Clinical trial NCT03946748
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Sponsor: Regeneron Pharmaceuticals
Start date: 2019-05-16; Completion date: 2021-06-10
Enrollment: 24 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of the study is to demonstrate a reduction in intravascular hemolysis by REGN3918 over 26 weeks of treatment in patients with active PNH who are treatment-naive to complement inhibitor therapy or have not recently received complement inhibitor therapy.

The secondary objectives of the study are:

* To evaluate the safety and tolerability of REGN3918.
* To evaluate the effect of REGN3918 on parameters of intravascular hemolysis
* To assess the concentrations of total REGN3918 in serum.
* To evaluate the incidence of treatment-emergent anti-drug antibodies to REGN3918 over time
* To evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring fatigue and health-related quality of life

Detailed description:

Arms: arm 1: Cohort A (Dose Confirmation) If a decision is made to expand Cohort A, patients will be assigned to Cohort A.

Cohort B (Dose Expansion) If a decision is made to progress to Cohort B, patients will be assigned to Cohort B.
Interventions: intervention 1: REGN3918
Intervention descriptions: intervention 1: Single intravenous (IV) dose, then a subcutaneous (SC) dose once weekly (QW).

Protocol documents:
Prot_000.pdf: 
EudraCT: 2018-002734-20 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
AN OPEN-LABEL, SINGLE ARM STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF REGN3918 IN PATIENTS WITH 
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) WHO ARE 
COMPLEMENT INHIBITOR-NAIVE OR HAVE NOT RECENTLY 
RECEIVED COMPLEMENT INHIBITOR THERAPY 
Compound: 
REGN3918 
Clinical Phase: 
2 
Protocol Number: 
R3918-PNH-1852 
Protocol Version: 
R3918-PNH-1852 Amendment 2 
Amendment 2 Date of Issue: 
See appended electronic signature page 
Amendment 1 Date of Issue: 
20 Feb 2019 
Original Date of Issue: 
02 Nov 2018 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
VV-RIM-00076004-2.0 Approved - 21 Jun 2019 GMT-5:00
NCT03946748


Clinical Study Protocol 
 
R3918-PNH-1852 Amendment 2 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 90 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 2  
The following changes were made in this amendment: 
Change and Rationale for Change 
Section Changed 
Removed Sponsor as a responsible party in the 
confirmation of a breakthrough hemolysis event. In this 
study, breakthrough hemolysis events as defined by 
symptoms or signs of PNH concomitant with lactate 
dehydrogenase level ≥2 × ULN will be ascertained 
based on the investigator's judgment. 
Section 3.2.2 Rationale for Key Secondary Endpoints 
Added language to clarify that blood collection should 
occur if a breakthrough hemolysis event is suspected. 
Breakthrough hemolysis is defined by LDH ≥2 × ULN 
concomitant 
with 
symptoms. 
If 
a 
breakthrough 
hemolysis event is suspected based on clinical 
symptoms, blood will be collected for the analysis of 
LDH, drug concentration, ADA, total C5, and CH50. 
Table 1 Schedule of Events 
Section 8.1.3 Unscheduled Visits 
Section 8.2.4.4 Laboratory Testing 
Updated the duration of the open-label extension study. 
Section 5.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Section 7.5 Post-Study Treatment Access 
Clarified the weekly subcutaneous dose (800 mg SC 
QW) that will be used for the initial cohort A patients. 
Section 5.1 Study Description and Duration 
Section 7.2 Drug Administration 
Revised with clarifications related to data analysis to 
specify (where applicable):  
 Inclusion of baseline data in the week 8 analysis 
 Inclusion of an absence of breakthrough hemolysis in 
the assessment of adequate control at week 26 
 Use of t-statistic vs z-statistic in analyses 
Clinical Study Protocol Synopsis: Statistical Plan 
Section 5.1.1 Description of Study Cohorts 
Section 10.4.3.1 Primary Efficacy Analysis 
Section 10.4.3.2 Secondary Efficacy Analysis 
Removed irrelevant information related to blinding for 
the interim analysis. This is an open-label study. 
Section 5.2 Planned Interim Analysis 
Revised exclusion requirement for peripheral blood 
absolute neutrophil count to <500/μL. 
Section 6.2.2 Exclusion Criteria (Criterion #5) 
Revised study drug description to remove details that are 
more appropriately addressed in the pharmacy manual.  
Amended exclusion criterion #21 to exclude patients 
with known hypersensitivity to components of the drug 
product. 
Section 6.2.2  Exclusion Criteria (Criterion #21) 
Section 7.1 Investigational Treatment 
Section 7.11.1 Packaging, Labeling, and Storage 
Section 8.1.1 Footnotes for the Schedule of Events 
Table 
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Change and Rationale for Change 
Section Changed 
Revised 
description 
of 
PNH 
erythrocytes 
and 
granulocytes to reflect typical laboratory output for these 
analytes.  
Updated inclusion criterion #3 to specify PNH 
granulocytes that are denoted as polymorphonuclear 
(PMN). 
Clinical Study Protocol Synopsis: Population 
Section 4.2.3 Exploratory Endpoints 
Section 6.2.1 Inclusion Criteria (Criterion #3) 
Table 1 Schedule of Events 
Section 8.2.8 Pharmacodynamic and Exploratory 
Biomarker Procedures 
Revised 
language 
for 
mandatory 
meningococcal 
vaccinations to allow flexibility on the timing of the 
administration per local practice. 
Section 7.4.1 Meningococcal Vaccinations 
Table 1 Schedule of Events 
Clarified that risk assessment and mitigation for 
Neisseria gonorrhea begin at screening. 
Section 5.1 Study Description and Duration 
Section 7.8 Risk Management of Neisseria Gonorrhea 
Table 1 Schedule of Events 
Section 8.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Added 
blood 
sample 
collection 
for 
PK 
and 
immunogenicity assessment in the event of a suspected 
hypersensitivity reaction. 
Section 8.1.3 Unscheduled Visits 
Section 8.2.4.4 Laboratory Testing 
Reduced number of exploratory biomarkers. 
Section 4.5 Exploratory Biomarker Variables 
Table 1 Schedule of Events 
Section 8.2.8 Pharmacodynamic and Exploratory 
Biomarker Procedures 
Clarified that the hepatitis B and C screening test (to be 
performed as need per local practice) may be analyzed at 
the central laboratory. 
Table 1 Schedule of Events 
Section 8.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Updated the background information on paroxysmal 
nocturnal hemoglobinuria to include information on 
newly approved ravulizumab. 
Section 1.1 Background on Paroxysmal Nocturnal 
Hemoglobinuria 
Updated the descriptions and timing of clinical outcome 
assessments used in this study. 
The PNH Symptom-Specific Questionnaire will be 
completed daily by the patient. 
Section 4.2.3 Exploratory Endpoints 
Section 8.1 Schedule of Events 
Table 1 Schedule of Events 
Section 8.2.3.6 Clinical Outcome Assessments 
Section 8.2.7 Clinical Outcome Assessments 
Section 8.2.7.1 Patient-Reported Outcome Assessments 
Section 22 References 
Added time points for the collection of blood samples 
for optional research. 
Table 1 Schedule of Events 
 
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Change and Rationale for Change 
Section Changed 
Corrected numbering of study days and updated 
Schedule of Events to reflect changes made in this 
amendment. Clarified timing of endpoints based on 
these changes. 
Clinical Study Protocol Synopsis: Objectives, Study 
Duration, Endpoints, Statistical Plan 
Section 2.1 Primary Objectives 
Section 3.2.1 Rationale for Study Design 
Section 3.2.1.2 Rationale for the Co-Primary Endpoints 
Section 4.2.1 Primary Endpoints 
Section 4.2.2 Secondary Endpoints 
Section 4.2.3 Exploratory Endpoints 
Section 5.1.1 Description of Study Cohorts 
Section 5.2 Planned Interim Analysis 
Section 6.4 Replacement of Patients 
Section 7.2 Drug Administration 
Section 7.10.1 Method of Treatment Assignment 
Table 1 Schedule of Events 
Section 8.1.2 Premature Discontinuation and Follow-up 
Section 10.2 Justification of Sample Size 
Section 10.4.3.2 Secondary Efficacy Analysis 
Section 10.5 Interim Analysis 
Clarified that additional screening visits can be added 
within the screening period. 
Updated the list of historical parameters that will be 
collected as part of medical history. 
Section 8.2.1 Procedures Performed Only at the 
Screening/Baseline Visit 
Added references to procedures and recommendations 
related to study drug administration described elsewhere 
in the protocol. 
Section 5.1 Study Description and Duration 
Section 8.2.2 Study Drug Administration (section 
added) 
Revised the language related to the analysis of 
immunogenicity data to provide clarification to sites. 
Section 4.4 Immunogenicity Variables 
Section 10.3.4 Immunogenicity Analysis Sets 
Section 10.4.6 Analysis of Immunogenicity Data 
Replaced safety definitions, reporting, and monitoring 
section with updated Sponsor protocol template 
language for consistency with current processes. 
Section 9 Safety Evaluation and Reporting (entire 
section, including subsections) 
Added section on data transparency for consistency with 
updated Sponsor protocol template language and 
processes. 
Section 14.5 Clinical Study Data Transparency (section 
added) 
 
