3918-PNH-1868) is an open-label extension (OLE), single-arm study 
with a 2-year open-label treatment period followed by an optional post-end-of-treatment (EOT) 
period with continued treatment with REGN3918 of variable duration in patients with PNH who 
have completed 1 of the 2 parent studies (R3918-PNH-1852 or 
).  In the parent 
studies, the duration of the treatment period is 26 weeks because it is anticipated that there will be 
a rapid initiation of clinical benefit of REGN3918 on intravascular hemolysis.  It is expected, if 
approved, that REGN3918 would be administered in clinical practice for a duration of years, which 
is consistent with the current practice for eculizumab and ravulizumab.  The longer-term treatment 
duration provided through this study will enable the evaluation of whether or not the initial clinical 
benefit anticipated in the parent studies is maintained and will provide further insight into the 
safety profile.   
The study population includes patients coming from the parent studies as follows: 
 R3918-PNH-1852: Approximately 30 patients and up to 42 patients with PNH having 
active signs and symptoms who are complement inhibitor-naïve or have not recently 
received complement inhibitor therapy will be enrolled into this parent study.   
 
 
 
 
Therefore, R3918-PNH-1868 will enroll approximately up to 
 patients from the parent studies. 
3.2.1.1. 
Rationale for the Primary Safety and Efficacy Endpoints 
The primary objective of the study is to evaluate the long-term safety, tolerability, and effect on 
intravascular hemolysis of REGN3918.  The long-term safety and tolerability will be assessed by 
the incidence and severity of treatment-emergent adverse events (TEAEs) and other safety 
variables during the 2-year open-label treatment period of the study.  The effect on intravascular 
hemolysis will be assessed by the proportion of patients achieving LDH ≤1.5×ULN over 26 weeks.  
The treatment periods of the 2 parent studies are of 26 weeks in duration each, which is sufficient 
to gain information on the efficacy on intravascular hemolysis.  However, these trials still leave 
unanswered the efficacy and longer-term-safety of REGN3918 beyond 26 weeks.  The effect on 
intravascular hemolysis over 26 weeks in the OLE study enables an evaluation of the maintenance 
of effect that will have been achieved after 26 weeks in the parent studies.  An LDH ≤1.5×ULN is 
a clinically meaningful threshold for disease activity; an LDH greater than 1.5×ULN, along with 
related clinical symptoms, is considered as an indication for treatment with eculizumab 
(Soliris PI, 2018) (Ultomiris PI, 2018) (Sahin, 2016).  Reductions in LDH ≤1.5×ULN threshold 
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with eculizumab therapy have been shown to be correlated with improvement in patient’s 
symptoms, quality of life measures, and transfusion requirements (Brodsky, 2008).  The safety 
assessment over 2 years in the OLE study allows us to answer some key questions, such as whether 
the safety observed over the 26 weeks in the parent studies is maintained with prolonged treatment 
exposure and whether any long-term safety risks, including AEs, emerge over time.  Answering 
such questions relies on the accrual of long-term safety data, not only to confirm initial findings 
from the parent studies, but also to record an acceptable risk–benefit ratio that supports the 
continued development of the REGN3918 program.   
3.2.1.2. 
Rationale for Secondary Efficacy Endpoints 
Breakthrough intravascular hemolysis and a return of PNH symptoms occur in approximately 25% 
of patients with PNH treated with the approved dose of eculizumab and may result in direct clinical 
consequences for patients (Al-Ani, 2016).  In this study, breakthrough hemolysis is a key 
secondary efficacy endpoint, defined by the measurement of LDH ≥2×ULN concomitant with 
associated signs or symptoms at any time subsequent to an initial achievement of disease control 
(ie, LDH ≤1.5×ULN) (Brodsky, 2018).  Examples of signs or symptoms include the following: 
new onset or worsening fatigue, headache, dyspnea, hemoglobinuria, abdominal pain, scleral 
icterus, erectile dysfunction, chest pain, confusion, dysphagia, anemia (hemoglobin value 
significantly lower as compared to patient’s known baseline hemoglobin values), and thrombotic 
event.  An event of breakthrough hemolysis as defined here will be confirmed based on investigator 
judgment.   
The key secondary efficacy endpoint of the number of transfusions with RBCs and the number of 
units of RBCs transfused and the other secondary efficacy endpoint of transfusion avoidance (as 
assessed by the proportion of patients who are transfusion-free) is a clinical measure of reduced 
disease activity.  In the eculizumab pivotal studies of patients with PNH who were treatment-naïve, 
TRIUMPH (Hillmen, 2006) and SHEPHERD (Brodsky, 2008), 0% of patients were transfusion 
independent at enrollment, with 49% and 51% achieving transfusion avoidance during the studies 
respectively.  Similarly, the more recent study evaluating ravulizumab vs.  eculizumab in PNH 
naïve patients reported 18.4% and 17.4%, respectively, transfusion independence in the year prior 
to the study with 73.6% and 66.1%, respectively, transfusion avoidance over 26 weeks (Lee, 2019).  
In another recent study with ravulizumab vs.  eculizumab in patients previously treated with 
eculizumab, the difference in transfusion avoidance was 5.5% (95% CI -4.27, 15.68) 
(Kulasekararaj, 2019).  A predefined algorithm for transfusion allows for standardization in the 
current study and captures a clinically meaningful event related to complement mediated 
intravascular hemolysis. 
The other secondary efficacy endpoints, proportion of patients achieving target LDH reduction 
and change from baseline in LDH, evaluate the accepted objective laboratory measure of control 
of intravascular hemolysis.  The assessment of intravascular hemolysis, as measured by LDH, is 
central to the clinical monitoring of PNH (Rother, 2005), as demonstrated in eculizumab studies.  
Pivotal eculizumab studies, subsequent studies using eculizumab as a comparator to ravulizumab 
(ALXN1210, a humanized monoclonal antibody to C5 engineered from the parent molecule 
eculizumab), to provide extended half-life, and the PNH Registry have shown that the active PNH 
population has LDH elevated in the range of 6× to 8×ULN (Roth, 2018b).  Upon treatment with 
anti-C5 antibody, LDH levels fall rapidly in all patients with the clinical goal of achieving an LDH 
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of ≤1.5×ULN.  In a switch paradigm, whereby patients treated with eculizumab subsequently 
received either ravulizumab or continued eculizumab, the percent change from baseline in LDH 
with ravulizumab was shown to be non-inferior as compared with eculizumab (difference 
of -9.21% [95% CI: –18.84, 0.42]) (Kulasekararaj, 2019).  In addition to the secondary endpoint 
of the proportion of patients reaching an LDH ≤1.5×ULN over week 78 and over week 104, a more 
stringent criterion of LDH normalization will be analyzed; however, an additional clinical benefit 
of more stringent LDH control has not been fully established.  Aside from achievement of 
normalization of LDH (as defined by LDH ≤1.0×ULN), LDH will be reported using change and 
percent change from baseline of the OLE study.  It should be noted that the degree of change from 
baseline has not been correlated, to date, with any clinically meaningful disease control 
parameters.  While this continuous outcome measure is efficient at showing a drug effect on 
hemolysis with very few patients, it does not allow for an assessment of likelihood of clinical 
disease control. 
Hemoglobin levels in patients with PNH can be measured as RBC hemoglobin or as free 
hemoglobin.  Reductions in RBC hemoglobin levels are correlated with symptoms and are used to 
guide decisions on the need for transfusion.  Intravascular hemolysis releases free hemoglobin into 
the plasma.  Free plasma hemoglobin scavenges nitric oxide, and depletion of nitric oxide at the 
tissue level contributes to numerous PNH manifestations, including esophageal spasm, male 
erectile dysfunction, renal insufficiency, and thrombosis.  Thus, free hemoglobin levels are a useful 
clinical parameter in patients with PNH. 
3.2.2. 
Rationale for Dose Selection  
The dose and dosing interval of REGN3918 will be a continuation of the dosage regimen from the 
parent studies; however, some patients in the current study may require an adjustment to the 
selected dosage regimen (see Section 8.2).  The maximum dosage regimen will be 800 mg QW.  
This dosage regimen will be finalized based on the emerging data from cohort A of the parent 
study R3918-PNH-1852, in active PNH patients who have never received a C5 inhibitor, or have 
not received complement inhibitor therapy in the past 6 months and require treatment with a C5 
inhibitor.  A key aspect of the emerging data will focus on patients achieving LDH ≤1.5×ULN and 
safety at 8 weeks of treatment with REGN3918.   
3.3. 
 Benefit-Risk 
The benefit of blocking C5 complement activity in PNH has been clearly established by 
eculizumab.  REGN3918 offers potential additional benefits of better control of breakthrough 
hemolysis by providing maximal and durable inhibition of C5 throughout the dosing interval, 
improving the dosing regimen, binding to the polymorphic variant C5 protein which renders 
eculizumab ineffective, and development of a convenient SC formulation. 
An established risk of blocking C5 complement activity is an increased susceptibility to infections, 
specifically to encapsulated organisms, the most potentially severe of which is infection with 
Neisseria meningitidis (Figueroa, 1991).  Experience with eculizumab suggests that pretreatment 
with appropriate vaccinations covering multiple serotypes and concurrent therapy with oral 
antibiotics is effective at mitigating this risk (Soliris PI, 2018) (Hillmen, 2013).  Current treatment 
guidelines for PNH and the eculizumab package insert recommend such vaccination prior to 
dosing.  In various disease settings such as asplenia in sickle cell disease, and with terminal 
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complement deficiency, use of long-term prophylactic antibiotics has been safely implemented for 
the prevention of encapsulated organisms including N. meningitidis (Gaston, 1986) 
(Wedzicha, 2008).  Because vaccination does not provide 100% coverage to all strains and there 
are no proven titer levels associated with 100% protection, prophylactic oral antibiotics are also 
commonly given to patients with genetic or pharmacologic deficiency in terminal complement 
activity.  Therefore, vaccination prior to administration (or at the time of administration, based on 
local practice, Section 8.4.1) will sufficiently mitigate the risk of single and multiple doses of 
REGN3918 in patients to a level that has been considered acceptable in other anti-C5 clinical 
development programs.  In addition, concurrent therapy with oral antibiotics is recommended 
(Section 8.4.2). 
Recently, serious infections with Neisseria species (other than N. meningitidis), including 
disseminated gonococcal infections, have been reported during eculizimab treatment 
(Soliris PI, 2018).  Counseling about Neisseria gonorrhea prevention, testing, and treatment is to 
be performed in accordance with local practice/national guidelines (see Section 8.7). 
A risk-benefit statement for REGN3918 is provided in the Investigator’s Brochure. 
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4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Safety Endpoint 
The primary safety endpoint is incidence and severity of TEAEs and other safety variables during 
the 2-year open-label treatment period of the study in patients treated with REGN3918.   
Adverse events (AEs), SAEs, and AEs of special interest (AESIs) will be analyzed over the 2-year 
open-label treatment period.  For other safety variables, including laboratory data, vital signs, and 
electrocardiograms (ECGs), analysis will be conducted in reference to the baseline of the parent 
study, as this is the time point prior to any exposure to REGN3918.   
4.1.2. 
Primary Efficacy Endpoint 
The proportion of patients achieving LDH ≤1.5×ULN over week 26, defined as LDH ≤1.5×ULN 
at every scheduled time point up to week 26 (inclusive), will be the primary efficacy endpoint.   
The baseline for the primary analysis of the primary efficacy endpoint is the baseline of the OLE 
(ie, this study), as it is expected that at this time point the 2 different populations from the parent 
studies should converge with regard to their control of intravascular hemolysis. 
4.1.3. 
Key Secondary Efficacy Endpoints 
 The proportion of patients with breakthrough hemolysis over week 26 
 The rate and number of units of transfusion over week 26 
4.1.4. 
Other Secondary Endpoints 
 The proportions of patients with breakthrough hemolysis over week 78 and week 104 
 The rates and numbers of units of transfusion with RBCs over week 78 and week 104 
 The proportions of patients who are transfusion-free (with RBCs) over week 26, 
week 78, and week 104 
 The proportions of patients achieving adequate control of their intravascular 
hemolysis, defined as LDH ≤1.5×ULN at every scheduled time point up to week 78 
(inclusive), and week 104 (inclusive) 
 The proportions of patients achieving normalization of their intravascular hemolysis, 
defined as LDH ≤1.0×ULN at every scheduled time point up to week 26 (inclusive), 
week 78 (inclusive), and week 104 (inclusive) 
 Changes and percent changes in LDH from baseline of the OLE study to week 26, 
week 78, and week 104 
 Changes in RBC hemoglobin levels from baseline of the OLE study to week 26, 
week 78, and week 104 
 Changes in free hemoglobin levels from baseline of the OLE study to week 26, 
week 78, and week 104 
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 Concentrations of REGN3918 in serum assessed throughout the study  
 Incidence of treatment-emergent anti-drug antibodies (ADA) to REGN3918 
throughout the study  
4.2. 
Exploratory Endpoints 
 Changes in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline of the OLE study to week 26, week 78, and week 104 
 Changes in haptoglobin from baseline of the OLE study to week 26, week 78, and 
week 104 
 Changes in bilirubin from baseline of the OLE study to week 26, week 78, and 
week 104 
 Changes in reticulocyte count from baseline of the OLE study to week 26, week 78, 
and week 104 
 Changes and percent change in CH50 from baseline of the OLE study to week 26, 
week 78, and week 104 
 Changes in total C5 from baseline of the OLE study to week 26, week 78, and 
week 104 
 Incidences of MAVE over week 26, week 78, and week 104 
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5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics (as allowed to be collected per local regulations) will include standard 
demographic information (eg, age, race, weight, height, etc.), disease characteristics, medical 
history, and medication history for each patient.   
5.2. 
Efficacy Variables 
5.2.1. 
Laboratory Variables for the Assessment of Efficacy 
Efficacy in this study is evaluated by the following laboratory assessments: 
 Serum LDH 
 RBC hemoglobin 
 Free hemoglobin 
These laboratory variables are relevant to the characterization and disease mechanisms of PNH 
(Brodsky, 2014). 
5.2.2. 
Transfusion Record 
Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusion 
for symptomatic management.  The frequency of blood transfusion has been used in other studies 
of PNH to assess efficacy (Hillmen, 2006) (Roth, 2018a). 
5.3. 
Safety Variables 
Safety variables in this study include: 
 TEAEs 
 ECGs 
 Vital signs (temperature, sitting blood pressure, and pulse rate) 
 Routine safety laboratory tests (hematology, chemistry, urinalysis, and pregnancy testing 
(for women of childbearing potential [WOCP] only) 
5.4. 
Pharmacokinetic Variables 
The pharmacokinetic (PK) variable is the concentration of total REGN3918 at each time point.  
The sampling time points are specified in Table 1. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are anti-drug antibody (ADA) status, titer, neutralizing antibody 
(NAb) status, and time point/visit.  Samples in this study will be collected at the clinic visits 
specified in Table 1.  
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6. 
STUDY DESIGN  
6.1. 
Study Description and Duration 
This study is an open-label, single-arm study with REGN3918.  The total number of patients 
included in the study is a maximum of 
 patients.  The study schematic is presented in Figure 1. 
 