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Change and Rationale for Change 
Section Changed 
Clarifications and corrections. 
Title page 
Section 1.2 Background on REGN3918 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Section 3.2.3 Rationale for Dose Selection 
Section 5.1 Study Description and Duration 
Section 6.1 Number of Patients Planned 
Table 1 Schedule of Events 
Section 8.2.3.2 Transfusion Record Update 
Section 8.2.5 Drug Concentration and Measurements 
Section 10.3.3 Pharmacokinetic Analysis Sets 
Section 10.3.4 Immunogenicity Sets 
Section 10.3.5.1 Exploratory Biomarker Endpoint 
Analysis Set 
Section 10.3.5.2 Exploratory Clinical Outcome 
Assessment Analysis Set 
Section 10.4.4.2 Other Safety 
Section 12.3 Case Report Form Requirements 
Section 22 References 
Minor editorial changes 
Throughout the document 
 
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Amendment 1 
Changes were made to address comments following the European Union (EU) regulatory review.  
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Section Changed 
Study phase changed from phase 3 to phase 2 
Title page 
Clarified that safety is part of the decision to progress 
from cohort A to cohort B 
Section 5.1.1 Description of Study Cohorts 
Revised exclusion criterion #7 to exclude patients with 
active or latent tuberculosis infection 
Section 6.2.2 Exclusion Criteria (Criterion #7) 
Section 8.1 – Table 1 Schedule of Events 
Section 8.2.1 Procedures Performed Only at Screening/ 
Baseline Visit 
Section 8.2.4.4 Laboratory Testing 
Added exclusion criteria to exclude patients with known 
chronic infection with hepatitis B or C and patients with 
pre-existing or acute liver disease 
Section 6.2.2 Exclusion Criteria (Criterion #14 and #29) 
 
Extended the recommended contraception use period and 
safety follow-up period to 21 weeks 
Section 6.2.2 Exclusion Criteria (Criterion #28) 
Section 7.4.2 Oral Antibiotics 
Section 8.1.2 Premature Discontinuation and Follow-up 
Section 9.4.2 Serious Adverse Events  
Section 9.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
Section 10.4.4.1 Adverse Events  
Specified that a maximum of 6 patients may be replaced 
in cohort A 
Section 6.4 Replacement of Patients 
Added language to emphasize that the administration, 
duration, and choice of concomitant antibiotics are at the 
discretion of the investigator 
Section 7.4.2 Oral Antibiotics 
Revised language regarding risk assessment and risk 
management of Neisseria gonorrhea 
Section 7.8 Risk Management of Neisseria Gonorrhea 
Clarified in the statistical methods that the cohorts will be 
analyzed separately if there is a change in dosing regimen 
between cohort A and cohort B, and that cohort B will be 
the primary analysis cohort in this situation 
Section 10.4 Statistical Methods 
Revised with details of the analysis of secondary 
endpoints 
Section 10.4.3.2 Secondary Efficacy Analysis 
Minor editorial/formatting corrections 
Various 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
An Open-Label, Single Arm Study to Evaluate the Efficacy and Safety of 
REGN3918 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) 
who are Complement Inhibitor-Naive or Have Not Recently Received 
Complement Inhibitor Therapy  
Site Location(s) 
Coordinating Investigator 
Multiple Global Sites 
Anita Hill, MBChB (Hons), MRCP, FRCPath, Ph.D. 
Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and 
Honorary Senior Lecturer at the University of Leeds 
Objectives 
The primary objective of the study is to demonstrate a reduction in 
intravascular hemolysis by REGN3918 over 26 weeks of treatment (assessed 
at week 26) in patients with active PNH who are treatment-naive to 
complement inhibitor therapy or have not recently received complement 
inhibitor therapy. 
The secondary objectives of the study are: 
 
To evaluate the safety and tolerability of REGN3918  
 
To evaluate the effect of REGN3918 on parameters of intravascular 
hemolysis  
 
To assess the concentrations of total REGN3918 in serum 
 
To evaluate the incidence of treatment-emergent anti-drug antibodies 
to REGN3918 over time 
 
To evaluate the effect of REGN3918 on patient-reported outcomes 
(PROs) measuring fatigue and health-related quality of life 
Study Design 
This is an open-label, single arm, 26-week treatment study in patients with 
confirmed diagnosis of PNH and active signs and symptoms who either are 
complement inhibitor naive or have received prior treatment with a 
complement inhibitor, but not within 6 months prior to screening visit.  
In this study, there will be two cohorts, one for dose confirmation (cohort A) 
and one for dose expansion (cohort B). Dose confirmation will be made at the 
interim analysis. The inclusion and exclusion criteria and schedule of events 
are the same for cohort A and cohort B. During the assessment of data from 
cohort A, recruitment into the study will continue, with patients recruited 
being assigned subsequently as follows: if a decision is made to expand 
cohort A, they will be assigned to cohort A. If a decision is made to progress to 
cohort B, they will be assigned to cohort B. 
Patients will be given a single loading dose of REGN3918 30 mg/kg 
intravenous (IV) on day 1, then a dose not greater than 800 mg subcutaneous 
(SC) once weekly (QW; ± 1 day) to week 26.   
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Study Duration 
The duration of the study for a patient is approximately 27 weeks, excluding 
the screening period. The study consists of a screening period (up to 4 weeks), 
26-week treatment period, and an end-of-study visit one week after the last 
study drug administration. After completion of the 26-week treatment period, 
patients may enroll into a separate open-label extension study, which will 
provide uninterrupted treatment with REGN3918. Patients who discontinue 
treatment will have a minimum of a 21-week follow-up period. 
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 30 to 42 adults (men and women) are planned to be enrolled.  
 
Target Population: 
The study population will consist of adult male and female patients with 
confirmed diagnosis of PNH and active signs and symptoms who either are 
complement inhibitor-naive or have received prior treatment with a 
complement inhibitor, but not within 6 months prior to screening visit. 
Key Inclusion Criteria: 
 
Male or female ≥ 18 years of age or legal age of majority at 
screening, whichever is greater 
 
Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) confirmed 
by high-sensitivity flow cytometry  
 
Active disease, as defined by the presence of 1 or more PNH-related 
signs or symptoms or history of red blood cell (RBC) transfusion due 
to PNH within 3 months of screening. 
 
Lactate dehydrogenase (LDH) level ≥ 2 × upper limit of normal 
(ULN) at screening visit. 
 
PNH granulocytes (denoted as polymorphonuclear [PMN]) >10% at 
screening visit. 
Key Exclusion Criteria: 
 
Prior treatment with a complement inhibitor either within 6 months 
prior to screening visit or at any time where the patient was refractory 
to complement inhibitor therapy, in the opinion of the investigator 
(with the exception of eculizumab refractory patients due to the C5 
variant R885H/C) 
Treatment 
 
 
Study Drug 
 
Dose/Route/Schedule: 
REGN3918 
Patients will be given a single loading dose of REGN3918 30 mg/kg IV on 
day 1, then a dose no greater than 800 mg SC QW  
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Endpoints 
 
 
 
Primary: 
The co-primary endpoints are: 
 
The proportion of patients achieving adequate control of their 
intravascular hemolysis, defined as LDH ≤ 1.5 x ULN at every 
scheduled time point between week 4 and week 26, inclusive 
 
The proportion of patients achieving transfusion avoidance defined as 
no post baseline transfusion of RBCs per protocol through week 26  
 
Secondary: 
The secondary endpoints are: 
 
The rate of breakthrough hemolysis through week 26, defined as the 
measurement of LDH ≥ 2 x ULN concomitant with associated signs 
or symptoms at any time subsequent to an initial achievement of 
disease control (ie, LDH ≤ 1.5 x ULN)  
 
The proportion of patients achieving normalization of their 
intravascular hemolysis, defined as LDH ≤ 1.0 x ULN at every 
scheduled time point between week 4 through week 26, inclusive 
 
Time to first LDH ≤ 1.5 x ULN 
 
Percentage of days with LDH ≤ 1.5 x ULN between week 4 and 
week 26, inclusive 
 
Change and percent change in LDH levels from baseline to week 26 
 
The rate and number of units of transfusion with RBCs through 
week 26 
 
Change in RBC hemoglobin levels from baseline to week 26 
 
Change in free hemoglobin levels from baseline to week 26 
 
Change and percent change in total complement hemolytic activity 
assay (CH50) from baseline to week 26 
 
Change in patient-reported outcomes (fatigue as measured by the 
FACIT-Fatigue and health-related quality of life as measured by the 
European Organization for Research and Treatment of Cancer 
[EORTC]-QLQ-30 and EQ-5D-3L) from baseline to week 26   
 
Incidence and severity of treatment-emergent adverse events 
(TEAEs) and other safety variables through week 26 
 
Concentrations of total REGN3918 in serum assessed throughout the 
study 
 
Incidence of treatment-emergent anti-drug antibodies (ADA) to 
REGN3918 in patients over time  
Procedures and Assessments 
Procedures and Assessments are detailed in the protocol body  
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Statistical Plan 
This is a single-arm open-label study, and a formal power calculation for 
comparison with a control is not intended. A sample size of 30-42 patients will 
provide sufficient precision for estimation of the co-primary endpoints. For 
cohort A, a sample size of 6 is standard in assessing safety and tolerability of a 
drug dose first tested in patients. Also, it was assessed that sufficient assurance 
of efficacy with the initial dosing regimen will be provided for a decision to 
progress from cohort A to cohort B if all 6 cohort A patients achieve an LDH 
≤ 1.5 x ULN at week 8. 
The full analysis set (FAS) includes all enrolled patients who received any 
study drug.  
For the co-primary endpoint of the proportion of patients achieving adequate 
control of their intravascular hemolysis, defined as LDH ≤ 1.5 x ULN at every 
scheduled time point between week 4 and week 26, inclusive, the analysis set 
will consist of all FAS patients. Patients who have one or more of the 
following will be considered as not achieving adequate control of their 
intravascular hemolysis:  
 
Discontinue from study treatment early 
 
Have 3 consecutive missing values of the scheduled LDH 
measurements between week 4 and week 26  
 
Have 50% or more missing values of the scheduled LDH 
measurements between week 4 and week 26 
 
Experience breakthrough hemolysis event (as defined in the 
secondary endpoint) while on treatment through week 26. 
Patients who complete study treatment, have no more than 2 consecutive 
missing values of the scheduled LDH measurements between week 4 and 
week 26, have fewer than 50% missing values of the scheduled LDH 
measurements between week 4 and week 26, and have no breakthrough 
hemolysis while on treatment will be evaluated based on their non-missing 
LDH measurements.   
The proportion of patients achieving adequate control of their intravascular 
hemolysis will be calculated, along with a 95% confidence interval, by 
approximation of a one-sample z-statistic, as primary analysis and by exact 
methods as sensitivity analysis. A sensitivity analysis by multiple imputation 
of missing LDH measurements will also be performed. Multiple imputation 
methods to be applied will be detailed in the statistical analysis plan (SAP).  
For the co-primary endpoint of the proportion of patients achieving transfusion 
avoidance, the analysis set will consist of all FAS patients. A transfusion will 
be counted only if the transfusion follows the predefined transfusion 
algorithm. A time-to-first-event analysis will be used to estimate the 
proportion of patients achieving transfusion avoidance at week 26 and a 95% 
confidence interval. 
 
Sensitivity analyses of the co primary endpoints will also be conducted for 
subgroups of FAS patients, including all complement inhibitor naive patients 
(no prior complement inhibitor therapy) in cohort A and cohort B, all patients 
in cohort B, and all complement inhibitor naive patients in cohort B. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AH50 
Alternative pathway hemolytic activity assay 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
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 
EORTC 
European Organization for Research and Treatment of Cancer 
EoS 
End of study 
eGFR 
Estimated glomerular filtration rate 
F1+2 
D-dimer and N-terminal prothrombin fragments 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full analysis set 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GPI 
Glycophosphatidylinositol 
HRQoL 
Health-related quality of life 
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 
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LLOQ 
Lower limit of quantification  
MAC 
Membrane attack complex 
MAVE 
Major adverse vascular event 
MMRM 
Mixed-effect model for repeated measures 
NAb 
Neutralizing Antibody 
NOAEL 
No observable adverse effect level 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PIGA 
Phosphatidylinositol glycan anchor biosynthesis class A 
PGIC 
Patient global impression of change 
PGIS 
Patient global impression of severity 
PK 
Pharmacokinetic 
PMN 
Polymorphonuclear 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PRO 
Patient reported outcome 
PT 
Preferred term 
Q2W 
Every 2 weeks 
QLQ-C30 
Quality of life questionnaire-core 30 
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 
TEAE 
Treatment-emergent adverse event 
TFPI 
Tissue Factor Pathway Inhibitor 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
WBC 
White blood cell 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................11 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Background on Paroxysmal Nocturnal Hemoglobinuria ............................................19 
1.2. 
Background on REGN3918 ........................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................22 
2.1. 
Primary Objective .......................................................................................................22 
2.2. 
Secondary Objectives .................................................................................................22 
2.3. 
Exploratory Objectives ...............................................................................................22 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................23 
3.1. 
Hypothesis ..................................................................................................................23 
3.2. 
Rationale .....................................................................................................................23 
3.2.1. 
Rationale for Study Design .........................................................................................23 
3.2.1.1. 
Rationale for Study Population ...................................................................................23 
3.2.1.2. 
Rationale for the Co-Primary Endpoints ....................................................................24 
3.2.2. 
Rationale for Key Secondary Endpoints .....................................................................25 
3.2.3. 
Rationale for Dose Selection ......................................................................................25 
3.3. 
Risk-Benefit ................................................................................................................26 
4. 
STUDY VARIABLES................................................................................................28 
4.1. 
Demographic and Baseline Characteristics ................................................................28 
4.2. 
Endpoints ....................................................................................................................28 
4.2.1. 
Primary Endpoints ......................................................................................................28 
4.2.2. 
Secondary Endpoints ..................................................................................................28 
4.2.3. 
Exploratory Endpoints ................................................................................................29 
4.3. 
Pharmacokinetic Variables .........................................................................................29 
4.4. 
Immunogenicity Variables ..........................................................................................29 
4.5. 
Exploratory Biomarker Variables ...............................................................................29 
5. 
STUDY DESIGN .......................................................................................................30 
5.1. 
Study Description and Duration .................................................................................30 
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5.1.1. 
Description of Study Cohorts .....................................................................................30 
5.1.2. 
End of Study Definition ..............................................................................................32 
5.2. 
Planned Interim Analysis ............................................................................................32 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............33 
6.1. 
Number of Patients Planned .......................................................................................33 
6.2. 
Study Population .........................................................................................................33 
6.2.1. 
Inclusion Criteria ........................................................................................................33 
6.2.2. 
Exclusion Criteria .......................................................................................................34 
6.3. 
Premature Withdrawal from the Study .......................................................................36 
6.4. 
Replacement of Patients .............................................................................................36 
7. 
STUDY TREATMENTS............................................................................................37 
7.1. 
Investigational Treatments ..........................................................................................37 
7.2. 
Drug Administration ...................................................................................................37 
7.3. 
Transfusion Algorithm ................................................................................................38 
7.4. 
Pretreatments ..............................................................................................................38 
7.4.1. 
Meningococcal Vaccinations ......................................................................................38 
7.4.2. 
Oral Antibiotics ..........................................................................................................38 
7.5. 
Post-Study Treatment Access .....................................................................................39 
7.6. 
Dose Modification and Study Treatment Discontinuation Rules ...............................39 
7.6.1. 
Study Drug Discontinuation .......................................................................................39 
7.6.1.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................39 
7.6.1.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................40 
7.7. 
Management of Acute Reactions ................................................................................40 
7.7.1. 
Acute Intravenous Infusion Reactions ........................................................................40 
7.7.1.1. 
Interruption of the Intravenous Infusion .....................................................................40 
7.7.1.2. 
Termination of the Intravenous Infusion ....................................................................41 
7.7.2. 
Acute Injection Reactions ...........................................................................................41 
7.7.2.1. 
Systemic Injection Reactions ......................................................................................41 
7.7.2.2. 
Local Injection Site Reactions ....................................................................................41 
7.8. 
Risk Management of Neisseria Gonorrhea .................................................................42 
7.9. 
Dose Modification ......................................................................................................42 
7.10. 
Measures to Reduce Bias ............................................................................................42 
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7.10.1. 
Method of Treatment Assignment ..............................................................................42 
7.10.2. 
Blinding ......................................................................................................................42 
7.11. 
Treatment Logistics and Accountability .....................................................................43 
7.11.1. 
Packaging, Labeling, and Storage ..............................................................................43 
7.11.2. 
Supply and Disposition of Treatments .......................................................................43 
7.11.3. 
Treatment Accountability ...........................................................................................43 
7.11.4. 
Treatment Compliance ................................................................................................43 
7.12. 
Concomitant Medications ...........................................................................................43 
7.12.1. 
Prohibited Medications ...............................................................................................44 
7.12.2. 
Permitted Medications ................................................................................................44 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................45 
8.1. 
Schedule of Events .....................................................................................................45 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................51 
8.1.2. 
Premature Discontinuation and Follow-up .................................................................51 
8.1.3. 
Unscheduled Visits .....................................................................................................51 
8.2. 
Study Procedures ........................................................................................................52 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................52 
8.2.2. 
Study Drug Administration.........................................................................................52 
8.2.3. 
Efficacy Procedures ....................................................................................................53 
8.2.3.1. 
Serum Lactate Dehydrogenase ...................................................................................53 
8.2.3.2. 
Transfusion Record Update ........................................................................................53 
8.2.3.3. 
Total Hemolytic Complement Activity ......................................................................53 
8.2.3.4. 
Red Blood Cell Hemoglobin ......................................................................................53 
8.2.3.5. 
Free Hemoglobin ........................................................................................................53 
8.2.3.6. 
Clinical Outcome Assessments ...................................................................................53 
8.2.4. 
Safety Procedures .......................................................................................................55 
8.2.4.1. 
Vital Signs ..................................................................................................................55 
8.2.4.2. 
Physical Examination and Body Weight ....................................................................55 
8.2.4.3. 
Electrocardiogram .......................................................................................................55 
8.2.4.4. 
Laboratory Testing ......................................................................................................55 
8.2.5. 
Drug Concentration and Measurements .....................................................................57 
8.2.6. 
Anti-Drug Antibody Measurements and Samples ......................................................57 
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8.2.7. 
Clinical Outcome Assessments ...................................................................................57 
8.2.7.1. 
Patient-Reported Outcome Assessments ....................................................................57 
8.2.7.2. 
Wearable Activity Tracker .........................................................................................58 
8.2.8. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................58 
8.2.9. 
Future Biomedical Research (Optional) .....................................................................59 
8.2.9.1. 
Pharmacogenomic Analysis (Optional) ......................................................................59 
9. 
SAFETY EVALUATION AND REPORTING .........................................................61 
9.1. 
Recording and Reporting Adverse Events ..................................................................61 
9.1.1. 
General Guidelines .....................................................................................................61 
9.1.2. 
Data Collection Period ................................................................................................62 
9.1.3. 
Reporting Procedure ...................................................................................................62 
9.1.4. 
Events that Require Expedited Reporting to Sponsor ................................................62 
9.2. 
Definitions ..................................................................................................................63 
9.2.1. 
Adverse Event .............................................................................................................63 
9.2.2. 
Serious Adverse Event ................................................................................................63 
9.2.3. 
Adverse Events of Special Interest .............................................................................63 
9.2.4. 
Infusion Reactions ......................................................................................................64 
9.2.5. 
Severity .......................................................................................................................64 
9.2.6. 
Causality .....................................................................................................................65 
9.3. 
Safety Monitoring .......................................................................................................66 
9.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................66 
10. 
STATISTICAL PLAN................................................................................................67 
10.1. 
Statistical Hypothesis ..................................................................................................67 
10.2. 
Justification of Sample Size........................................................................................67 
10.3. 
Analysis Sets ...............................................................................................................68 
10.3.1. 
Efficacy Analysis Sets ................................................................................................68 
10.3.2. 
Safety Analysis Set .....................................................................................................68 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................68 
10.3.4. 
Immunogenicity Sets ..................................................................................................68 
10.3.5. 
Exploratory Analysis Sets ...........................................................................................68 
10.3.5.1. 
Exploratory Biomarker Endpoint Analysis Set ..........................................................68 
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10.3.5.2. 
Exploratory Clinical Outcome Assessment Analysis Set ...........................................69 
10.4. 
Statistical Methods ......................................................................................................69 
10.4.1. 
Patient Disposition ......................................................................................................69 
10.4.2. 
Demography and Baseline Characteristics .................................................................69 
10.4.3. 
Efficacy Analyses .......................................................................................................70 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................70 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................71 
10.4.4. 
Safety Analysis ...........................................................................................................72 
10.4.4.1. 
Adverse Events ...........................................................................................................72 
10.4.4.2. 
Other Safety ................................................................................................................72 
10.4.4.3. 
Treatment Exposure ....................................................................................................73 
10.4.4.4. 
Treatment Compliance ................................................................................................73 
10.4.5. 
Pharmacokinetics ........................................................................................................73 
10.4.5.1. 
Analysis of Drug Concentration Data .........................................................................73 
10.4.6. 
Analysis of Immunogenicity Data ..............................................................................73 
10.4.7. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data ..............................74 
10.4.8. 
Analysis of Exploratory Clinical Outcome Assessment Data ....................................74 
10.5. 
Interim Analysis ..........................................................................................................74 
10.6. 
Additional Statistical Data Handling Conventions .....................................................74 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........75 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................76 
11.1. 
Data Management .......................................................................................................76 
11.2. 
Electronic Systems ......................................................................................................76 
12. 
STUDY MONITORING ............................................................................................77 
12.1. 
Monitoring of Study Sites ...........................................................................................77 
12.2. 
Source Document Requirements ................................................................................77 
12.3. 
Case Report Form Requirements ................................................................................77 
13. 
AUDITS AND INSPECTIONS .................................................................................78 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................79 
14.1. 
Good Clinical Practice Statement ...............................................................................79 
14.2. 
Informed Consent .......................................................................................................79 
14.3. 
Patients Confidentiality and Data Protection ..............................................................79 
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14.4. 
Institutional Review Board/Ethics Committee ...........................................................80 
14.5. 
Clinical Study Data Transparency ..............................................................................80 
15. 
PROTOCOL AMENDMENTS ..................................................................................81 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................82 
16.1. 
Premature Termination of the Study ...........................................................................82 
16.2. 
Close-out of a Site ......................................................................................................82 
17. 
STUDY DOCUMENTATION ...................................................................................83 
17.1. 
Certification of Accuracy of Data ...............................................................................83 
17.2. 
Retention of Records ..................................................................................................83 
18. 
DATA QUALITY ASSURANCE ..............................................................................84 
19. 
CONFIDENTIALITY ................................................................................................85 
20. 
FINANCING AND INSURANCE .............................................................................85 
21. 
PUBLICATION POLICY ..........................................................................................85 
22. 
REFERENCES ...........................................................................................................86 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................89 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................90 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................46 
Table 2: 
Minimal and Maximal Planned Sample Size ..............................................................68 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................31 
 