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Figure 1: 
Study Schema 
  
 
 
*Patients who do not enter into the optional post-EOT period should be followed for 21 weeks after the end of the 2-year open-label treatment period.  Patients 
should return for monthly visits with assessments corresponding to the week 104 (EOT) visit. 
**The optional post-EOT period includes continued REGN3918 treatment of variable duration.  Patients may continue REGN3918 treatment after they have 
completed the 2-year open-label treatment period if they derive clinical benefit and have potential risk upon discontinuation of REGN3918.  The optional post-
EOT period ends when 1 of the following is reached: clinical development of REGN3918 is terminated, risk-to-benefit profile of REGN3918 in this patient 
population is deemed unfavorable, or REGN3918 is approved by the regulatory authority governing the location of the study site. 
 
 
 
 
 
Open-Label Extension 2-year 
REGN3918 treatment period* 
R3918-PNH-1852
I
W26
W52
W39
W104 (End-
Of-2-year-
Treatment 
[EOT] visit)
D1 / W0
W13
End-of-Post 
EOT period 
visit
W78
W91
Clinic Visit Every 6 Months
Optional Post EOT period with 
continued REGN3918 treatment of 
variable duration**
W65
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6.1.1. 
Study Periods 
This study contains 2 study periods: the 2-year open-label treatment period and the optional post-
EOT period (ie, after completion of the 2-year open-label treatment period).  Please see Figure 1. 
6.1.1.1. 
Two-year Open-Label Treatment Period with REGN3918 
Patients who have completed 1 of the 2 parent studies (ie, either R3918-PNH-1852 or 
) will be eligible for screening for this OLE study.  The 2-year open-label 
treatment period will have assessments as described in Table 1 occurring approximately quarterly 
and ending at week 104 (EOT). 
The transition of treatment with REGN3918 from the parent study to the OLE study is planned to 
be uninterrupted.  Therefore, the day 1 visit of the 2-year open-label treatment period will occur 
on the same visit as the EOT study visit in the parent study and overlapping assessments do not 
need to be repeated in this OLE study.  Patients will continue their dose of up to 800 mg QW from 
the parent study starting at day 1 in the OLE study, with a potential change in dose/dosing interval 
(on day 1 or subsequently) only for patients in cohort A of the parent study R3918-PNH-1852, if 
applicable.  As part of risk mitigation for this study, it is recommended for patients to receive 
updated meningococcal vaccination (Section 8.4.1), daily oral antibiotic prophylaxis 
(Section 8.4.2), and counselling regarding risk of Neisseria gonorrhea (Section 8.7), as applicable.  
In addition, blood transfusions should proceed according to the algorithm in Section 8.3.  
Breakthrough hemolysis is defined in Section 3.2.1.2. 
Patients who do not enter into the optional post-EOT period should be followed for 21 weeks after 
the end of the 2-year open-label treatment period.  Patients should return for monthly visits with 
assessments corresponding to week 104 (EOT) visit. 
6.1.1.2. 
Optional Post-End-of-Treatment Period 
The optional post-EOT period includes continued REGN3918 treatment of variable duration.  
Patients may continue REGN3918 treatment after they have completed the 2-year open-label 
treatment period and if they derive clinical benefit and have potential risk upon discontinuation of 
REGN3918.  Eligible patients will be asked to provide separate consent for continuing onto the 
optional post-EOT period.  The optional post-EOT period ends when 1 of the following is met: 
 Clinical development of REGN3918 is terminated. 
 Risk-to-benefit profile of REGN3918 in this patient population is deemed unfavorable. 
 REGN3918 is approved by the regulatory authority governing the location of the study 
site.   
The additional safety information accrued in the post-EOT period will be reported.   
6.1.1.3. 
Duration of Study 
It is projected that the first patients enrolled and who continue into the optional post-EOT period 
will have a study duration of approximately 4 years and the last patients enrolled will have a study 
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duration of at least 2 years.  However, the study duration is dependent on the criteria mentioned in 
Section 6.1.1.2. 
6.1.2. 
End of Study Definition 
At a study level, the end of study is defined as the last visit of the last patient. 
At a patient level, the end of study is defined as the end of treatment period (EOT) or, depending 
on the particular circumstances of the patient (see Section 6.1.1.2), at the end of post-EOT period, 
which is of variable duration. 
6.2. 
Planned Interim Analysis  
There will not be a formal interim analysis. 
An interim data lock(s) for regulatory submissions of REGN3918 or publication purposes may be 
conducted. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately up to 
 patients are expected to enroll in this study. 
This study will be conducted at multiple global sites that enroll patients in the 2 parent studies.  
Enrollment for this study will be driven by enrollment in the parent studies (R3918-PNH-1852 
 
). 
7.2. 
Study Population  
The study population will consist of adult male and female patients with confirmed diagnosis of 
PNH who have completed 1 of the 2 parent studies (R3918-PNH-1852 
). 
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Patients with PNH who have completed, without discontinuation, study treatment in 1 of 
the parent studies in which they participated (either R3918-PNH-1852 
) 
2. Willing and able to comply with clinic visits and study-related procedures 
3. Provide informed consent signed by study patient  
7.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Significant protocol deviation(s) in the parent study based on the investigator’s judgment 
and to the extent that these would (if continued) impact the study objectives and/or safety 
of the patient (for example, repetitive non-compliance with dosing by the patient). 
2. Any new condition or worsening of an existing condition which, in the opinion of the 
investigator, would make the patient unsuitable for enrollment or could interfere with the 
patient participating in or completing the study. 
3. Pregnant or breastfeeding women 
4. Women of childbearing potential* 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 21 weeks after the last dose.  Highly effective contraceptive measures include:  
a. stable use of combined (estrogen and progestogen-containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening 
b. intrauterine device; intrauterine hormone-releasing system 
c. bilateral tubal ligation 
d. vasectomized partner 
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e. and/or sexual abstinence†, ‡. 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
†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 
treatments.  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 are not 
acceptable methods of contraception.  Female condom and male condom should not be 
used together.   
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 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.5.1. 
7.4. 
Replacement of Patients  
Patients prematurely withdrawn from the study/study drug will not be replaced. 
8. 
STUDY TREATMENTS  
8.1. 
Investigational Treatments 
REGN3918 drug product may be initially provided in lyophilized form in a sterile, single-use glass 
vial for SC administration that requires reconstitution with sterile water for injection to 150 mg/mL 
REGN3918, and then transitioned to a sterile, single-use glass vial containing a liquid 200 mg/mL 
REGN3918 formulation that will not require reconstitution.  However, the study may begin 
directly with the liquid formulation.  The compositions of the lyophilized and liquid formulations 
differ, mainly as a result of the inclusion of a viscosity reducer (arginine hydrochloride) in the 
high-concentration liquid formulation.  The liquid drug product may then be switched to a pre-
filled syringe (PFS). 
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Study drug will be supplied by the sponsor.  The admixture solutions needed for delivery of the 
lyophilized drug product for SC administration will be sourced locally, or may be supplied by the 
sponsor, as necessary.  Detailed information about the drug product and dose preparation is 
provided in the pharmacy manual. 
8.2. 
Drug Administration 
Patients will be given a dose no greater than 800 mg SC QW (±1 day) over the treatment period. 
The dose and dosing interval of REGN3918 will be finalized based on the emerging data from 
cohort A of the parent study R3918-PNH-1852, in active PNH patients who have never received 
a C5 inhibitor, or have not received complement inhibitor therapy in the past 6 months and require 
treatment with a C5 inhibitor.  It is anticipated that most or nearly all patients will continue their 
dose and dosing interval from the parent study.  However, some patients may or may not require 
an adjustment to their dosage regimen if they enter the current study before the decision on the 
final dose/dosing interval is made based on the R3918-PNH-1852 study.   
The location and administration options for SC route of administration will depend on the 
preference of the investigator and patient (eg, abdomen, thigh, or upper arm), the availability of 
clinical supply, and the home healthcare visiting professional.  Clinic visits for SC administration 
may or may not be needed. 
If self-administration/administration by patient/designated person is allowed locally, then 
sufficient injection training at the scheduled injection with REGN3918 will be provided.  After 
training, observation of self-administration/administration by patient/designated person will be 
conducted by the clinical site personnel or visiting healthcare professional.  Once this observation 
is considered satisfactory, then the study drug can be subsequently administered independently by 
the patient/designated person for the remainder of the study.   
In addition, a patient diary will be provided prior to initiation of self-administration.  The diary 
should be completed upon each the study drug administration.  A study drug kit will be dispensed 
at clinical site visit, using a direct-to-patient (DTP) service provider, or transported by a healthcare 
professional, as applicable. 
Detailed information about the study drug administration is provided in the pharmacy manual.   
8.3. 
Transfusion Algorithm 
Transfusions with RBCs during the study should proceed according to the following predefined 
criteria that will trigger a transfusion; however, the actual number of units to be transfused is at 
the discretion of the investigator: 
 Transfuse with RBC(s) if the post-baseline* hemoglobin level is <9 g/dL with 
symptoms resulting from anemia, or 
 Transfuse with RBC(s) if the post-baseline* hemoglobin level is <7 g/dL. 
*Baseline is the baseline of OLE study. 
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8.4. 
Pretreatments  
Enrolled patients should receive updated meningococcal vaccination, as needed, concomitant to 
enrollment into the OLE.  Oral antibiotics are recommended during the treatment period, according 
to local practice. 
8.4.1. 
Meningococcal Vaccinations 
Patients will have had previous documented vaccination for meningococcus and should be 
re-immunized based on local practice.  Patients should be closely monitored for early signs and 
symptoms of meningococcal infection and evaluated immediately if an infection is suspected.  
Patients will be provided with a patient safety card describing signs and symptoms of 
meningococcal infection, along with instructions in case of a potential meningococcal infection, 
as well as information for the non-investigator healthcare provider.  The vaccinations will be 
sourced locally by the investigator or designee and reimbursed by the sponsor.  Serologic titers for 
to determine adequate meningococcal immunity can be done if clinically indicated.  Revaccination 
is not mandatory if serologic titers to serogroups of Neisseria meningitidis demonstrate adequate 
immunity, as per local practice. 
8.4.2. 
Oral Antibiotics 
It is recommended that daily oral antibiotic prophylaxis commence on the day of first dosing with 
REGN3918, unless the risks outweigh the benefits or it is inconsistent with local practice, and 
continue for the duration of the study.  It is recommended that patients who prematurely 
discontinue REGN3918 receive at least 21 weeks of oral antibiotic prophylaxis after discontinuing 
REGN3918 or a duration consistent with local guidelines, whichever is longer (Section 9.1.2).  It 
is suggested that antibiotic prophylaxis be penicillin V 500 mg twice a day (BID).  In the case of 
penicillin allergy, Erythromycin® 500 mg BID may be used at the discretion of the investigator.  
Ultimately, the decision to administer prophylaxis with oral antibiotics, the duration of 
prophylaxis, the choice and dosage regimen of antibiotics will be at the discretion of the 
investigator.  The oral antibiotics will be sourced locally by the investigator or designee and 
reimbursed by the sponsor. 
8.5. 
Dose Modification and Study Treatment Discontinuation Rules 
8.5.1. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.2. 
8.5.1.1. 
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 
 Liver impairment as evidenced by one or more of the following criteria: 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8×ULN or 
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 ALT or AST >5×ULN for more than 2 weeks, or 
 ALT or AST >3×ULN and total bilirubin >2×ULN (or international normalized 
ratio (INR) >1.5) and no other reason can be found to explain the combination of 
increased AST/ALT and total bilirubin, such as viral hepatitis A, B, or C; 
pre-existing or acute liver disease; or another drug capable of causing the 
observed injury 
 Patient withdrawal of consent 
 Patient non-compliance (eg, not complying with protocol-required visits, 
assessments, and/or dosing instructions) 
 Investigator’s clinical judgment that it is in the best interest of the patient 
8.5.1.2. 
Reasons for Temporary Discontinuation of Study Drug 
Temporary discontinuation may be considered by the investigator because of suspected AEs.  The 
investigator can reinitiate treatment with study drug under close and appropriate clinical and/or 
laboratory monitoring upon determining, according to his/her best medical judgment, that the 
responsibility of the study drug in the occurrence of the concerned event was unlikely. 
8.6. 
Management of Acute Reactions  
8.6.1. 
Acute Injection Reactions 
8.6.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use at the site.  All injection reactions must be reported as AEs (as defined in 
Section 10.2) and graded using the grading scales as instructed in Section 10.2.4. 
Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice. 
8.6.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
8.7. 
Risk Management of Neisseria Gonorrhea 
Patients should be counseled about Neisseria gonorrhea prevention and regular testing should be 
advised for at-risk patients. 
A risk factor assessment should be based on local practice or national guidelines.  The investigator 
should make his/her own assessment of risk (and if needed, consultation with other healthcare 
provider) to determine if the patient is at risk, which would lead to further management on 
prevention, testing, and treatment of Neisseria gonorrhea. 
Testing and treatment should be in accordance with local practice/national guidelines. 
General preventive measures include abstinence and use of a condom.  Additional preventive 
measures should be considered based on local practice or national guidelines. 
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8.8. 
Dose Modification 
Dose modification for an individual patient is not allowed by the investigator.  Dose modification 
for the study may be conducted by the sponsor as per Section 8.2. 
8.9. 
Method of Treatment Assignment 
All patients who sign the informed consent form (ICF) will be assigned a patient number.  
Treatment assignment will be performed in an unblinded fashion.  Patients will be enrolled 
sequentially in order of confirmed eligibility. 
Treatment will be assigned by an interactive voice response system (IVRS)/interactive web 
response system (IWRS) and provided to the site as shown in Table 1. 
8.9.1. 
Blinding 
This is an open-label study. 
8.10. 
Treatment Logistics and Accountability 
8.10.1. 
Packaging, Labeling, and Storage  
REGN3918 for injection will be provided as open-label supplies packaged in carton boxes.  Each 
carton box will contain 1 labeled vial or PFS.  The carton box and vial or PFS will be labeled with 
a booklet label indicating the protocol number, product identity and strength, medication/reference 
number, batch number, directions for use, route of administration, expiry date, sponsor 
information, and storage conditions, and will correspond to all regulatory requirements. 
Study drug will be stored according to labeled storage conditions at a temperature of 2ºC to 8ºC. 
8.10.2. 
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 on-site or at a destruction 
depot after accountability and reconciliation.   
8.10.3. 
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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8.10.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.11. 
Concomitant Medications  
Any treatment administered from the time of informed consent to the end of the final study visit 
will be considered concomitant medication.  This includes medications that were started before 
the study and are ongoing during the study. 
8.11.1. 
Prohibited Medications  
The following medications are prohibited, with the exception of those listed in Section 8.11.2, as 
described below: 
 Within 24 hours prior to each clinic visit when blood is drawn, patients should not 
consume any alcohol 
 Beginning on day 1 and continuing throughout the study, while the patient is 
continuing REGN3918, the patient should not take any other complement inhibitor 
therapy 
8.11.2. 
Permitted Medications  
The following medications and procedures will be permitted, under the following conditions: 
 Any medication required to treat an AE, including systemic corticosteroids, at the 
discretion of the investigator 
 Meningococcal vaccination, as described in Section 8.4.1 
 Oral antibiotic prophylaxis, as described in Section 8.4.2 
 Oral contraceptives and hormone-replacement therapy may continue 
 Acetaminophen/paracetamol, aspirin, or ibuprofen at the recommended dose per the 
local label 
 Erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic agents, 
anticoagulants, iron supplements, and folic acid are permitted and, if possible, should 
be kept constant throughout the study; any changes to these concomitant medications 
will be at the discretion of the investigator and consistent with practice prior to 
enrollment 
 Any medication required for the treatment of patient's background medical conditions 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events  
Study assessments and procedures are presented by study period and visit in Table 1.   
When multiple procedures are scheduled for the same visit/time point, the following guidance 
should be followed: 
 Vital signs and ECGs should be performed prior to blood draws and study drug 
administration 
 PK/ADA sampling should be performed as soon as possible after an ECG 
 Collect safety (including ADA), PK, efficacy, followed by biomarker samples prior to 
study drug administration  
Patients will be provided the following:  
 A patient diary will be provided to patients who self-administer the study drug to 
collect relevant information 
 Patient safety card for Neisseria meningitidis (see Section 8.4.1) 
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Table 1: 
Schedule of Events  
Study Period 
2-Year Open-Label Treatment Period1 
Optional Post-EOT Period2 
Study Week 
Day 1/ 
Week 05 
Week  
Every 6 months after EOT until  
End of Post-EOT period 
13 
26 
39 
52 
65 
78 
91 
EOT 
(104) 
 
Visit Window (weeks) 
 
±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w 
± 2 w 
Clinic Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
X2 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Risk assessment for Neisseria gonorrhea3 
X 
 
 
 
 
 
 
 
 
 
Enrollment via IVRS/IWRS 
X 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
REGN3918 administration4 
--------------------------------------X4--------------------------------- 
X 
Oral antibiotics 
--------------------------------------X--------------------------------- 
X 
Meningococcal vaccine (as needed) 
--------------------------------------X--------------------------------- 
X 
Patient diary (if applicable, compliance check)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
Serum LDH6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion record update 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RBC hemoglobin7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Free hemoglobin7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Study Period 
2-Year Open-Label Treatment Period1 
Optional Post-EOT Period2 
Study Week 
Day 1/ 
Week 05 
Week  
Every 6 months after EOT until  
End of Post-EOT period 
13 
26 
39 
52 
65 
78 
91 
EOT 
(104) 
 
Visit Window (weeks) 
 
±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w 
± 2 w 
Safety: 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
X 
 
X 
 
X 
 
X 
X 
Electrocardiogram 
X 
 
 
 
X 
 
 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient safety card for Neisseria meningitidis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
Hematology7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (WOCP only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Titers to Neisseria meningitidis (only if indicated as per local 
practice)8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK, ADA and Biomarker Samples: 
 
 
 
 
 
 
 
 
 
 
PK sample of REGN3918 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Total C5 (plasma) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complement hemolytic assay (serum CH50) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bilirubin6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Reticulocyte count7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADA sample for REGN3918 
X 
 
X 
 
X 
 
X 
 
X 
X9 
Optional Research: 
 
 
 
 
 
 
 
 
 
 
Future biomedical research (optional) 
X 
X 
X 
 
X 
 
 
 
X 
 
Whole blood for DNA isolation (optional)10 
X 
 
 
 
 
 
 
 
 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. After completion of the 2-year open-label treatment period, patients who do not enter into 
the optional post-EOT period should be followed for 21 weeks.  Patients should return for 
monthly clinic visits with assessments corresponding to week 104 (EOT) visit.   
2. The optional post-EOT period includes continued REGN3918 treatment of variable 
duration.  Patients may continue REGN3918 treatment after they have completed the 2-
year open-label treatment period and if they derive clinical benefit and have potential risk 
to discontinue REGN3918.  The optional post-EOT period ends when 1 of the following 
is reached: clinical development of REGN3918 is terminated, risk-to-benefit profile of 
REGN3918 in this patient population is deemed unfavorable, or REGN3918 is approved 
by the regulatory authority governing the location of the study site.  Patients will be asked 
to provide separate consent for continuing onto the optional post-EOT period. 
3. Risk assessment for Neisseria gonorrhea is described in Section 8.7. 
4. Study drug administration will occur QW throughout the entire study, starting from the 
day 1 visit until and including the end-of-treatment visit (for the 2-year open-label 
treatment period) and for the optional post-EOT period (if applicable).  Administration of 
study drug may be done at the clinical site, by a healthcare professional at the patient’s 
home, or by self-administration/administration by the patient or designated person, 
respectively.  These various options for administration will depend on the preference of 
the investigator and patient, the availability of clinical supply, and the home healthcare 
visiting professional, and presentation of the study drug that may change during the 
course of the study.  If the presentation of the study drug becomes available for self-
administration /administration by patient or designated person, then sufficient injection 
training at the scheduled administration(s) with REGN3918 will be provided prior to 
undertaking study drug administration.  Study drug kits will be dispensed at the clinical 
site visit or, as applicable, transported to the patient by a healthcare professional or by a 
DTP service provider. 
The recommended daily oral antibiotic prophylaxis will commence on the day of dosing 
and will consist of penicillin V 500 mg BID, or Erythromycin 500 mg BID in the case of 
penicillin allergy (to be determined by the investigator).  See Section 8.4.2. 
5. A patient diary will be provided to collect information that may include AEs, study drug 
administration, concomitant medications, vital signs, etc.  depending on availability of a 
home healthcare visiting professional and other considerations.  For self-
administration/administration by a designated person, a compliance check with the 
patient diary will be undertaken at clinic visits. 
6. On visits where chemistry overlaps with serum LDH and/or bilirubin assessments, the 
chemistry testing will include these assessments. 
7. On visits where hematology overlaps with RBC hemoglobin, free hemoglobin, and/or 
reticulocyte count assessments, the hematology testing will include these assessments. 
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8. Revaccinate patients at any time throughout the study.  If the patient has had titers 
measured for Neisseria meningitidis and they demonstrate inadequate level of immunity, 
then revaccination should be done. 
9. ADA samples will be collected every 12 months after EOT and until the end of post-EOT 
period.  Samples will be used for detecting the presence of ADA only; NAb positivity 
will only be assessed for treatment-emergent ADA-positive samples. 
10. Whole blood sample for DNA should be collected on day 1 (predose) but can be 
collected at a later study visit.  Patients who had consented to DNA testing in the parent 
study and had provided a sample for analysis do not need to provide separate 
consent/sample for the OLE study. 
9.1.2. 
Early Termination Visit  
Patients who discontinue the study prematurely during the 2-year open-label treatment period (ie, 
are withdrawn from the study before the EOT visit) will be asked to return to the clinic for an early 
termination visit consisting of the EOT assessments described in Table 1. 
Patients who discontinue treatment prematurely during the 2-year open-label treatment period 
should have an early EOT visit consisting of the EOT assessments described in Table 1, followed 
by monthly visits until 21 weeks after last dose of study drug.  These monthly follow-up visits will 
consist of assessments listed for the EOT visit in Table 1. 
Patients who discontinue the study prematurely during the optional post-EOT period (ie, are 
withdrawn from the study before the end of post-EOT period) will be asked to return to the clinic 
for an early termination visit consisting of the end of post-EOT assessments described in Table 1. 
Patients who discontinue treatment prematurely during the optional post-EOT period should have 
an early end of post-EOT visit consisting of the end of post-EOT assessments described in Table 1, 
followed by monthly follow-up visits until 21 weeks after last dose of study drug consisting of 
assessments listed for the end of post-EOT visit. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
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9.2. 
Study Procedures 
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:  
 Informed consent 
 Medical history (including disease characteristics and medication history) 
 Demographics 
 Height 
 Risk assessment for Neisseria gonorrhea (Section 8.7) 
 Provide patient safety card for Neisseria meningitidis (Section 8.4.1).  Replacement 
cards may be provided at any visit. 
Patients who meet the inclusion and exclusion criteria for the study will be enrolled into the OLE 
study via IVRS/IWRS.  The IVRS/IWRS may be contacted for drug resupply at any subsequent 
visit. 
9.2.2. 
Study Drug Administration 
Study drug will be administered as described in Section 8.2.  Re-immunization with 
meningococcal vaccine(s) may be performed according to local practice (Section 8.4.1).  Daily 
oral antibiotic prophylaxis is recommended (Section 8.4.2).   
Compliance with study drug administration may be monitored with a patient diary according to 
Table 1. 
9.2.3. 
Efficacy Procedures  
9.2.3.1. 
Serum Lactate Dehydrogenase  
Blood samples for LDH testing will be collected as part of the routine safety chemistry panel 
(Section 9.2.4.5) according to Table 1.  Serum LDH levels will be measured in a central laboratory.   
9.2.3.2. 
Transfusion Record Update 
During the study, the number of transfusions and number of units per transfusion with RBCs will 
be recorded in the case report form (CRF) according to Table 1. 
Hemoglobin levels pre- and post-transfusion will be obtained (including local values). 
9.2.3.3. 
Red Blood Cell Hemoglobin  
Blood samples for RBC hemoglobin testing will be collected as part of the routine safety 
hematology panel (Section 9.2.4.5) according to Table 1 and measured in a central laboratory.   
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9.2.3.4. 
Free Hemoglobin  
Blood samples for free hemoglobin testing will be collected as part of the routine safety 
hematology panel (Section 9.2.4.5) according to Table 1 and measured in a central laboratory.   
9.2.4. 
Safety Procedures  
9.2.4.1. 
Concomitant Medications 
Concomitant medications will be reviewed at each visit according to Table 1. 
9.2.4.2. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, and pulse rate, will be collected predose 
at time points according to Table 1. 
Vital signs will be obtained after patient has been sitting quietly for at least approximately 
5 minutes.  The same arm that was used in the parent study will be selected for measurement 
throughout the current study. 
9.2.4.3. 
Physical Examination and Body Weight 
A thorough and complete physical examination will be performed at time points according to 
Table 1.  Each physical examination will include an evaluation of the head and neck, lungs, heart, 
abdomen, extremities, and skin.  Care should be taken to examine and assess any abnormalities 
that may be present, as indicated by the patient’s medical history. 
Body weight will be measured at time points according to Table 1.  Body weight should be 
obtained with the patient wearing undergarments or very light clothing and no shoes.  If possible, 
the same type/model of scale should be used throughout the study. 
9.2.4.4. 
Electrocardiogram 
A standard 12-lead ECG will be performed locally at time points according to Table 1. 
Twelve-lead ECGs will be systematically recorded 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.  Any new and/or clinically significant 
changes in ECG parameters should be immediately rechecked 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 recorded from the ventricular rate, and the PR, QRS, RR, QT intervals, and 
QTcF will be recorded.  The ECG strips or reports will be retained with the source. 
9.2.4.5. 
Laboratory Testing 
Blood samples for laboratory testing will be collected at visits according to Table 1. 
Hematology, chemistry (except total C5), urinalysis, and pregnancy testing samples may be 
analyzed by a local/central laboratory.   
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Other testing will be done by a central or specialized laboratory as outlined in the sample 
management plan.   
Detailed instructions for blood sample collection are in the sample management plan provided to 
study sites. 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine kinase 
Glucose 
Alkaline phosphatase 
eGFR 
Albumin 
LDH 
High-sensitivity C-reactive protein 
*(low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) 
Blood chemistry should be performed after the patients have fasted for at least approximately 8 hours at the 
following visits defined in the schedule of events.   
Hematology 
Hemoglobin 
Differential: 
Free Hemoglobin 
 