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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 (WBCs) 
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). PNH 
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 approval of eculizumab has been its effectiveness in PNH, as evidenced by the 
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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 (Ultomiris™) 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). Eculizumab administration every 2 weeks (Q2W) by intravenous (IV) infusion 
has been described as burdensome for patients.  
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 subcutaneous (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 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 
100 mg/kg/week 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 100 mg/kg, 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. 
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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 QW SC doses of 400 mg following a 15 mg/kg IV loading dose, 
resulted in one resolved serious adverse event (SAE) in the study, an episode of salpingitis of 
undetermined microbial 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.  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 demonstrate a reduction in intravascular hemolysis by 
REGN3918 over 26 weeks of treatment (assessed at week 26) in patients with active PNH who 
are treatment-naive to complement inhibitor therapy or have not recently received complement 
inhibitor therapy. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the safety and tolerability of REGN3918 
 To evaluate the effect of REGN3918 on parameters of intravascular hemolysis  
 To assess the concentrations of total REGN3918 in serum 
 To evaluate the incidence of treatment-emergent anti-drug antibodies to REGN3918 
over time 
 To evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring 
fatigue and health-related quality of life 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
 To explore the effect on clinical thrombosis events 
 To explore the effect on renal function and renal injury biomarkers 
 To explore the effect of REGN3918 on complement activation and intravascular 
hemolysis relevant to PNH and other related diseases 
 To explore the effect of REGN3918 on the level of total C5 protein 
 To explore the effect of REGN3918 on PNH clone size  
 To explore the effect of REGN3918 on treatment satisfaction and a novel PRO 
measuring PNH-specific symptoms  
 To explore factors contributing to changes in well-being such as fatigue or quality of 
life in a subset of patients at participating sites (ie, sub-study) 
 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 
The clinical hypothesis of the study is that REGN3918 will reduce complement-mediated 
intravascular hemolysis as measured by reduction in LDH and reduce the requirement for 
transfusion with RBCs in patients with active PNH who are complement inhibitor-naive or have 
not recently received complement inhibitor therapy.  
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
The study is a single-arm study and thus patients and the investigator will be aware of treatment 
allocation. This is deemed acceptable as 1 of the 2 co-primary endpoints of the study is an 
objective, laboratory-based parameter (ie, LDH) that is less likely to be biased by knowledge of 
treatment assignment. The other co-primary endpoint is transfusion avoidance, and the study 
protocol includes a transfusion algorithm that will standardize the decision to transfuse and thus 
minimize bias from knowledge of treatment assignment.  
The study does not include a placebo control, because there is an approved treatment for PNH 
(ie, eculizumab), and not treating patients with active PNH increases the risk of serious or 
irreversible harm from sequelae of the disease.  
In this study, there will be two cohorts, one for dose confirmation (cohort A) and one for dose 
expansion (cohort B). Cohort A will comprise of patients whose data will contribute to an initial 
evaluation at week 8, after 8 weeks of therapy, the purpose of which is the confirmation of the 
adequacy of the selected dose regimen (Section 5.1). 
3.2.1.1. 
Rationale for Study Population 
The study population will consist of adult male and female patients with confirmed diagnosis of 
PNH and active signs and symptoms, who either are complement inhibitor-naive or have 
received prior treatment with a complement inhibitor, but not within 6 months prior to screening 
visit. Active signs and symptoms are defined as: The presence of PNH-related signs or 
symptoms in the 3 months prior to screening, or having received at least one RBC transfusion 
within 3 months of screening along with LDH ≥2 x upper limit of normal (ULN).  
The complement inhibitor-naive population was selected because these patients are known to 
benefit from complement therapy, as demonstrated by effectiveness of eculizumab. The 
effectiveness of eculizumab has been shown to be directly related to its ability to completely 
inhibit complement-mediated hemolysis. Finally, the inhibition of complement-mediated 
intravascular hemolysis in patients with active PNH can readily be measured in vivo by a rapid 
reduction in serum LDH levels.  
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Patients with PNH who had previously received complement inhibitor therapy could benefit 
from an alternative treatment with REGN3918. These patients discontinued prior complement 
inhibitor therapy for a number of reasons, and the fact that they have active PNH is an indication 
for reinitiating anti-C5 therapy unless the patient was refractory to complement inhibitory 
therapy, with the exception of eculizumab-refractory patients due to the C5 variant R885H/C.  
3.2.1.2. 
Rationale for the Co-Primary Endpoints 
The choice of a co-primary endpoint of LDH reduction and transfusion avoidance combines the 
accepted objective laboratory measure of control of intravascular hemolysis with a clinical 
measure of reduced disease activity: transfusion avoidance. Additionally, these measures have 
several important precedents and disease-specific rationale for their use as co-primary endpoints. 
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 6-8 x ULN (Roth, 2018). Upon treatment with anti-C5 antibody, 
LDH levels fall rapidly in all patients with the clinical goal of achieving an LDH of ≤1.5 x ULN.  
An LDH of 1.5 x ULN is a clinically meaningful threshold for disease activity: greater than 
1.5 x ULN, along with related clinical symptoms, is considered as an indication for treatment 
with eculizumab (Sahin, 2016) (Soliris®, 2019). Although not included as an endpoint in the 
efficacy section of the US Prescribing Information (USPI), reductions in LDH below the 
1.5 x ULN threshold with eculizumab therapy have been shown to be correlated with 
improvement in patient’s symptoms, quality of life measures, and transfusion requirements 
(Brodsky, 2008). Furthermore, in the ravulizumab treatment study in patients with PNH who are 
naive to complement inhibitor therapy (ravulizumab vs eculizumab) (Roth, 2018), the mean 
LDH at baseline was >6 x ULN and was reduced by >76% to a mean LDH between 1.0 to 
1.3 x ULN at each timepoint from day 29 through day 183 of the study.  
Transfusion avoidance is utilized in combination with LDH reduction as co-primary endpoints 
because transfusion is a clinical measure disease activity. In the eculizumab pivotal studies of 
patients with PNH who were treatment-naive, TRIUMPH (Sahin, 2016) and SHEPHERD 
(Roth, 2018), 0% of patients were transfusion-independent at enrollment, with 51% and 56% 
achieving transfusion avoidance during the studies, respectively. Similarly, the more recent study 
evaluating ravulizumab vs. eculizumab in PNH naive patients reported 18% and 17%, 
respectively, transfusion independence in the year prior to the study with 73.6% and 66.1%, 
respectively, transfusion avoidance through week 26. A predefined algorithm for transfusion 
allows for standardization in the current study and captures a clinically meaningful event related 
to complement-mediated intravascular hemolysis. 
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3.2.2. 
Rationale for Key Secondary 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. In this study, breakthrough hemolysis is a key secondary 
endpoint, defined by the measurement of LDH ≥ 2 x ULN concomitant with associated signs or 
symptoms at any time subsequent to an initial achievement of disease control (ie, 
LDH ≤ 1.5 x ULN) (Roth, 2018) as determined by the investigator. 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.  
In addition to the co-primary endpoint of the proportion of patients reaching an 
LDH ≤ 1.5 x ULN, 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 x ULN), LDH will be 
reported using change and percent change from baseline. 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. 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. 
3.2.3. 
Rationale for Dose Selection  
A single loading dose of REGN3918 30 mg/kg IV on day 1, then 800 mg SC once weekly (QW), 
has been initially selected based on safety and pharmacokinetic (PK)/pharmacodynamic (PD) 
data from the first-in-human (FIH) study R3918-HV-1659 in healthy volunteers, as well as 
toxicology data in cynomolgus monkeys. Total complement hemolytic activity assay (CH50) 
was used as the principal PD marker and total C5 concentration in plasma was used as a 
secondary PD marker (ie, Section 1.2).  
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Descriptive and model-based PK/PD analyses were performed to facilitate dose selection for the 
current study. These analyses indicate that on average, a minimum concentration of 100 mg/L 
REGN3918 is required to maximally suppress C5 activity across the treated population. The 
dosing regimen was selected to achieve higher concentrations than this for three reasons: 
 To ensure that all patients achieve this threshold in spite of uncertainty in the 
population PK/PD model and variability in PK and response among patients  
 To ensure that the REGN3918 serum concentration remains above this threshold 
despite any increases in C5 production, which may occur during intercurrent 
illnesses, such as infections 
 A single dose of 30 mg/kg IV was well tolerated in study R3918-HV-1659. 
The loading dose of 30 mg/kg IV will help to quickly achieve the steady-state trough 
concentration required for sustained maximal CH50 inhibition. 
At the proposed ≤800 mg SC QW regimen, the steady-state weekly area under the curve (AUC) 
(AUCtau) in patients is predicted to be well below the cumulative AUC observed in monkeys at 
NOAEL dose. Also, it is expected that the peak concentration (Cmax) in this study will not exceed 
that in the FIH study. Therefore, the proposed dose is expected to be tolerated.  
 