Neutrophils 
Hematocrit 
 
Lymphocytes 
Red blood cells (RBCs) 
 
Monocytes 
White blood cells 
 
Basophils 
Red cell indices 
 
Eosinophils 
Platelet count 
 
Reticulocytes 
Urinalysis 
pH 
Protein 
Leukocytes  
Specific gravity 
Glucose 
Nitrite 
Ketones 
Bilirubin 
 
Note: If macroscopy is abnormal then reflex to microscopy. 
Other Laboratory Tests 
Other laboratory tests include:  
 Pregnancy testing: serum human chorionic gonadotrophin pregnancy testing, urine 
pregnancy testing.  In WOCP only.  Postmenopausal women must be amenorrheic for 
at least 12 months in order not to be considered of childbearing potential.  Pregnancy 
testing and contraception are not required for women with documented hysterectomy 
or tubal ligation. 
 Titers to assess risk of Neisseria meningitidis (only if indicated by local practice).  
Revaccination is recommended if titers do not demonstrate an adequate level of 
immunity (Section 8.4.1) 
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 PD and Exploratory Biomarker Procedures (Section 9.2.7) 
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 10.1.1. 
9.2.5. 
Drug Concentration and Total C5 Measurements 
Blood samples for drug concentration (PK sample) will be collected prior to drug administration 
at the time points and visits listed in Table 1.  The exact sampling time must be recorded, as 
allowed per local regulation. 
Blood samples for total C5 protein (plasma) will be collected at time points according to the 
timepoints in Table 1  
Any unused samples may be used for exploratory biomarker research, as allowed per local 
regulation. 
9.2.6. 
Immunogenicity Measurements and Samples 
Blood samples for ADA and NAb assessments in serum will be collected prior to drug 
administration at time points listed in Table 1. 
Detailed instructions for blood sample collection are included in the laboratory manual provided 
to study sites.   
Any unused samples may be used for exploratory biomarker research, as allowed per local 
regulation. 
9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Blood samples for CH50, haptoglobin, reticulocyte count, and bilirubin will be collected at time 
points listed in Table 1.  Reticulocyte count and bilirubin are collected as part of routine safety 
hematology and chemistry samples, respectively (Section 9.2.4.5). 
The results of analyses performed on these samples will be presented in the CSR.  (Note: Data 
collected for these analytes in the post-EOT period are for safety monitoring only and will not be 
included in the PD and biomarker analysis.) 
Detailed instructions for blood sample collection are included in the laboratory manual provided 
to study sites.   
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9.2.8. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research sub-study will be required to 
consent to this optional sub-study before collection of the serum and plasma samples.  The unused 
biomarker samples for study-related research, as well as unused PK and ADA samples, will be 
stored for up to 15 years after the final date of the database lock.  The unused samples may be 
utilized for future biomedical research of REGN3918, the complement pathway, PNH, and related 
diseases.  Additional samples will be collected for future biomedical research according to 
Schedule of Events in Table 1.  After 15 years, any residual samples will be destroyed.  The results 
of these future biomedical research analyses will not be presented in the CSR. 
9.2.8.1. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples (note: patients who had consented to DNA 
testing in the parent study and had provided a sample for analysis do not need to provide separate 
consent/sample for this part of the OLE study).  Whole blood samples for DNA extraction should 
be collected on day 1 (predose), but can be collected at a later study visit (Table 1). 
DNA samples will be collected for pharmacogenomics analyses.  These samples will be 
single-coded as defined by the International Council on Harmonisation (ICH) guideline E15.  
Samples will be stored for up to 15 years after the final date of the database lock.  If there are 
specific site or country requirements involving the pharmacogenomic analyses with which the 
sponsor is unable to comply, samples will not be collected at those sites.   
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical 
(safety or efficacy) or biomarker response to REGN3918, the complement pathway, PNH and 
related complement-mediated diseases, clinical outcome measures, and possible AEs.  In addition, 
associations between genomic variants and prognosis or progression of PNH and related 
complement-mediated diseases may also be studied.  These data may be used or combined with 
data collected from other studies to identify and validate genomic markers related to the study 
drug, target pathway, or PNH and related diseases.   
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, transcriptome sequencing 
(or other methods for quantitating RNA expression), and methods for quantifying epigenetic 
modifications may also be performed.  The list of methods may be expanded to include novel 
methodology that may be developed during the course of this study or sample storage period.   
Results from the genomic analyses will not be reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data collection 
period (see Section 10.1.2).  Medical conditions that existed or were diagnosed prior to the signing 
of the Informed Consent will be recorded as part of medical history.  Abnormal laboratory values 
and vital signs observed at the time of Informed Consent should also be recorded as medical 
history.  Any subsequent 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 
should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient.  Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit.  Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms.  The investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2.  
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature.  The investigator should follow up on SAEs (and AESIs) until they 
have resolved or are considered clinically stable; AEs should be followed until they are resolved 
or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported 
as AEs if they are symptomatic, lead to study drug discontinuation, lead to dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (SAE; diagnosis or symptom requiring hospitalization).  A procedure 
is not an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior 
to signing the ICF) procedures, treatments requiring hospitalization for pre-existing conditions that 
do not worsen in severity, and admission for palliative or social care should not be reported as 
SAEs (see Section 10.2 for definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (end of the follow-up) that the 
investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.4.   
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10.1.2. 
Data Collection Period 
The investigator will record all events, serious and non-serious, that occur from the time of signing 
the informed consent and for 21 weeks after the last dose of study drug (ie, the follow-up period).  
The follow-up period applies to all patients who complete the study or terminate early (excludes 
those who withdraw consent).   
10.1.3. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the study drug.  For SAEs and AESIs, a detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome, should be 
provided on the AE CRF.  Specific or estimated dates of event onset, treatment, and resolution 
should be included when available.  Medical history, concomitant medications, and laboratory data 
that are relevant to the event should also be summarized in the narrative.  For fatal events, the 
narrative should state whether an autopsy was or will be performed, and include the results if 
available.  Information not available at the time of the initial report must be documented in a 
follow-up report.  Source documents (including hospital or medical records, diagnostic reports, 
etc.) will be summarized in the narrative on the AE CRF, and retained at the study center and 
available upon request.   
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.   
10.1.4. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
 SAEs. 
 Adverse Events of Special Interest (AESI; serious and non-serious): Adverse events 
of special interest for this study include the following:  
 Confirmed Neisseria infection  
 Any thrombotic or embolic event 
 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  or female partner of a male, during 
the study or within 21 weeks 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. 
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10.2. 
Definitions 
10.2.1. 
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 
(ICH, 1994). 
10.2.2. 
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 or an emergency room 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). 
Criteria for reporting SAEs must be followed for these events.   
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest 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.   
Adverse events of special interest for this study are listed in Section 10.1.4. 
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10.2.4. 
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. 
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 
10.2.5. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the AE, based on evidence or facts, his/her clinical judgment, and 
the following definitions.  The causality assessment must be made based on the available 
information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
 Temporal relationship: time to onset vs time drug was administered 
 Nature of the reactions: immediate vs.  long term 
 Clinical and pathological features of the events  
 Existing information about the drug & same class of drugs  
 Concomitant medications  
 Underlying and concurrent illnesses  
 Response to dechallenge (drug discontinuation) or dose reduction  
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 Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
 Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
 The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is 
predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
 Related: 
 The AE follows a reasonable temporal sequence from a protocol specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
 Not Related: 
 The AE does not follow a reasonable sequence from a protocol specified 
procedure, or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
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, Pharmacovigilance; Risk Management; 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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10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, IECs/IRBs, and the 
participating investigators of any SUSARs (Suspected Unexpected Serious Adverse Reactions) 
occurring in other study centers or other studies of the active study drug (REGN3918), as 
appropriate per local reporting requirements.  In addition, the sponsor and/or CRO will comply 
with any additional local safety reporting requirements.   
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for study drug (REGN3918) is assessed against the Reference Safety 
Information section of the current Investigator’s Brochure. 
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 IECs/IRB as appropriate. 
11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (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. 
Analysis variables are listed in Section 5. 
11.1. 
Statistical Hypothesis  
The primary objective of the study is to evaluate the long-term safety and tolerability of 
REGN3918 in patients with PNH, as well as the effect of REGN3918 on intravascular hemolysis 
as measured by LDH.  No formal statistical hypothesis will be tested.   
11.2. 
Justification of Sample Size 
As this study is a follow-on that plans to include patients from the parent studies, R3918-PNH-
1852 
, no calculation for sample size was performed.  It is expected to enroll 
up to 
 patients with PNH based on the maximum number of patients who could complete the 
parent study in the selected/participating countries. 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all enrolled patients who received any study drug.  Efficacy 
endpoints will be analyzed using the FAS analysis set, unless otherwise specified (see 
Section 11.4.3).   
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11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all enrolled patients who received any study drug.  
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result for concentration of REGN3918 following the first dose of study drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set will consist of all patients who received any study drug and who had at least 
one non-missing ADA result after first dose of the study drug.   
Positive treatment-emergent ADA samples will be assessed for neutralizing antibodies. 
11.3.5. 
Exploratory Analysis Sets 
11.3.5.1. Exploratory Biomarker Endpoint Analysis Set 
The pharmacodynamic analysis populations include all patients who received any study drug and 
who had at least 1 non-missing analyte measurement following the first dose of study drug. 
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, standard deviation, minimum, and 
maximum.   
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
In addition to summary statistics, data will be plotted whenever needed.   
11.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients who met the inclusion criteria regarding the 
target indication and signed the ICF 
 The total number of enrolled patients 
 The total number of patients in each analysis set (eg, provided in Section 11.3) 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients enrolled but not treated 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
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11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
11.4.3. 
Efficacy Analyses 
The primary efficacy endpoint is the proportion of patients achieving LDH ≤1.5×ULN over week 
26, defined as LDH ≤1.5×ULN at every scheduled time point up to week 26 (inclusive). 
All other efficacy analyses of this study are secondary.   
For efficacy endpoints that are defined by dichotomy of multiple measurements of a variable 
through a period of time, including the proportions of patients achieving LDH ≤1.0×ULN and 
LDH ≤1.5×ULN over week 26, week 78 and week 104, the analysis set consists of all FAS 
patients.  For this category of efficacy endpoints, including the primary efficacy endpoint, patients 
who fulfill 1 or more of the following will be considered as not meeting the endpoint: 
 Discontinue prematurely from study treatment  
 Have ≥50% missing values of measurements of the analyzed variable during the assessed 
period.  Note: For the primary efficacy endpoint, it means having missing LDH value at 
week 13 or week 26. 
 Have breakthrough hemolysis (as defined in the secondary endpoint and based on 
investigator judgment) while on treatment over the assessed period. 
Patients who do not fulfill the above criteria will be evaluated based on their non-missing 
measurements of the variable.   
For secondary endpoints that are defined by a change or percent change from baseline of the OLE 
study to a time point in a variable, the analysis set will consist of all FAS patients who have a 
non-missing baseline measurement of the variable.  This category of endpoints includes: 
 Percent changes and changes from baseline of the OLE study in LDH levels to week 26, 
week 78, and week 104 
 Changes from baseline of the OLE study RBC hemoglobin levels to week 26, week 78, 
and week 104 
 Changes from baseline of the OLE study in free hemoglobin levels to week 26, week 78, 
and week 104 
For secondary endpoints that are defined by any occurrence of a defined event during a period, the 
analysis set will consist of all FAS patients.  This category of endpoints includes: 
 The proportions of patients with breakthrough hemolysis over week 26, week 78, and 
week 104 
 The proportions of patients who are transfusion-free (with RBCs) over week 26, week 78, 
and week 104  
For the rates and numbers of units of transfusion with RBCs over week 26, week 78 and week 104, 
the analysis set consists of all FAS patients.  The rate of units of transfusion for a patient will be 
calculated based on the duration of treatment exposure of the patient.   
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For binary efficacy endpoints, means and 95% confidence intervals by approximation of a 
one-sample t-statistic as primary analysis and by exact methods, as sensitivity analysis will be 
calculated for this category of efficacy endpoints.  Sensitivity analysis by multiple imputation of 
missing measurements of the analyzed variable may be performed, which will be detailed in the 
SAP. 
For continuous efficacy endpoints, means and 95% confidence intervals will be derived from 1-
sample t-test, analysis of covariance (ANCOVA) modeling, or MMRM (mixed-effect model for 
repeated measures) analysis.  Handling of missing data will be specified in the SAP.   
11.4.4. 
Safety Analysis 
Evaluation of long-term safety and tolerability of REGN3918 is part of the primary objective of 
the study.  Safety variables including AEs, laboratory test results, and vital signs will be 
descriptive, based on the safety population and no formal statistical testing will be performed.  
Safety analysis will focus on the treatment period as defined below. 
For analyses of changes from baseline in laboratory and vital signs parameters, baseline of the 
parent study will be considered.  In addition, baseline of the current study may also be considered. 
11.4.4.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF for the OLE 
study to before the first dose of study drug of the OLE study. 
 The treatment period is defined as the time from the first dose of study drug of the 
OLE study to the end of the 2-year open-label treatment period, or, in patients who 
prematurely discontinue/do not enter into the optional post-EOT period, from the first 
dose of study drug of the OLE study to the last dose of study drug + 21 weeks (ie, 
147 days).   
 The posttreatment period of the OLE study is defined as the time after the treatment 
period of the OLE study. 
Treatment-emergent adverse events are defined as those AEs that occur or worsen in severity or 
become serious during the treatment period or represent the exacerbation of a pre-existing 
condition during the 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: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
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 TEAEs by severity (according to the grading scale outlined in Section 10.2.4), 
presented by SOC and PT 
 TEAEs by relationship to treatment (related/not related), presented by SOC and PT 
 Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
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) will be summarized by baseline of the parent study 
and change from baseline of the parent study to each scheduled assessment time with descriptive 
statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline of the parent study and change from 
baseline of the parent study to each scheduled assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-enrollment time point will be summarized for each clinical laboratory test.   
Shift tables based on baseline of the parent study 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. 
Electrocardiograms 
Electrocardiogram results will be summarized by parameter at each time point using descriptive 
statistics. 
11.4.4.3. Treatment Exposure 
The observation period (defined as the time between the date of first study drug administration 
and the date of the end of treatment visit [ie, week 104] or the date of early discontinuation for 
the patient) will be presented.   
11.4.4.4. Treatment Compliance 
Analysis of treatment compliance will be described in the SAP. 
11.4.5. 
Pharmacokinetics 
11.4.5.1. Analysis of Drug Concentration Data 
The PK endpoint is concentration of total REGN3918 in serum over time.   
A summary of total drug concentrations and total C5 will be presented by nominal time point (ie, 
the time points specified in the protocol).  Individual data will be presented by actual time.  Plots 
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of the concentrations of REGN3918 and total C5 will be presented over time (linear and log 
scales).  When the scale is linear, concentrations below the lower limit of quantification (LLOQ) 
will be set to zero.  In the log-scaled figures, concentrations below the LLOQ will be imputed as 
LLOQ/2.  Summary statistics of concentrations of total REGN3918 and total C5 may include, but 
are not limited to arithmetic mean, standard deviation, standard error of the mean, coefficient of 
variation (%), minimum, Q1, median, Q3, and maximum. 
No formal statistical analysis will be performed. 
11.4.6. 
Analysis of Immunogenicity Data 
Anti-drug antibodies will be characterized by the type and titer level of the observed response.     
Anti-drug antibodies response categories and titer categories that will be assessed are as follows: 
 Pre-existing immunoreactivity 
 Treatment-emergent response 
 Treatment-boosted response 
 Neutralizing antibody response in ADA-positive patients 
 Titer value category (titer range) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
Listings of pre-existing, treatment-boosted and treatment-emergent ADA responses, ADA titers, 
and NAb status presented by patient, time point, and dose cohort/group (if applicable) will be 
provided.  Incidence of treatment-emergent ADA response and NAb status 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 ADA and NAb on individual 
PK profiles may be evaluated.  Assessment of impact of ADA and NAb on safety and efficacy 
may be provided. 
11.4.7. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data 
Analysis of biomarker data is defined in the SAP. 
11.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
 Definition of baseline:  
 Unless otherwise specified, the baseline assessment is programmatically defined 
as the latest available measurement taken before first administration of study 
treatment in the OLE study (including last available measurement from the parent 
study if measurement is missing in OLE study).  For patients enrolled but not 
treated, the baseline will be the last available measurement before enrollment. 
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 General rules for handling missing data: 
Rules for handling missing data for assessment (other than efficacy): 
 If the start date of an AE or concomitant medication is incomplete or missing, it 
will be assumed to have occurred on or after the intake of study medication, 
except if an incomplete date (eg, month and year) clearly indicates that the event 
started prior to treatment.  If the partial date indicates the same month or year of 
the intake of study medication date, then the start date by the study medication 
intake date will be imputed; otherwise, the missing day or month by the first day 
or the first month will be imputed.   
 No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
 Visit windows: 
 Assessments taken outside of protocol-allowable windows will be displayed 
according to the case CRF assessment recorded by the investigator. 
 Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with nonprotocol 
clinical visits or obtained in the course of investigating or managing AEs) will be 
included in listings, but not summaries.  If more than 1 laboratory value is 
available for a given visit, the first observation will be used in summaries and all 
observations will be presented in listings. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a 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 15.1. 
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12. 
QUALITY CONTROL AND 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 described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
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 the sponsor’s facilities. 
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 CRF data for this study will be collected with an electronic data capture (EDC) system. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS system – randomization, study drug supply 
 EDC system – data capture  
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.  This study will 
use the principles of risk-based monitoring (ICH).  This means that the number of visits for any 
given site may vary based on site risk indicators.  The investigator must allow study-related 
monitoring. 
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. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).  The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
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. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel.  All required CRFs must be completed for each and 
every patient enrolled in the study.  The investigator must ensure the accuracy, completeness, and 
timeliness of the data reported to the sponsor in the CRFs.  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. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
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: 
 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. 
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12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
CRF that will be provided to the sponsor. 
12.4.2. 
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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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
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. 
13.2. 
Informed Consent 
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 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. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, 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. 
13.3. 
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. 
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. 
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13.4. 
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/EC approval letter with a current list of the IRB/EC 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/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigational site 
thereafter. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment.  Where required per local legislation, regulatory authority approval will also 
be sought. 
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
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. 
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15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
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. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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Paroxysmal Nocturnal Hemoglobinuria. Biol Pharm Bull 2016; 39(2):285-8. 
Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, et al. Genetic 
variants in C5 and poor response to eculizumab. N Engl J Med 2014; 370(7):632-9. 
Peffault de Latour R, Fremeaux-Bacchi V, Porcher R, Xhaard A, Rosain J, Castaneda DC, et al. 
Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving 
eculizumab. Blood 2015; 125(5):775-83. 
Preis M, Lowrey CH. Laboratory tests for paroxysmal nocturnal hemoglobinuria. Am J Hematol 
2014; 89(3):339-41. 
Roth, A; Egyed, M; Ichikawa, S; Kim, JS; Nagy, Z; Weisinger, JG; Panse, JP; de Latour, RP; de 
Fontbrune, FS; Sica, S; Usuki, K; Yoon, SS; Winter, E; Hsu, JC; Dieckmann, A; Anzures-
Cabrera, J; Jordan, G; Shinomiya, K; Klughammer, B; Bucher, C; Jahreis, A; Nishimura, JI. 
2018a  #535 The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and 
Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). In: American Society of 
Hematology (ASH) 2018a, Orlando, FL. 
Roth A, Rottinghaus ST, Hill A, Bachman ES, Kim JS, Schrezenmeier H, et al. Ravulizumab 
(ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 
studies. Blood Adv 2018b; 2(17):2176-85. 
Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and 
extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 
293(13):1653-62. 
Sahin F, Akay OM, Ayer M, Dal MS, Ertop S, Ilhan O, et al. Pesg PNH diagnosis, follow-up and 
treatment guidelines. Am J Blood Res 2016; 6(2):19-27. 
Soliris PI. 2018. Alexion Pharmaceuticals, Prescribing information (eculizumab). 
Ultomiris PI. 2018. Alexion Pharmaceuticals, Prescribing information (ravulizumab). 
Wedzicha JA. Antibiotics at COPD exacerbations: the debate continues. Thorax 2008; 
63(11):940-2. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “An Open-label Extension Study to Evaluate the Long-term 
Safety, Tolerability, and Efficacy of REGN3918 in Patients with Paroxysmal Nocturnal 
Hemoglobinuria” 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/EC.  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 Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
An Open-label Extension Study to Evaluate the Long-term Safety, Tolerability, and 
Efficacy of REGN3918 in Patients with Paroxysmal Nocturnal Hemoglobinuria 
Protocol Number: 
Protocol R3918-PNH-1868 
Protocol Version:  
Protocol R3918-PNH-1868 Original  
 
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 Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Signature Page for VV-RIM-00072054 v1.0
Signature Page for VV-RIM-00072054 v1.0 Approved
ESig Approval
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ESig Approval
19 13:06:12 GMT+0000
ESig Approval
-2019 13:13:21 GMT+0000
ESig Approval
000
                                        VV-RIM-00072054-1.0 Approved - 19 Mar 2019 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: 
AN OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY, 
TOLERABILITY, AND EFFICACY OF 
REGN3918 IN PATIENTS WITH PAROXYSMAL 
NOCTURNAL HEMOGLOBINURIA 
Compound: 
REGN3918 
Protocol Number: 
R3918-PNH-1868 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date: 
Original Statistical Analysis Plan / Jun 4, 2021 
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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 Pharmacology Lead 
 
See appended electronic signature page 
Study Bioanalytical Sciences Lead 
 
See appended electronic signature page 
Study Medical Director 
 
See appended electronic signature page 
Project Biostatistician  
 
See appended electronic signature page 
Head of BDM or designee 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale for Study Design ......................................................................8 
1.2. 
Study Objectives ...........................................................................................................8 
1.2.1. 
Primary Objective .........................................................................................................8 
1.2.2. 
Secondary Objectives and Exploratory Objectives ......................................................8 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ..................................9 
1.2.4. 
Revision History for SAP Amendments .......................................................................9 
2. 
INVESTIGATION PLAN ..........................................................................................10 
2.1. 
Study Design ...............................................................................................................10 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................11 
3. 
ANALYSIS POPULATIONS ....................................................................................12 
3.1. 
The Full Analysis Set (FAS) .......................................................................................12 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................12 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................12 
3.4. 
The Anti-drug Antibody Analysis Set ........................................................................12 
3.5. 
The Exploratory Biomarker Endpoint Analysis Set ...................................................12 
4. 
ANALYSIS VARIABLES .........................................................................................13 
4.1. 
Demographic and Baseline Characteristics ................................................................13 
4.2. 
Medical History ..........................................................................................................13 
4.3. 
Prior/Concomitant Medication and Procedures ..........................................................13 
4.4. 
Prohibited Medication During Study ..........................................................................14 
4.5. 
Efficacy Variables ......................................................................................................14 
4.5.1. 
Primary Efficacy Variable ..........................................................................................14 
4.5.2. 
Key Secondary Efficacy Variables .............................................................................14 
4.5.3. 
Other Secondary Efficacy Variables ..........................................................................14 
4.5.4. 
Exploratory Efficacy Variables ..................................................................................15 
4.6. 
Safety Variables ..........................................................................................................15 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................15 
4.6.2. 
Adverse Events of Special Interest .............................................................................16 
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4.6.3. 
Laboratory Safety Variables .......................................................................................16 
4.6.4. 
Vital Signs ..................................................................................................................16 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................16 
4.6.6. 
Physical Examination Variables .................................................................................16 
4.7. 
Pharmacokinetic Variables .........................................................................................16 
4.8. 
Immunogenicity Variables ..........................................................................................17 
4.9. 
Pharmacodynamic Variables ......................................................................................17 
5. 
STATISTICAL METHODS .......................................................................................18 
5.1. 
Demographics and Baseline Characteristics ...............................................................18 
5.2. 
Medical History ..........................................................................................................18 
5.3. 
Prior/concomitant Medications ...................................................................................18 
5.4. 
Prohibited Medications ...............................................................................................18 
5.5. 
Patient Disposition ......................................................................................................19 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................19 
5.6.1. 
Measurement of Compliance ......................................................................................19 
5.6.2. 
Exposure to Investigational Product ...........................................................................19 
5.7. 
Analyses of Efficacy Variables ..................................................................................20 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................20 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................20 
5.8. 
Analysis of Safety Data ..............................................................................................22 
5.8.1. 
Adverse Events ...........................................................................................................22 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................23 
5.8.3. 
Clinical Laboratory Measurements.............................................................................24 
5.8.4. 
Analysis of Vital Signs ...............................................................................................24 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................24 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................24 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................24 
5.9.2. 
Analysis of Immunogenicity Data ..............................................................................25 
5.9.2.1. 
Analysis of ADA Data ................................................................................................25 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................26 
5.9.3.1. 
Immunogenicity and Exposure ...................................................................................26 
5.9.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................26 
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5.10. 
Analysis of Pharmacodynamic and Biomarker Data ..................................................27 
6. 
DATA CONVENTIONS ............................................................................................28 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................28 
6.2. 
Data Handling Convention for Missing Data .............................................................28 
6.2.1. 
Adverse events ............................................................................................................28 
6.2.2. 
PCSV ..........................................................................................................................30 
6.2.3. 
Date of first / last study drug administration ..............................................................30 
6.3. 
Analysis Visit Windows .............................................................................................31 
6.4. 
Unscheduled Assessments ..........................................................................................32 
7. 
INTERIM ANALYSIS ...............................................................................................33 
8. 
SOFTWARE ...............................................................................................................34 
9. 
REFERENCES ...........................................................................................................35 
10. 
APPENDIX.................................................................................................................36 
10.1. 
Summary of Statistical Analyses ................................................................................36 
10.2. 
Schedule of Time and Events .....................................................................................37 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................42 
 
LIST OF TABLES 
Table 1:  
General Analysis Windows ........................................................................................31 
Table 2: 
Efficacy Analysis Windows .......................................................................................31 
 
 
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CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BID 
Twice a day 
CH50 
Total complement hemolytic activity assay 
CRF 
Case report form (electronic or paper) 
ECG 
Electrocardiogram 
EOT 
End of treatment 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification  
MAVE 
Major adverse vascular event 
NAb 
Neutralizing antibody 
OLE 
Open-label extension 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PT 
Preferred term 
QW 
Once weekly 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
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SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WOCP 
Women of childbearing potential 
 
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1. 
OVERVIEW 
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 this study. 
1.1. 
Background/Rationale for Study Design 
Background information on paroxysmal nocturnal hemoglobinuria (PNH) and REGN3918 may 
be found in the protocol. 
The current clinical trial (R3918-PNH-1868) is an open-label extension (OLE), single-arm study 
with a 2-year open-label treatment period followed by an optional post-end-of-treatment (EOT) 
period with continued treatment with REGN3918 of variable duration in patients with PNH who 
have completed 1 of the 2 parent studies (R3918-PNH-1852 
).  In the parent 
studies, the duration of the treatment period is 26 weeks because it is anticipated that there will be 
a rapid initiation or maintenance of clinical benefit of REGN3918 on intravascular hemolysis.  
It is expected, if approved, that REGN3918 would be administered in clinical practice for a duration 
of years, which is consistent with the current practice for eculizumab and ravulizumab. The longer-
term treatment duration provided through this study will enable the evaluation of whether or not the 
initial clinical benefit anticipated in the parent studies is maintained and will provide further insight 
into the safety profile.  
The study population includes patients coming from the parent study R3918-PNH-1852, which 
enrolled 24 patients with PNH having active signs and symptoms who are complement inhibitor-
naïve or have not recently received complement inhibitor therapy. 
 was 
planned, and would have provided patients for the current study, but it was canceled for business 
reasons. 
Therefore, R3918-PNH-1868 will enroll up to 24 patients from the parent study. 
 