 
 
 
.  
3.3. 
 Risk-Benefit  
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 subcutaneous (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 (Hillmen, 2013) (Soliris®, 2019). 
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 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 7.4.1) will sufficiently mitigate the risk of single 
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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 7.4.2). 
Recently, serious infections with Neisseria species (other than N. meningitidis), including 
disseminated gonococcal infections, have been reported during eculizumab treatment 
(Soliris®, 2019). Counseling about Neisseria gonorrhea prevention, testing, and treatment is to be 
performed in accordance with local practice/national guidelines (see Section 7.8). 
A risk-benefit statement for REGN3918 is provided in the Investigator’s Brochure. 
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4. 
STUDY VARIABLES  
4.1. 
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. 
4.2. 
Endpoints 
4.2.1. 
Primary Endpoints 
The co-primary endpoints are: 
 The proportion of patients achieving adequate control of their intravascular hemolysis, 
defined as LDH ≤ 1.5 x ULN at every scheduled time point between week 4 and 
week 26, inclusive 
 The proportion of patients achieving transfusion avoidance defined as no post-baseline 
transfusion of RBCs per protocol through week 26 
4.2.2. 
Secondary Endpoints 
The secondary endpoints are: 
 The rate of breakthrough hemolysis through week 26, defined as the measurement of 
LDH ≥ 2 x ULN concomitant with associated signs or symptoms at any time subsequent 
to an initial achievement of disease control (ie, LDH ≤ 1.5 x ULN)  
 The proportion of patients achieving normalization of their intravascular hemolysis, 
defined as LDH ≤ 1.0 x ULN at every scheduled time point between week 4 through 
week 26, inclusive 
 Time to first LDH ≤ 1.5 x ULN 
 Percentage of days with LDH ≤ 1.5 x ULN between week 4 and week 26, inclusive. 
 Change and percent change in LDH levels from baseline to week 26 
 The rate and number of units of transfusion with RBCs through week 26  
 Change in RBC hemoglobin levels from baseline to week 26 
 Change in free hemoglobin levels from baseline to week 26 
 Change and percent change in CH50 from baseline to week 26. 
 Change in patient-reported outcomes (FACIT-Fatigue, European Organization for 
Research and Treatment of Cancer [EORTC]-QLQ-30, and EQ-5D-3L) from baseline to 
week 26  
 Incidence and severity of treatment-emergent adverse events (TEAEs) and other safety 
variables through week 26 
 Concentrations of total REGN3918 in serum assessed throughout the study 
 Incidence of treatment-emergent anti-drug antibodies (ADA) to REGN3918 in patients 
over time  
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4.2.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
 Incidence of MAVE through week 26 
 Change in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline to week 26 
 Treatment satisfaction as measured by the Treatment Satisfaction Questionnaire for 
Medication (TSQM) at week 26 
 Change in PNH symptoms as measured by the de novo PNH symptom-specific 
questionnaire at week 26 
 Change in haptoglobin from baseline to week 26 
 Change in bilirubin from baseline to week 26 
 Change in reticulocyte count from baseline to week 26 
 Change and percent change in alternative pathway hemolytic activity assay (AH50) from 
baseline to week 26 
 Change in Total C5 from baseline to week 26 
 Change in PNH erythrocytes and granulocytes from baseline to week 26 
 Change in metrics recorded by wearable activity tracker through week 12 in a subset of 
patients at participating sites. 
4.3. 
Pharmacokinetic Variables 
The PK variable is the concentration of total REGN3918 at each time point. The sampling time 
points are specified in Table 1. 
4.4. 
Immunogenicity Variables 
The immunogenicity variables are 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.   
4.5. 
Exploratory Biomarker Variables 
Exploratory variables may include, but are not limited to, the following: 
 Markers for renal injury, eg, clusterin (CLU), Cystatin-C (CysC), Kidney Injury 
Molecule-1 (KIM-1), Nacetyl-beta-D-glucosaminidase (NAG), Neutrophil 
Gelatinase-Associated Lipocalin (NGAL), and osteopontin (OPN) 
 Markers for pulmonary arterial hypertension, eg, NT-proBNP 
 Markers of thrombosis (D-dimer, N-terminal prothrombin fragments [F1+2], tissue 
Factor Pathway Inhibitor (TFPI), and inflammation (interleukin 6 [IL-6]) 
 Additional exploratory biomarkers (PD, predictive, and prognostic) potentially related to 
REGN3918 treatment exposure, clinical activity, or underlying disease may be 
investigated 
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5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This is an open-label, single arm, 26-week treatment study in patients with confirmed diagnosis 
of PNH and active signs and symptoms who either are complement inhibitor-naive or have 
received prior treatment with a complement inhibitor, but not within 6 months prior to screening 
visit.  
Patients will be given a single loading dose of REGN3918 30 mg/kg IV on day 1, then a dose no 
greater than 800 mg SC QW (± 1 day) over the treatment period.  The weekly subcutaneous dose 
is 800 mg SC QW (±1 day) for the initial cohort A patients. 
The study consists of a screening period (up to 4 weeks) followed by a 26-week treatment period 
(from week 0 to week 25), and an end-of-study visit one week after the last study drug 
administration (at week 26). After completion of the 26-week treatment period, patients may 
enroll into a separate open-label extension (OLE) study, which will extend treatment with 
REGN3918 for an additional 2 years, with the possibility of continuation for suitable patients 
(Section 7.5).  Patients who discontinue treatment (including those who decline enrollment into 
the optional OLE study) will have a minimum of a 21-week follow-up period (Section 8.1.2). 
As part of risk mitigation for this study, patients should receive updated meningococcal 
vaccination (Section 7.4.1), and are recommended to receive daily oral antibiotic prophylaxis 
(Section 7.4.2) and counseling regarding potential risk of Neisseria gonorrhea (Section 7.8), as 
applicable.  In addition, blood transfusions should proceed according to the algorithm in 
Section 7.3.  Breakthrough hemolysis is defined in Section 3.2.2.   
5.1.1. 
Description of Study Cohorts  
In this study, there will be two cohorts, one for dose confirmation (cohort A) and one for dose 
expansion (cohort B). Dose confirmation will be made at the interim analysis (Section 5.2). The 
inclusion and exclusion criteria and schedule of events are the same for cohort A and cohort B. 
During the assessment of data from cohort A, recruitment into the study will continue, with 
patients recruited being assigned subsequently as follows: If a decision is made to expand 
cohort A, they will be assigned to cohort A. If a decision is made to progress to cohort B, they 
will be assigned to cohort B. 
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Figure 1: 
Study Flow Diagram  
 