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety, tolerability, and effect on 
intravascular hemolysis (i.e., proportion of patients achieving LDH ≤1.5× upper limit of normal 
[ULN] over 26 weeks of REGN3918 treatment in patients with PNH). 
1.2.2. 
Secondary Objectives and Exploratory Objectives 
The secondary objectives of the study are: 
• To evaluate the long-term effect of REGN3918 on intravascular hemolysis 
• To assess the concentrations of total REGN3918 in serum 
• To evaluate the immunogenicity of REGN3918 
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The exploratory objectives of the study are: 
• To explore the long-term effect on clinical thrombotic events 
• To explore the long-term effect on renal function 
• To explore the long-term effect of REGN3918 on complement activation and 
intravascular hemolysis relevant to PNH and other related diseases 
• To explore the long-term effect of REGN3918 on the concentrations of total C5 
protein 
• To collect future biomedical research samples from consented patients in order to 
study REGN3918 mechanism of action (including relationship to safety and efficacy), 
complement pathway biology, PNH, and related complement-mediated diseases  
• To collect whole blood DNA and RNA from consented patients in order to explore 
whether potential differences in patient efficacy and safety are associated with 
genotype and gene expression, and to further study C5, PNH, or other conditions 
associated with complement-mediated injury 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
There are no modifications from the statistical section of the protocol. 
1.2.4. 
Revision History for SAP Amendments 
Not applicable. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This study contains 2 study periods: the 2-year open-label treatment period and the optional post- 
EOT period (i.e., after completion of the 2-year open-label treatment period). 
Patients who have completed the  parent study R3918-PNH-1852  will be eligible for screening 
for this OLE study.  The 2-year open-label treatment period will have assessments as described in 
the protocol occurring approximately quarterly and ending at week 104 (EOT). 
The transition of treatment with REGN3918 from the parent study to the OLE study is planned to 
be uninterrupted.  Therefore, the day 1 visit of the 2-year open-label treatment period will occur 
on the same visit as the EOT study visit in the parent study and overlapping assessments do not 
need to be repeated in this OLE study. Patients will continue their dose of up to 800 mg QW from 
the parent study starting at day 1 in the OLE study, with a potential change in dose/dosing interval 
(on day 1 or subsequently) only for patients in cohort A of the parent study R3918-PNH-1852, if 
applicable.  As part of risk mitigation for this study, it is recommended for patients to receive 
updated   meningococcal vaccination, daily oral antibiotic prophylaxis, and counselling regarding 
risk of Neisseria gonorrhea, as applicable. In addition, blood transfusions should proceed 
according to the algorithm in the protocol. Breakthrough hemolysis is defined in the protocol. 
Patients who do not enter the optional post-EOT period should be followed for 21 weeks after the 
end of the 2-year open-label treatment period.  Patients should return for monthly visits with 
assessments corresponding to week 104 (EOT) visit. 
The optional post-EOT period includes continued REGN3918 treatment of variable duration. 
Patients may continue REGN3918 treatment after they have completed the 2-year open-label 
treatment period and if they derive clinical benefit and have potential risk upon discontinuation of 
REGN3918.  Eligible patients will be asked to provide separate consent for continuing onto the 
optional post-EOT period.  The optional post-EOT period ends when 1 of the following is met: 
• Clinical development of REGN3918 is terminated 
• Risk-to-benefit profile of REGN3918 in this patient population is deemed 
unfavorable 
• REGN3918 is approved by the regulatory authority governing the location of the 
study site 
The additional safety information accrued in the post-EOT period will be reported. 
It is projected that the first patients enrolled and who continue into the optional post-EOT period 
will have a study duration of approximately 4 years and the last patients enrolled will have a study 
duration of at least 2 years. However, the study duration is dependent on the criteria mentioned in 
the protocol. 
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At a study level, the end of study is defined as the last visit of the last patient. 
At a patient level, the end of study is defined as the end of treatment period (EOT) or, depending 
on the particular circumstances of the patient, at the end of post-EOT period, which is of variable 
duration. 
2.2. 
Sample Size and Power Considerations 
As this study is a follow-on that plans to include patients from the parent study R3918-PNH-
1852, no calculation for sample size was performed. It is expected to enroll up to 24 patients with 
PNH based on the maximum number of patients who could complete the parent study in the 
selected/participating countries. 
2.3. 
Study Plan 
The Study event table is presented in Appendix 10.2. 
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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), the following populations will be used for 
statistical analysis: 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all enrolled patients who received any study drug. Efficacy 
endpoints will be analyzed using the FAS analysis set, unless otherwise specified.   
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all enrolled patients who received any study drug. 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF. 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic (PK) analysis set includes all patients who received any study drug and who 
had at least 1 non-missing result for concentration of REGN3918 following the first dose of study 
drug. 
3.4. 
The Anti-drug Antibody Analysis Set 
The ADA analysis set (AAS) includes all patients who received study drug and had at least one 
non-missing ADA result following the first dose of study drug. 
3.5. 
The Exploratory Biomarker Endpoint Analysis Set 
The exploratory biomarker endpoint (PD) analysis set includes all patients who received any study 
drug and who had at least 1 non-missing analyte measurement following the first dose of study 
drug. 
 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized:  
• Age at screening (years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino) 
• Baseline Weight 
• Baseline Height 
• Baseline Body mass index (BMI) calculated from weight and height 
• Months from PNH diagnosis to baseline 
• History of PNH signs and symptoms 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to Medical Dictionary for Regulatory Activities (MedDRA®). 
4.3. 
Prior/Concomitant Medication and Procedures 
Medications will be recorded from the day of informed consent until the end-of-study (EOS) visit. 
Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to WHO Drug Dictionary (WHODD). Patients will be 
counted once in all ATC categories linked to the medication. 
Prior medications are medications taken prior to administration of the first dose of study drug. 
Concomitant medications are medications taken between the first dose of study drug and the EOS 
visit. 
Prior/concomitant medications will be summarized, including Meningococcal vaccinations and 
oral antibiotic prophylaxes. 
Prior/concomitant procedures will be recorded.  Prior procedures are procedures performed prior 
to administration of the first dose of study drug.  Concomitant procedures are procedures 
performed between the first dose of study drug and the EOS visit. 
In addition, erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic agents, 
anticoagulants, iron supplements, and folic acid will be summarized. 
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4.4. 
Prohibited Medication During Study 
The use of the following concomitant medications is not permitted during the study: 
• Alcohol, during the 24 hours prior to each clinic visit when blood is drawn 
• Complement inhibitors besides REGN3918 starting on Day 1 
4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variable 
The proportion of patients achieving LDH ≤1.5×ULN over 26 weeks, defined as LDH ≤1.5×ULN 
at every scheduled time point up to week 26 (inclusive), will be the primary efficacy variable. 
4.5.2. 
Key Secondary Efficacy Variables 
The key secondary efficacy variables are: 
• The proportion of patients with breakthrough hemolysis over 26 weeks 
• The rate and number of units of transfusion over week 26 
4.5.3. 
Other Secondary Efficacy Variables 
Other secondary efficacy variables are: 
• The proportions of patients with breakthrough hemolysis over 78 weeks and over 104 
weeks 
• The rates and numbers of units of transfusion with RBCs over 78 weeks and over 104 
weeks 
• The proportions of patients who are transfusion-free (with RBCs) over over 26 
weeks, over 78 weeks, and over 104 weeks 
• The proportions of patients achieving adequate control of their intravascular 
hemolysis, defined as LDH ≤1.5×ULN at every scheduled time point up to week 78 
(inclusive), and week 104 (inclusive) 
• The proportions of patients achieving normalization of their intravascular hemolysis, 
defined as LDH ≤1.0×ULN at every scheduled time point up to week 26 (inclusive), 
week 78 (inclusive), and week 104 (inclusive) 
• Changes and percent changes in LDH from baseline of the OLE study to week 26, 
week 78, and week 104 
• Changes in RBC hemoglobin levels from baseline of the OLE study to week 26, week 
78, and week 104 
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• Changes in free hemoglobin levels from baseline of the OLE study to week 26, week 
78, and week 104 
• Concentrations of REGN3918 in serum assessed throughout the study 
• Incidence of treatment-emergent anti-drug antibodies (ADA) to REGN3918 
throughout the study 
4.5.4. 
Exploratory Efficacy Variables 
The exploratory efficacy variables are: 
• Changes in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline of the OLE study to week 26, week 78, and week 104 
• Changes in haptoglobin from baseline of the OLE study to week 26, week 78, and 
week 104 
• Changes in bilirubin from baseline of the OLE study to week 26, week 78, and week 
104 
• Changes in reticulocyte count from baseline of the OLE study to week 26, week 78, 
and week 104 
• Changes and percent change in CH50 from baseline of the OLE study to week 26, 
week 78, and week 104 
• Changes in total C5 from baseline of the OLE study to week 26, week 78, and week 
104 
• Incidences of MAVE over 26 weeks, over 78 weeks, and over 104 weeks 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
“Preferred Term (PT)” and associated primary “System Organ Class (SOC)” according to the 
Medical Dictionary for Regulatory Activities (MedDRA, the most current available version). 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. 
The severity of AEs will be graded according to the criteria given in the protocol.  
Section 10.1.1 in the protocol gives the criteria for whether laboratory results, vital signs, or ECG 
abnormalities are to be recorded as AEs.  
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4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol. In 
this study, AESIs are listed below (as provided in the protocol): 
• Confirmed Neisseria infection (N. meningitidis or N. gonorrhea) 
• Any thrombotic or embolic event, using the Embolic and thrombotic events SMQ, 
which includes (1) arterial, (2) venous and (3) unspecified and mixed arterial and 
venous events 
4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, urinalysis, and other. 
Clinical laboratory values will be grouped by function in summary tables. Conventional units may 
be provided. Laboratory tests are categorized in the protocol as follows: 
• Blood chemistry 
• Hematology 
• Urinalysis 
• Other tests 
4.6.4. 
Vital Signs 
Temperature, pulse rate, and sitting blood pressure will be collected. 
4.6.5. 
12-Lead Electrocardiography (ECG) 
Heart rate will be recorded from the ventricular rate. PR, QRS, RR and QT intervals will be 
recorded, as well as QTcF. 
4.6.6. 
Physical Examination Variables 
Physical examination variables include findings that result from evaluations of head and neck, 
lungs, heart, abdomen, extremities, and skin.  Findings may be included in AE and MH tables. 
4.7. 
Pharmacokinetic Variables  
The PK variable is concentration of total REGN3918.  The sampling time points are specified in 
Appendix 10.2. 
The total target variable is the concentrations of total C5 at the sampling times specified in 
Appendix 10.2. 
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4.8. 
Immunogenicity Variables  
The immunogenicity variables are ADA status, titer at nominal sampling time/visit. Samples in 
this study will be collected at the clinic visits specified in Section 10.2. 
4.9. 
Pharmacodynamic Variables 
CH50 is included as a pharmacodynamic biomarker. Change and percent change in CH50 from 
baseline of the OLE study to week 26, week 78, and week 104 will be assessed. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, Q1, Q3, minimum, and 
maximum. Patients at VHP sites will have more visits than those listed in the Schedule of Events, 
and these patients will have more visits with laboratories, vital signs and physical examinations.  
These extra visits will be included in the by-visit tables for those domains. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively.  Continuous data will 
be summarized using the number of patients with data, mean, median, standard deviation, Q1, Q3, 
minimum and maximum.  Categorical and ordinal data will be summarized using the number and 
percentage of patients. 
5.2. 
Medical History 
Medical history will be descriptively summarized overall for the study in safety population. 
All reported patient medical history will be presented by primary SOC and PT.  The tables will be 
presented by SOC sorted alphabetically and decreasing patient frequency of PT.   
5.3. 
Prior/concomitant Medications  
All prior medications, dictionary coded by WHODD, will be descriptively summarized for the 
study, for patients in the safety 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 the 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 again for a different category if the same 
medication falls under multiple categories.   
All concomitant medications during the treatment period, dictionary coded by WHODD, will be 
descriptively summarized for patients in the safety set.  In the 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, and hence may be 
counted again for a different category if the same medication falls under multiple categories. 
For the post-treatment period, medications will be dictionary coded by WHODD and will be 
descriptively summarized as described for the treatment period.  Summaries will present patient 
counts (and percentages). 
5.4. 
Prohibited Medications 
A listing of prohibited medications, found in Section 4.4, will be provided for the patients in the 
safety analysis set for the treatment period and post-treatment period. 
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5.5. 
Patient Disposition 
The following displays will be provided: 
• The total number of screened patients  
• The total number of enrolled patients 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Compliance with protocol-defined investigational product will be calculated as follows: 
Treatment Compliance = (Number of investigational product doses taken during study 
period)/(Number of investigational product doses prescribed to be taken during period) x 
100%, 
where temporary dose discontinuation is ignored. 
The percentage of patients who have <60%, 60-80%, 80-100%, and >100% compliance will be 
summarized. 
5.6.2. 
Exposure to Investigational Product 
Exposure to investigational product will be examined for each patient. 
The total number of complete and incomplete injections administered will be summarized. SC 
injection location will also be summarized overall and by the person administering the injection. 
In addition, duration of treatment will be calculated as: [last dose day] – [first dose day] + 1.  The 
number of patients exposed to the investigational product will be presented by specific time 
period. The time periods of interest are as follows: 
• ≥ 13 weeks 
• ≥ 26 weeks 
• ≥ 39 weeks  
• ≥ 52 weeks  
• ≥ 65 weeks 
• ≥ 78 weeks 
• ≥ 91 weeks 
• ≥ 104 weeks 
In addition, frequencies and percentages of SC injections by location will be presented. 
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5.7. 
Analyses of Efficacy Variables 
5.7.1. 
Analysis of Primary Efficacy Variable 
The primary efficacy endpoint is the proportion of patients achieving LDH ≤1.5×ULN over 
week 26, defined as LDH ≤1.5×ULN at every scheduled time point up to week 26 (inclusive). 
For this efficacy endpoint, the analysis set consists of all FAS patients.  Patients who fulfill 1 or 
more of the following will be considered as not meeting the endpoint: 
1. Discontinue before week 26 
2. Have missing LDH value at week 13 and week 26 
3. Have breakthrough hemolysis (as defined in the secondary endpoint and based on 
investigator judgment) while on treatment in the first 26 weeks 
Patients who do not fulfill the above criteria will be evaluated based on their non-missing LDH 
measurements. 
The proportion of patients achieving LDH ≤1.5×ULN over week 26 will be calculated, along with 
a 95% confidence interval, by a normal approximation as primary analysis and by the exact 
Clopper Pearson method as a sensitivity analysis. 
The primary endpoint analysis will also be repeated on the subset of patients who were responders 
in the parent study.   
5.7.2. 
Analysis of Secondary Efficacy Variables 
Key Secondary Efficacy Variables: 
For the key secondary variable of the rate of breakthrough hemolysis through week 26, the 
numerator is the number of patients with at least one measurement of LDH ≥ 2 x ULN concomitant 
with associated signs or symptoms at any time subsequent to an initial achievement of disease 
control (i.e., LDH ≤ 1.5 x ULN).  The denominator is the number of patients who achieved initial 
disease control. This proportion will be calculated, along with a 95% confidence interval, by a 
normal approximation as primary analysis and by the exact Clopper Pearson method as a 
sensitivity analysis.  
For the key secondary variable of the number of units of transfusion over week 26, the mean and 
95% confidence interval will be calculated, based on the assumption of a negative binomial 
distribution of the number of units of transfusions with RBCs, adjusted for the time on study.  A 
transfusion will be counted only if the transfusion follows the predefined transfusion algorithm. 
For the key secondary variable of the rate of transfusion with RBCs through week 26 (annualized 
to transfusions per year), the mean and 95% confidence interval will be calculated, based on the 
assumption of a negative binomial distribution of the number of units of transfusions with RBCs, 
adjusted for the time on study. 
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A transfusion will be counted only if the transfusion follows the predefined transfusion algorithm: 
Transfusions with RBCs during the study should proceed according to the following predefined 
criteria that will trigger a transfusion; however, the actual number of units to be transfused is at 
the discretion of the investigator: 
• Transfuse with RBC(s) if the post-baseline (of the OLE) hemoglobin level is <9 g/dL 
with symptoms resulting from anemia, or 
• Transfuse with RBC(s) if the post-baseline (of the OLE) hemoglobin level is <7 g/dL. 
Of note, hemoglobin measurements from local laboratories are allowed. 
The key secondary endpoint analyses will also be repeated on the subset of patients who were 
responders in the parent study. 
Other Secondary Efficacy Variables 
For the following secondary variables, the analysis set will consist of all FAS patients who have a 
non-missing baseline measurement of the variable: 
• Percent changes and changes from baseline of the OLE study in LDH levels to week 
26, week 78, and week 104 
• Changes from baseline of the OLE study RBC hemoglobin levels to week 26, week 
78, and week 104 
• Changes from baseline of the OLE study in free hemoglobin levels to week 26, week 
78, and week 104 
For these variables, means and 95% confidence intervals based on 1-sample t-test will be reported 
for applicable weeks.  
For secondary endpoints that are defined by any occurrence of a defined event during a period, the 
analysis set will consist of all FAS patients.  This category of endpoints includes: 
• The proportions of patients with breakthrough hemolysis over 78 weeks and over 104 
weeks 
• The proportions of patients who are transfusion-free (with RBCs) over 26 weeks, 
over 78 weeks, and over 104 weeks 
• The proportions of patients achieving adequate control of their intravascular 
hemolysis, defined as LDH ≤1.5×ULN at every scheduled time point up to week 78 
(inclusive), and week 104 (inclusive) 
• The proportions of patients achieving normalization of their intravascular hemolysis, 
defined as LDH ≤1.0×ULN at every scheduled time point up to week 26 (inclusive), 
week 78 (inclusive), and week 104 (inclusive) 
For these binary efficacy endpoints, means and 95% confidence intervals, by normal 
approximation for primary analyses and by the exact Clopper Pearson method for sensitivity 
analyses, will be calculated. 
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For the rates and numbers of units of transfusion with RBCs over week 78 and week 104, the 
analysis set consists of all FAS patients.  The mean and 95% confidence interval will be calculated, 
based on the assumption of a negative binomial distribution of the number of units of transfusions 
with RBCs.  Rates (transfusions per year) will be adjusted for the time on study.  A transfusion 
will be counted only if the transfusion follows the predefined transfusion algorithm.   
See Section 5.9  for a description of the analyses of the following secondary efficacy variables: 
• Concentrations of REGN3918 in serum assessed throughout the study 
• Incidence of treatment-emergent anti-drug antibodies (ADA) to REGN3918 
throughout the study 
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs and 12-lead ECG).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Appendix 10.3 . 
For safety variables, 3 observation periods are defined: 
• The pre-treatment period is defined as the time from signing the ICF for the OLE 
study to before the first dose of study drug of the OLE study. 
• The treatment period is defined as the time from the first dose of study drug of the 
OLE study to the end of the 2-year open-label treatment period, or, in patients who 
prematurely discontinue/do not enter into the optional post-EOT period, from the first 
dose of study drug of the OLE study to the last dose of study drug + 21 weeks (i.e., 
147 days).   
• The post-EOT period of the OLE study is defined as the time after the treatment 
period of the OLE study. 
The summary of safety results will be presented overall. 
5.8.1. 
Adverse Events  
The verbatim text, the PT, and the primary SOC will be listed in patient listings. Summaries that 
include frequencies and proportions of patients reporting AEs will include the PTs and the SOCs. 
Treatment-emergent adverse events are defined as those AEs that occur or worsen in severity or 
become serious during the treatment period or represent the exacerbation of a pre-existing 
condition during the treatment period. 
The focus of adverse event summaries in the clinical study report will be on TEAEs. 
For details on handling missing data and partial dates, see Section 6. 
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Summaries of all TEAEs will include: 
• 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 4.6.1), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined by experiencing a prespecified PT or 
prespecified grouping of PTs, or by being put in a grouping specified in the CRF) 
Deaths and other SAEs will be listed and summarized. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
Summaries of all TEAEs will include: 
• All TEAEs by SOC and PT 
• Related TEAEs by severity and SOC and PT 
• Serious adverse events: All TEAEs by SOC and PT 
• Death: All fatal TEAEs by SOC 
• Discontinuation: All TEAEs by SOC and PT 
• Non-serious related TEAEs by SOC and PT 
Counts will be provided by parent study and overall for each PT within each SOC. Percentages 
will be calculated using the number of patients from the safety population. 
Primary SOCs will be sorted according to the order described in the Guideline on summary of 
product characteristics (December 1999, European commission), with the total overall classes 
coming first and labeled “Any class”. Within each primary SOC, PTs will be sorted by decreasing 
frequency of investigational product. 
A second type of table with counts of each primary SOC in decreasing order of frequency will be 
provided.  A third type of table with counts of each PT in decreasing order of frequency will also 
be provided. 
5.8.2. 
Analysis of Adverse Events of Special Interest 
Treatment emergent adverse events of special interest (see Section 4.6.2) will be presented by 
SMQ and PT (when selection is based on SMQs) and by SOC and PT (when selection is based on 
the e-CRF tick box).  The summaries will be sorted by decreasing incidence of PT within each 
SOC/SMQ. 
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5.8.3. 
Clinical Laboratory Measurements  
A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory value 
that was normal at Screening and Baseline but abnormal after treatment with investigational 
product, or a laboratory value that was abnormal at Baseline and exacerbates after treatment with 
investigational product.  “Exacerbations” will be identified by the Medical Monitor using clinical 
judgment.  
Laboratory test results (absolute values and changes from baseline) will be summarized by 
scheduled assessment time with descriptive statistics.   
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-enrollment 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. 
For categorical urinalysis variables, counts and percentages will be presented. 
Unless otherwise specified, laboratory displays will be from the central laboratory. 
5.8.4. 
Analysis of Vital Signs 
Vital signs (absolute values and changes from baseline of temperature, pulse, blood pressure) will 
be summarized by scheduled assessment time with descriptive statistics.   
5.8.5. 
Analysis of 12-Lead ECG 
ECG parameters (PR interval, QT interval, QTcF interval, QRS interval, and heart rate [from 
ventricular rate]) will be summarized at each time point using descriptive statistics.      
ECG status (i.e. normal, abnormal) will be reported. Shift tables will be provided to present the 
post-baseline status according to the baseline status (normal or missing, abnormal).  
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data 
5.9.1. 
Analysis of Pharmacokinetic Data  
The PK variable is concentration of total REGN3918 in serum over time. The total target variable 
is the concentrations of total C5 in serum over time. 
A summary of total drug concentrations and total C5 will be presented by nominal time point (i.e., 
the time points specified in the protocol).  Individual data will be presented by actual time.  Plots 
of the concentrations of REGN3918 and total C5 will be presented over time (linear and log 
scales).  When the scale is linear, concentrations below the lower limit of quantification (LLOQ) 
will be set to zero.  In the log-scaled figures, concentrations below the LLOQ will be imputed as 
LLOQ/2.  Summary statistics of concentrations of total REGN3918 and total C5 may include, but 
are not limited to arithmetic mean, standard deviation, standard error of the mean, coefficient of 
variation (%), minimum, Q1, median, Q3, and maximum. 
No formal statistical analysis will be performed. 
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5.9.2. 
Analysis of Immunogenicity Data 
5.9.2.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 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.  
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 weeks 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 
• Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
The maximum titer of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
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The following analysis will be provided: 
• Number (n) and percent (%) of ADA-negative patients  
• Number (n) and percent (%) of pre-existing patients 
• Number (n) and percent (%) of treatment-emergent ADA positive patients by ADA 
titer categories 
- 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 by ADA titer 
categories  
Listings of all ADA titer levels will be provided for pateints with pre-existing, treatment-boosted 
and treatment-emergent ADA responses. 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.9.3.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to REGN3918 will be 
explored. Plots of REGN3918 concentration may be provided for analyzing the potential impact 
of ADA category and maximum titer on PK. 
5.9.3.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• 
Injection site reaction (serious or severe and lasting 24 hours or longer) 
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g. scatter plot or spaghetti plot). 
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The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA positive  
Treatment-emergent 
Treatment-boosted 
• Maximum post-baseline titer for treatment-emergent or treatment-boosted ADA positive 
patients:  
o Low (titer <1,000) 
o Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
5.10. 
Analysis of Pharmacodynamic and Biomarker Data 
Descriptive statistics will be presented for the following PD and biomarker variables: 
• Changes and percent change in CH50 from baseline of the OLE study to week 26, 
week 78, and week 104 
• Changes in total C5 from baseline of the OLE study to week 26, week 78, and week 
104 CH50 and C5. 
 