Screening
Day -28
Week 0
Day 1
Week 8
Week 25*
Week 26
EOS
IV Loading
Dose
Weekly SC 
Doses
6 to 12 patients:
Efficacy and safety evaluation 
through week 8 of treatment
Cohort A
N=6 to 12
Screening
Day -28
Week 0
Day 1
Week 8
Week 25*
Week 26
EOS
IV Loading
Dose
Weekly SC 
Doses
Cohort B
N=24 to 30
Initial evaluation of safety and 
efficacy data in cohort A
 
EOS=end of study; IV=intravenous; SC=subcutaneous 
* Total treatment duration is 26 weeks, from first dose at week 0 to last dose at week 25. Data analysis occurs 
one week after the last dose of study drug, at week 26. 
At the time of the decision, other relevant available data may be considered as part of the 
decision-making process, including clinical data, REGN3918 PK (as available), CH50, total C5, 
the LDH level achieved in those not achieving ≤ 1.5 x ULN, and safety. 
The decision to progress from cohort A to cohort B will be made by the Sponsor in conjunction 
with the global principal investigator based on the achievement of LDH reduction 
to ≤ 1.5 x ULN and safety at week 8, as follows: 
 If all 6 out of 6 cohort A patients achieve an LDH ≤ 1.5 x ULN at week 8 and the 
dosing regimen is considered well tolerated, then either the dose regimen will be 
confirmed and the study will progress to cohort B, or the dosing regimen will be 
altered, with a lower dose and/or longer dosing interval being tested in an expanded 
cohort A (up to a further 6 subjects). These revisions would not be considered 
substantial and therefore would not require a formal protocol amendment. 
 If one or more patients fails to achieve LDH ≤ 1.5 x ULN at week 8, then after 
consideration of all data (including clinical and safety data, REGN3918 PK, CH50, 
total C5, baseline LDH, and the LDH level achieved), a decision will be made to 
either:  
 Confirm the dosing regimen and progress to cohort B, or  
 Continue with the selected dosing regimen and expand cohort A up to a maximum 
of 12 patients, or  
 Increase dose and/or reduce dose interval and re-assess cohort A. This option will 
require a substantial protocol amendment. 
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After the first administration of REGN3918 at the study site, subsequent administrations may 
either be continued at the clinical site, or by the site personnel or another healthcare professional 
at patient’s home (if possible), or self-administered/administered by the patient or designated 
person, respectively.  
5.1.2. 
 End of Study Definition 
At a study level, the end of study is defined as the last visit of the last patient. 
5.2. 
Planned Interim Analysis  
There will not be a formal interim analysis of efficacy data.  
There will be an interim analysis of the data from cohort A at week 8, the purpose of which is the 
confirmation of the adequacy of the selected dose regimen (Section 5.1.1).  
The interim analysis will be performed by a team from the Sponsor consisting of those from the 
following functions: Sample Management, Bioanalytical Sciences, Clinical Pharmacology and 
Quantitative Pharmacology, Regeneron Senior Physicians, Program Director, Precision 
Medicine, and Biostatistics.  
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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 30 to 42 adults (men and women) are planned to be enrolled in 2 cohorts: 
 Cohort A: 6 to 12 patients 
 Cohort B: Approximately 24 to 30 patients  
This study will be conducted at multiple global sites.  
6.2. 
Study Population  
The study population will consist of adult male and female patients with confirmed diagnosis of 
PNH and active signs and symptoms who either are complement inhibitor naive or have received 
prior treatment with a complement inhibitor, but not within 6 months prior to screening visit. 
Active signs and symptoms are defined as: The presence of PNH-related signs or symptoms in 
the 3 months prior to screening or having received at least one RBC transfusion within 3 months 
of screening, along with LDH ≥ 2 x ULN. 
6.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female ≥ 18 years of age or legal age of majority at screening, whichever is 
greater 
2. Diagnosis of PNH confirmed by high-sensitivity flow cytometry  
3. PNH granulocytes (denoted as polymorphonuclear [PMN]) > 10% at screening visit 
4. Active disease, as defined by the presence of 1 or more PNH-related signs or symptoms 
(eg, fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia 
[hemoglobin <10 g/dL], history of a MAVE [including thrombosis], dysphagia, or 
erectile dysfunction) or history of RBC transfusion due to PNH within 3 months of 
screening 
5. LDH level ≥ 2 × ULN at screening visit 
6. Willing and able to comply with clinic visits and study-related procedures 
7. Provide informed consent signed by study patient  
8. Able to understand and complete study-related questionnaires 
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6.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Prior treatment with a complement inhibitor either within 6 months prior to screening 
visit or at any time where the patient was refractory to complement inhibitor therapy, in 
the opinion of the investigator (with the exception of eculizumab refractory patients due 
to the C5 variant R885H/C) 
2. History of bone marrow transplantation 
3. Body weight < 40 kilograms at screening visit 
4. Planned modification (initiation, discontinuation, or dose / dosing interval change) to the 
following background concomitant medications, as applicable, during screening and 
treatment periods: erythropoietin, immunosuppressive drugs, corticosteroids, 
anti-thrombotic agents, anticoagulants, iron supplements, and folic acid 
5. Peripheral blood absolute neutrophil count (ANC) <500/μL [<1.0 x 109/L] or peripheral 
blood platelet count <50,000/μL 
6. No documented meningococcal vaccination within 3 years prior to screening and patient 
unwillingness to undergo vaccination during the study 
7. Documented history of systemic fungal disease or unresolved tuberculosis, or evidence of 
active or latent tuberculosis infection (LTBI) during screening period.  Assessment for 
active TB and LTBI should accord with local practice or guidelines, including those 
pertaining to risk assessment, and the use of tuberculin skin test or T-cell interferon-
gamma release assay 
8. Any contraindication for receiving Neisseria meningitidis vaccination and antibiotic 
prophylaxis therapy as recommended in the study 
9. Any active, ongoing infection within 2 weeks of screening or during the screening period 
10. A recent infection requiring ongoing systemic treatment with antibiotics, antivirals, or 
antifungals within 2 weeks of screening or during the screening period  
11. Immunization with a live-attenuated vaccine 1 month prior to REGN3918 administration 
12. Known hereditary complement deficiency 
13. Documented history of active, ongoing systemic autoimmune diseases 
14. Documented history of liver cirrhosis, or patients with liver disease unrelated to PNH 
with ALT or AST greater than 3× ULN at the screening visit 
15. Patients with an eGFR of < 30 mL/min/1.73m2 (according to Chronic Kidney 
Disease - Epidemiology Collaboration equation 2009) at screening visit 
16. Recent, unstable medical conditions, excluding PNH and PNH-related complications, 
within the past 3 months prior to screening visit (eg, myocardial infarction, congestive 
heart failure with New York Heart Association Class ≥ III, serious uncontrolled cardiac 
arrhythmia, cerebrovascular accident, active gastrointestinal bleed) 
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17. Anticipated need for major surgery during the study 
18. Coexisting, chronic anemia unrelated to PNH  
19. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer 
20. Participation in another interventional clinical study or use of any experimental therapy 
within 30 days before screening visit or within 5 half-lives of that investigational product, 
whichever is greater, with the exception of complement inhibitors (see Section 6.2.1) 
21. Known sensitivity to doxycycline or to any of the components of the REGN3918 
formulation and drug product 
22. History of significant multiple and/or severe allergies (including latex gloves) or has had 
an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs 
23. Any clinically significant abnormality identified at the time of screening that in the 
judgment of the Investigator or any sub-Investigator would preclude safe completion of 
the study or constrain endpoints assessment such as major systemic diseases, or patients 
with short life expectancy 
24. Considered by the Investigator or any sub-Investigator as inappropriate for this study for 
any reason, eg: 
 Deemed unable to meet specific protocol requirements, such as scheduled visits 
 Deemed unable to tolerate long-term injections as per the patient, the investigator, 
sub-Investigator, pharmacist, study coordinator, other study staff, or relative thereof 
directly involved in the conduct of the protocol, etc. 
 Presence of any other conditions (eg, geographic, social, etc), actual or anticipated, 
that the investigator feels would restrict or limit the patient’s participation for the 
duration of the study 
25. Women who are pregnant, breastfeeding, or who have a positive pregnancy test at 
screening visit or day 1 
26. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities 
27. Pregnant or breastfeeding women 
28. 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 (IUD); intrauterine hormone-releasing system (IUS) 
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c. bilateral tubal ligation 
d. vasectomized partner  
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 subject. 
‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) 
are not acceptable methods of contraception. Female condom and male condom 
should not be used together.  
29. Known chronic infection with hepatitis B or C, defined as a testing history showing a 
currently positive status for hepatitis B surface antigen (HBsAg), hepatitis B e antigen 
(HBeAg), hepatitis B virus DNA, or hepatitis C virus RNA (HCV RNA). 
6.3. 
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 8.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.6.1. 
6.4. 