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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, for efficacy the baseline assessment is defined as the latest available 
measurement taken before the first administration of study treatment in the OLE study (which 
corresponds to the last available measurement from the parent study, usually collected at the parent 
study’s EOT visit), as it is expected that at this time the two different populations from the parent 
studies should converge with regard to their control of intravascular hemolysis. 
For safety assessments, the baseline is defined as the latest available measurement taken before 
the first administration of OLE treatment.    For patients enrolled but not treated, the baseline will 
be the latest available measurement before enrollment in the OLE.  
6.2. 
Data Handling Convention for Missing Data 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 4.5.1  and Section 4.5.2. 
For categorical variables, patients with missing data are not included in calculations of percentages 
unless otherwise specified. When relevant, the number of patients with missing data is presented. 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
6.2.1. 
Adverse events 
If the severity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
severity of TEAE. If the measurement of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date  
AE start date will be used for AE classification and analysis. If AE start date is not complete, then 
the character variable will keep the original incomplete date, the numerical date variable will be 
imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead. Otherwise impute the AE start day using the first day of the month. If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
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If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use the last study 
visit date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 
31 December as the day and month. If this leads to a date after end of study follow up date, use 
the last study visit date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment (described in Section 5.8) medication or 
concomitant medication or both, the missing medication start date is estimated as early as possible, 
and the missing medication end date is estimated as late as possible. If the medication start date is 
missing, the onset day will not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before informed consent date. Imputation 
flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, in 
order to simplify the programming flow, the imputation is proposed to align with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date -
1 instead. Imputation flag is ‘M’ 
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Statistical Analysis Plan 
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If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit date 
instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
No imputations for missing laboratory data, ECG data, vital sign data, or physical examination 
data will be made. 
6.2.2. 
PCSV 
Patients who had post-baseline PCSV, but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.2.3. 
Date of first / last study drug administration 
Date of first study drug administration is the first non-missing start date of dosing filled in the CRF 
“Investigational Product” module. 
If a patient’s date of the last dose is totally missing or unknown, his/her last visit date will be 
substituted.  
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CONFIDENTIAL 
6.3. 
Analysis Visit Windows 
Data analyzed by visit (including efficacy, laboratory, vital sign, and ECG data) will be 
summarized by the study scheduled visits described in Appendix 10.2 (Schedule of Time and 
Events). Except for efficacy variables, the analysis visit windows will be exhaustive so that all 
available values obtained from unscheduled visits, early termination visit and end of treatment 
(EOT) have the potential to be summarized. The visit windows are constructed using ranges 
applied to the number of days in study (study days) when the measure is collected.  Day 1 is defined 
as the first date of study treatment.  Windows are given in Table 1. 
Table 1:  
General Analysis Windows 
Visit 
Targeted Study Day 
Window 
Day 1 
 