Replacement of Patients  
Patients prematurely withdrawn from the study/study drug in cohort A can be replaced, if 
needed, to ensure an adequate number of evaluable patients (ie, completing week 8 procedures). 
The Medical/Study Director, in cooperation with the Study Biostatistician, will decide whether 
or not to replace a withdrawn patient.  There will be a maximum of 6 patients that may be 
replaced. 
Patients prematurely withdrawn from the study/study drug in cohort B may not be replaced. 
Enrollment procedures for replacement of patients are provided in Section 7.10.1.  
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7. 
STUDY TREATMENTS  
7.1. 
Investigational Treatments 
REGN3918 drug product will be provided in a sterile, single-use glass vial for either IV or SC 
administration and will be supplied by the sponsor. 
IVRS/IWRS will be contacted according to Table 1.  
Detailed information about the drug product and dose preparation is provided in the pharmacy 
manual.  
7.2. 
Drug Administration 
Patients will be given a single loading dose of REGN3918 30 mg/kg IV on day 1, then a dose no 
greater than 800 mg SC QW (±1 day) over the treatment period.  The weekly subcutaneous dose 
is 800 mg SC QW (±1 day) for the initial cohort A patients. 
For cohort A, after the IV loading dose administration of REGN3918 at the study site, 
subsequent SC administrations may either be continued at the clinical site by the site personnel 
or at the patient’s home by another healthcare professional. After week 8, self-administration/ 
administration by the patient or designated person may occur.  
For cohort B, subsequent administrations may be continued at the clinic site, at the patient’s 
home by another healthcare professional, or by the patient/designated person. 
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 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 clinical site personnel or visiting healthcare professional. Once this observation is 
considered satisfactory, then the study drug can be subsequently administered independently by 
patient/designated person for the remainder of the study.  
In addition, a patient diary will be provided prior to initiation of self-administration (ie, week 8 
for cohort A and week 4 for cohort B). 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 study drug administration is provided in the pharmacy manual.  
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7.3. 
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. 
7.4. 
Pretreatments  
Enrolled patients will require evidence of meningococcal immunization or administration of 
vaccination during the screening period and oral antibiotics are recommended during the 
treatment period, according to local practice. 
7.4.1. 
Meningococcal Vaccinations 
Enrolled patients will require immunization with meningococcal vaccinations. Administration of 
vaccination should occur preferably at least 2 weeks prior to initiation of REGN3918, or at 
another time point according to local practice or national guidelines. If available, it is suggested 
that patients undergo vaccination for serotypes A, C, Y, W and serotype B. Patients who have 
had previous documented vaccination for meningococcus will 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. 
7.4.2. 
Oral Antibiotics 
It is recommended that daily oral antibiotic prophylaxis commence on the day of first dosing, 
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 8.1.2). 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. 
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7.5. 
Post-Study Treatment Access 
All patients who complete the study without discontinuing treatment due to an adverse event 
(AE) thought to be related to the study drug will be offered to enroll in another study, a 
long-term OLE clinical trial with REGN3918.  
The duration of the OLE is 2 years, with the option of extending treatment beyond the OLE 
treatment period for suitable patients. The transition of treatment with REGN3918 from the 
current study to the OLE is planned to be uninterrupted, whereby the day 1 visit of the OLE will 
correspond to the week 26 visit in the current study.   
7.6. 
Dose Modification and Study Treatment Discontinuation Rules 
7.6.1. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits, per Section 8.1.2. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 8.1.2. 
7.6.1.1. 
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 x ULN 
or 
 ALT or AST > 5 x ULN for more than 2 weeks or 
 ALT or AST > 3 x ULN and total bilirubin > 2 x ULN (or international 
normalized ratio (INR) > 1.5) 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 
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7.6.1.2. 
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 once the Investigator will have considered according to his/her best 
medical judgment that the responsibility of the study drug in the occurrence of the concerned 
event was unlikely. 
7.7. 
Management of Acute Reactions  
7.7.1. 
Acute Intravenous Infusion Reactions 
Patients should be observed for 30 minutes after the infusion. 
Emergency equipment and medication for the treatment of infusion reactions must be available 
for immediate use. All infusion reactions must be reported as AEs (as defined in Section 9.2.4) 
and graded using the grading scales as instructed in Section 9.2.5. 
7.7.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
 Cough 
 Rigors/chills 
 Rash, pruritus (itching) 
 Urticaria (hives, welts, wheals) 
 Diaphoresis (sweating) 
 Hypotension 
 Dyspnea (shortness of breath) 
 Vomiting 
 Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of 
the original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
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7.7.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
 Anaphylaxis* 
 Laryngeal/pharyngeal edema 
 Severe bronchospasm 
 Chest pain 
 Seizure 
 Severe hypotension 
 Other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis, etc) 
 Any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING: 
 Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
 Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
7.7.2. 
Acute Injection Reactions 
7.7.2.1. 
Systemic Injection Reactions 
Patients should be observed for 30 minutes after the first SC injection.  
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 and graded using 
the grading scales as instructed in Section 9.2.5. 
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.  
7.7.2.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 9.2.5. 
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7.8. 
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. Patients 
may be re-screened if they meet the exclusion criteria “A recent infection requiring ongoing 
systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks of screening or 
during the screening period” (Section 6.2.2) with successful resolution of the infection. 
General preventive measures include abstinence and use of a condom. Additional preventive 
measures should be considered based on local practice or national guidelines.  
7.9. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
7.10. 
Measures to Reduce Bias 
7.10.1. 
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. 
Recruitment will be continuous, and cohort assignment to cohort A or B after the completion of 
week 8 procedures for the first 6 patients will be based on analysis of the available data. For 
patients recruited after the first 6 patients’ week 8 data are available, and before a decision on 
progression to cohort B has been made, they will be categorized for analysis as follows:  
 In the event that a decision is made to progress to cohort B, they will be considered as 
part of cohort B.  
 In the event that a decision is made to expand cohort A, they will be considered as 
part of cohort A.  
7.10.2. 
Blinding 
This is an open-label study. 
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7.11. 
Treatment Logistics and Accountability 
7.11.1. 
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. Carton box and vial 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 at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
7.11.2. 
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.  
7.11.3. 
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. 
7.11.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.12. 
Concomitant Medications  
Any treatment administered from the time of informed consent to the end of final study visit will 
be considered concomitant medication. This includes medications that were started before the 
study and are ongoing during the study. 
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7.12.1. 
Prohibited Medications  
The following medications are prohibited, with the exception of those listed in Section 7.12.2, 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. 
7.12.2. 
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 7.4.1  
 Oral antibiotic prophylaxis, as described in Section 7.4.2  
 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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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
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: 
 PRO assessments should be completed prior to all other assessments and/or 
discussions about patient’s health 
 Electrocardiograms (ECGs) should be performed prior to blood draws and dosing 
 PK/ADA sampling should be performed as soon as possible after an ECG and prior to 
study drug administration 
 Collect safety and efficacy blood samples pre-dose prior to biomarker samples 
Patients will be provided the following:  
 Device for completing study questionnaires and other patient-reported assessments 
 Patient diary  
A patient diary will be provided to patients who self-administer the study drug to 
collect relevant information 
 Wearable device (see Section 8.2.7.2) in a subset of patients at participating sites 
 Patient safety card for Neisseria meningitidis (see Section 7.4.1) 
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Table 1: 
Schedule of Events  
Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Visit Location: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Visit 
X 
X X X 
X 
X 
X 
 