1 
1 
Week 13 
 
92 
[47, 137] 
Week 26 
 
183 
[138, 228] 
Week 39 
 
274 
[229, 319] 
Week 52 
 
365 
[320, 410] 
Week 65 
 
456 
[411, 501] 
Week 78 
 
547 
[502, 592] 
Week 91 
 
638 
[593, 683] 
Week 104 
 
729 
[684, 773] 
For efficacy variables, the analysis windows are the target dates ± 14 days for all visits starting 
with the Week 13 visit.  These windows are given in Table 2. 
Table 2: 
Efficacy Analysis Windows 
Visit 
Targeted Study Day 
 
Window 
Week 13 
 
92 
[78, 106] 
Week 26 
 
183 
[169, 197] 
Week 39 
 
274 
[260, 288] 
Week 52 
 
365 
[351, 379] 
Week 65 
 
456 
[442, 470] 
Week 78 
 
547 
[533, 561] 
Week 91 
 
638 
[624, 652] 
Week 104 
 
729 
[715, 743] 
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CONFIDENTIAL 
6.4. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations will 
be presented in listings. 
 
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CONFIDENTIAL 
7. 
INTERIM ANALYSIS 
There will not be a formal interim analysis. 
An interim data lock(s) for regulatory submissions of REGN3918 or publication purposes may be 
conducted. Safety data such as adverse event, laboratory parameters, vital signs, and ECG may be 
included in the analysis. 
 
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CONFIDENTIAL 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
 
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CONFIDENTIAL 
9. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
3. 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. 
4. Lee JW, Peffault de Latour R, Brodsky RA, Jang JH, Hill A, Röth A, Schreznemeier H, 
Wilson A, Marantz JL, Maciejewski JP. Effectiveness of eculizumab in patients with 
paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia in the 
International PNH Registry. Am J Hematol 2019; 94(1):E37-E41. 
 
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CONFIDENTIAL 
10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Endpoint 
Analysis 
Populations 
Statistical Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Efficacy analysis 
FAS 
Confidence intervals, 
Exact methods, 1-sample 
t-test   
MI and 
subgroup 
analyses for 
primary 
Yes 
Yes 
Adverse Events 
SAF 
Descriptive Statistics 
No 
No 
No 
Laboratory 
Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
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CONFIDENTIAL 
10.2. 
Schedule of Time and Events 
Study Period 
2-Year Open-Label Treatment Period1 
Optional Post-EOT Period2 
Study Week 
Day 1/ 
Week 05 
Week 
Every 6 months after EOT until 
End of Post-EOT period 
13 
26 
39 
52 
65 
78 
91 
EOT 
(104) 
Visit Window (weeks) 
±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w 
± 2 w 
Clinic Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening/Baseline: 
Inclusion/Exclusion criteria 
X 
Informed consent 
X 
X2 
Demographics 
X 
Medical history 
X 
Height 
X 
Risk assessment for Neisseria gonorrhea3 
X 
Enrollment via IVRS/IWRS 
X 
Treatment: 
REGN3918 administration4 
--------------------------------------X4---------------------------------
X 
Oral antibiotics 
--------------------------------------X---------------------------------
X 
Meningococcal vaccine (as needed) 
--------------------------------------X---------------------------------
X 
Patient diary (if applicable, compliance check)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
Study Period 
2-Year Open-Label Treatment Period1 
Optional Post-EOT Period2 
Study Week 
Day 1/ 
Week 05 
Week 
Every 6 months after EOT until 
End of Post-EOT period 
13 
26 
39 
52 
65 
78 
91 
EOT 
(104) 
Visit Window (weeks) 
±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w 
± 2 w 
Clinic Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Serum LDH6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion record update 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RBC hemoglobin7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Free hemoglobin7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient safety card for Neisseria meningitidis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
Hematology7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistry6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (WOCP only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Titers to Neisseria meningitidis (only if indicated as per local 
practice)8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
Study Period 
2-Year Open-Label Treatment Period1 
Optional Post-EOT Period2 
Study Week 
Day 1/ 
Week 05 
Week 
Every 6 months after EOT until 
End of Post-EOT period 
13 
26 
39 
52 
65 
78 
91 
EOT 
(104) 
Visit Window (weeks) 
±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w ±1 w 
± 2 w 
Clinic Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK, ADA and Biomarker Samples: 
PK sample of REGN3918 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total C5 (plasma) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement hemolytic assay (serum CH50) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bilirubin6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte count7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA sample for REGN3918 
X 
X 
X 
X 
X 
X9 
Optional Research: 
Future biomedical research (optional) 
X 
X 
X 
X 
X 
Whole blood for DNA isolation (optional)10 
X 
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CONFIDENTIAL 
Footnotes for the Schedule of Events Table 
1. 
After completion of the 2-year open-label treatment period, patients who do not enter 
into the optional post-EOT period should be followed for 21 weeks.  Patients should 
return for monthly clinic visits with assessments corresponding to week 104 (EOT) visit. 
2. 
The optional post-EOT period includes continued REGN3918 treatment of variable 
duration.  Patients may continue REGN3918 treatment after they have completed the 
2-year open-label treatment period and if they derive clinical benefit and have potential 
risk to discontinue REGN3918. The optional post-EOT period ends when 1 of the 
following is reached: clinical development of REGN3918 is terminated, risk-to-benefit 
profile of REGN3918 in this patient population is deemed unfavorable, or REGN3918 is 
approved by the regulatory authority governing the location of the study site.  Patients 
will be asked to provide separate consent for continuing onto the optional post-EOT 
period. 
3. 
Risk assessment for Neisseria gonorrhea is described in the protocol. 
4. 
Study drug administration will occur QW throughout the entire study, starting from the 
day 1 visit until and including the end-of-treatment visit (for the 2-year open-label 
treatment period) and for the optional post-EOT period (if applicable). Administration of 
study drug may be done at the clinical site, by a healthcare professional at the patient’s 
home, or by self-administration/administration by the patient or designated person, 
respectively. These various options for administration will depend on the preference of 
the investigator and patient, the availability of clinical supply, and the home healthcare 
visiting professional, and presentation of the study drug that may change during the 
course of the study.  If the presentation of the study drug becomes available for self-
administration /administration by patient or designated person, then sufficient injection 
training at the scheduled administration(s) with REGN3918 will be provided prior to 
undertaking study drug administration. Study drug kits will be dispensed at the clinical 
site visit or, as applicable, transported to the patient by a healthcare professional or by a 
DTP service provider. 
The recommended daily oral antibiotic prophylaxis will commence on the day of dosing 
and will consist of penicillin V 500 mg BID, or Erythromycin 500 mg BID in the case of 
penicillin allergy (to be determined by the investigator).  See the protocol for details. 
5. 
A patient diary will be provided to collect information that may include AEs, study drug 
administration, concomitant medications, vital signs, etc. depending on availability of a 
home healthcare visiting professional and other considerations. For self-
administration/administration by a designated person, a compliance check with the patient 
diary will be undertaken at clinic visits. 
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CONFIDENTIAL 
6. 
On visits where chemistry overlaps with serum LDH and/or bilirubin assessments, the 
chemistry testing will include these assessments. 
7. 
On visits where hematology overlaps with RBC hemoglobin, free hemoglobin, and/or 
reticulocyte count assessments, the hematology testing will include these assessments. 
8. 
Revaccinate patients at any time throughout the study. If the patient has had titers measured 
for Neisseria meningitidis and they demonstrate inadequate level of immunity, then 
revaccination should be done. 
9. 
ADA samples will be collected every 12 months after EOT and until the end of post-EOT 
period. Samples will be used for detecting the presence of ADA only; NAb positivity will 
only be assessed for treatment-emergent ADA-positive samples. 
10. Whole blood sample for DNA should be collected on day 1 (predose) but can be collected 
at a later study visit.  Patients who had consented to DNA testing in the parent study and 
had provided a sample for analysis do not need to provide separate consent/sample for the 
OLE study. 
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10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
For Studies in healthy 
subjects only 
Comments 
Clinical chemistry 
ALT 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline 
Phosphatase 
> 1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008 
Total Bilirubin 
> 1.5 ULN 
> 2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance Oct 2008 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Conjugated 
bilirubin 
> 35% total bilirubin (when 
total bilirubin >1.5 ULN) 
Conjugated bilirubin dosed on a case-by-case basis 
ALT and Total 
Bilirubin 
ALT > 3 ULN and Total 
Bilirubin > 2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
To be counted within the same treatment phase, whatever 
the interval between measurement 
CPK 
> 3 ULN 
>10 ULN 
FDA Feb 2005 
Am J Cardiol April 2006 
Categories are cumulative 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
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Parameter 
PCSV 
For Studies in healthy 
subjects only 
Comments 
Creatinine 
 150 mol/L (adults) 
   90 mol/L (6-12 year-old) 
 30% from baseline 
 100% from baseline 
Benichou C., 1994 
 
Creatinine 
Clearance 
(Cockcroft's 
formula) 
< 30 ml/min (severe renal 
impairment) 
30 - < 50 ml/min (moderate 
renal impairment) 
50 -  80 ml/min (mild renal 
impairment) 
Use is optional. 
FDA criteria May 1998 
Uric Acid 
Hyperuricemia: 
Hypouricemia: 
 
>408 µmol/L 
<120 µmol/L 
Harrison- Principles of internal Medicine 17th Ed. 2008 
Sodium 
129 mmol/L 
 160 mmol/L 
 
Potassium 
< 3  mmol/L 
 5.5 mmol/L 
FDA Feb 2005 
Total Cholesterol 
 7.74 mmol/L (3 g/L) 
Threshold for therapeutic intervention 
Triglycerides 
 4.6 mmol/L (4 g/L) 
Threshold for therapeutic intervention 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
  7 mmol/L (fasted);  11.1 
mmol/L (unfasted) 
 
ADA May 2005 
ADA Jan 2008 
 
CRP 
> 2 ULN or 
 >10 mg/L, if ULN not 
provided 
 FDA Sept 2005 
 
Hematology 
WBC 
< 3.0 Giga/L (3000/mm3) 
< 2.0 Giga/L (2000/mm3) 
(Black) 
Increase in WBC: not relevant 
To be interpreted only if no differential count available. 
Neutrophils 
< 1.5 Giga/L (1500/mm3) 
< 1.0 Giga/L (1000/mm3) 
Black 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
FDA criteria 
Eosinophils 
> 0.5 Giga/L (500/mm3) 
or > ULN if ULN  0.5 
Giga/L 
Gallin 1989, Harrisson 13th Ed, 1994. 
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CONFIDENTIAL 
Parameter 
PCSV 
For Studies in healthy 
subjects only 
Comments 
Hemoglobin 
At least 20 g/L (1.24 mmol/L) 
decrease versus baseline 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value.  
Other categories for decrease from baseline can be used 
( 30 g/L,  40 g/L,  50 g/L) 
Platelets 
< 100 Giga/L (100 000/mm3) 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
Vital signs 
HR 
 40 bpm and decrease from 
baseline  20 bpm 
 100 bpm and increase from 
baseline  20 bpm 
Proposed change: To be are applied for all positions 
(including missing) except STANDING 
SBP 
 95 mmHg and decrease 
from baseline  20 mmHg 
 140 mmHg and increase 
from baseline  20 mmHg 
Proposed change: To be are applied for all positions 
(including missing) except STANDING 
DBP 
Young and elderly subjects 
 45 mmHg and decrease 
from baseline  10 mmHg 
 90 mmHg and increase 
from baseline  10 mmHg 
 
Proposed change: To be are applied for all positions 
(including missing) except STANDING 
Orthostatic 
Hypotension 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
 
Weight 
 5 % increase versus 
baseline 
5% decrease versus baseline 
FDA Feb 2007  
ECG parameters 
CPMP 1997 guideline 
HR 
 40 bpm and decrease from 
baseline  20 bpm 
 100 bpm and increase from 
baseline  20 bpm 
 
PR 
 220 ms 
 
QRS 
 120 ms 
 
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CONFIDENTIAL 
Parameter 
PCSV 
For Studies in healthy 
subjects only 
Comments 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
                Males           
Females 
Borderline  
           431-450 ms     451-470 
ms 
Prolonged* 
           > 450 ms         > 470 
ms 
QTc   ≥500 ms           ≥ 500 
ms 
 
Increase versus baseline 
(Males and Females) 
Borderline 
 30-60 ms 
Prolonged * 
 > 60 ms 
To be applied to any kind of QT correction formula  
 
*QTc prolonged and QTc > 60 ms are the PCSA to be 
identified in individual subjects/patients listings. 
 
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