 
 
X 
 
X 
Mandatory clinic visit 
Clinic, Home Healthcare, 
or Phone Call Visit1 
 
 
 
 
 
 
 
X 
X2 
X 
 
X2 
 
Cohort A: Clinic visit mandatory for 
first visits up to and including week 8. 
Section 7.2. 
Screening:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Including optional sub-studies 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
May re-screen once, as described in 
Section 8.2.1  
Medical History  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
Prior Concomitant 
Medications    
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
Historical Lab Parameters 
for Hemolysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
If possible, 2 yr history. Section 8.2.1 
Neisseria Meningitidis 
Vaccination History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
TB history and assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1  
Testing history for 
hepatitis B and C 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Testing may be performed by the central 
lab as needed per local practice. 
Section 8.2.1 
Risk assessment for 
Neisseria gonorrhea 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 7.8 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
Enrollment  
 
X 
 
 
 
 
 
 
 
 
 
 
 
  
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Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
R3918 IV Administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Patients should be observed for at least 
30 minutes post-infusion. Section 7.2 
R3918 SC Administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cohort A: Only W9-25 may be 
self-administered. Section 7.2  
Oral Antibiotics  
 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Per local practice. Section 7.4.2  
Meningococcal Vaccine 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Per local practice. Section 7.4.1  
IVRS/IWRS Contact 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Patient Diary 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
For self-administration. Section 7.2 
Efficacy (central):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum LDH  
X 
X X X 
X 
X 
X 
 
X 
 
X 
X 
X 
Samples not required if blood chem. 
samples are taken. Section 8.2.3.1 
Transfusion Data 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.3.2  
Complement Hemolytic 
Assay (serum CH50)    
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
Day 1, pre-dose and end of the IV 
infusion. Pre-dose at all other visits. 
Section 8.2.3.3  
FACIT-Fatigue 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Section 8.2.3.6 
EORTC-QLQ-30 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Section 8.2.3.6 
EQ-5D-3L 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Section 8.2.3.6 
PGIS  
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 Section 8.2.3.6 
PGIC  
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 Section 8.2.3.6 
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Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Vital Signs 
X 
X X X 
X 
X 
X 
 
X 
 
 
 
X 
 Section 8.2.4.1  
Physical Examination 
X 
X X X 
 
 
X 
 
 
 
 
 
X 
 Section 8.2.4.2  
Body Weight 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 Section 8.2.4.2  
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 Section 8.2.4.3  
Adverse Events 
< -------------------------------------------------------x ----------------------------------------------------------- > 
If breakthrough hemolysis is suspected, 
blood samples will be collected for 
LDH and other assessments. Blood may 
also be collected in the event of drug 
hypersensitivity. Section 8.1.3 
Procedures for AEs, Section 9.  
Concomitant Meds & Tx 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Section 7.12  
Patient Safety Card  
 
X 
 
 
 
 
 
 
 
 
 
 
 
For Neisseria meningitidis  
Laboratory Testing: (Central): 
 
 
 
 
 
 
 
 
 
 
 
 
  
Hematology 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Includes RBC and free hemoglobin  
See Section 8.2.4.4 for analytes 
Blood Chemistry  
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Includes serum lactate dehydrogenase  
See Section 8.2.4.4 for analytes 
Pregnancy Test 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Serum at screening 
Urine at all other visits 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 See Section 8.2.4.4 for analytes 
C-Reactive Protein  
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
 
Direct Antiglobulin Test  
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
DAT or Coombs 
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Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
PK and ADA Samples: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
PK Sample  
 
X X X 
 
 
X 
 
 
 
 
 
X 
Day 1, sample pre-dose and end of the 
IV infusion. Pre-dose at all other visits. 
Section 8.2.5  
ADA Sample   
 
X 
 
 
 
 
X (W12) 
 
 
 
 
 
X 
Pre-dose. Section 8.2.6  
Exploratory PD/Biomarkers: 
 
 
 
 
 
 
 
 
Pre-dose, unless otherwise specified 
Haptoglobin 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Section 8.2.8  
Reticulocyte Count 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Complement Hemolytic 
Assay (serum AH50)   
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
Day 1, sample pre-dose and end of the 
IV infusion. Pre-dose at all other visits. 
Total Complement Levels 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
  
Total C5 (plasma) 
X 
X X 
 
 
 
X 
 
 
 
 
 
X 
Day 1, sample pre-dose and end of the 
IV infusion. Pre-dose at all other visits. 
C5a (plasma and urine) 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
sC5b-9 (plasma) 
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
 
PNH Erythrocyte Cells 
X 
X 
 
 
 
 
X (W8, 
W16) 
 
 
 
 
 
X 
 
PNH Granulocyte Cells 
X 
X 
 
 
 
 
X (W8, 
W16) 
 
 
 
 
 
X 
 
NT-proBNP 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Biomarkers of Thrombosis 
and Inflammation 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
May include D-dimer, F1+2, TFPI, and 
IL-6 
Renal Injury Markers 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
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Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Optional Samples: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum/Plasma 
(optional) 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
As permitted by local regulatory 
policies. Section 8.2.9  
Whole Blood for DNA 
Isolation (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.9.1  
Whole Blood for RNA 
Isolation (optional) 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
Section 8.2.9.1  
Clinical Outcome Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
  
PNH Symptom-Specific 
Questionnaire    
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
To be completed daily by patient. 
Patient will complete daily PNH 
Symptom-Specific Questionnaire on a 
device at least 7 days prior to day 1 
visit. Section 8.2.7.1  
Cohort A: Optional 
Cohort B: Mandatory when available 
TSQM 
 
 
 
 
 
 
X (W4, 
W16) 
 
 
 
 
 
X 
Section 8.2.7.1  
Cohort A: Optional  
Cohort B: Mandatory when available 
Wearable Device 
 
< ------------------------------ W0 to W12 ------------------------------------- > 
 
 
 
Should be worn according to the 
schedule set out in the study manual 
Section 8.2.7.2  
 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. Clinic visit may or may not be needed for these visits (see Section 7.2). In lieu of a clinic 
visit, any additional study procedures required for this visit may also be done by a 
healthcare professional at the patient’s home or, if the patient is self-administering the 
study drug, via a phone call from the site to the patient.  
2. If the patient is self-administering the study drug, a health care professional will visit the 
patient’s home to draw the scheduled blood samples.    
8.1.2. 
Premature Discontinuation and Follow-up 
Patients who discontinue treatment and do not withdraw from study should continue all study 
visits as scheduled. If the week 26 visit does not include at least 21 weeks of follow-up, then 
patient should continue with monthly site visits until 21 weeks after last dose of IMP. Each of 
these monthly visits will consist of the safety assessments, including laboratory tests 
(Section 8.2.4.4), listed for week 26 visit in Table 1. 
Patients who discontinue treatment and study should be requested to have an early termination 
visit consisting of assessments listed for week 26 visit (Table 1). If the patient agrees to a 
follow-up safety phone visit, then a follow-up phone call will be scheduled for 21 weeks after 
last IMP dose. 
Patients who complete the study treatment and study but do not want to enroll in the OLE 
(Section 7.5) should have monthly visits until 21 weeks after last dose of IMP. These visits will 
consist of the safety assessments, including laboratory tests (Section 8.2.4.4) listed for week 26 
visit in Table 1. 
8.1.3. 
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.  
In case of suspected breakthrough hemolysis as defined in Section 3.2.2, unscheduled blood 
samples (at either scheduled or unscheduled site visits) will be collected for the assessment of 
LDH, drug concentration (PK), ADA, total C5, and CH50 at or near the time of the event. 
In case of suspected systemic hypersensitivity and anaphylaxis, unscheduled blood samples may 
be collected for the assessment of drug concentration and ADA at or near the time of the event. 
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8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  
 Medical history, including history of transfusions for the past 12 months, 
breakthrough hemolysis for the past 12 months, and MAVE 
 Demographics 
 Prior concomitant medications (see Section 7.12) 
 Historical laboratory parameters for measurement of hemolysis 
If possible, obtain parameters (eg, LDH, hemoglobin, free hemoglobin, PNH 
granulocytes, and PNH erythrocytes) for the past 2 years from the patient’s medical 
history. 
 Neisseria meningitidis vaccination history (see Section 7.4.1)  
 Height 
 Risk assessment for Neisseria gonorrhea (see Section 7.8) 
 Testing history for hepatitis B and C. Testing may be performed by the central lab if 
needed per local practice 
 Tuberculosis history and assessment. Screening by tuberculin skin test or T-cell 
interferon-gamma release assay may be performed according to local practice or 
guidelines at the discretion of the investigator 
For screening purposes, one retest of laboratory testing is permitted for non-clinically significant 
abnormality. At the discretion of the investigator, additional visits during the screening period 
may be scheduled as needed to complete screening procedures: for example, sample collection 
for laboratory re-test or 7-day baseline data collection for the PNH Symptom-Specific 
Questionnaire (Section 8.2.7.1). 
8.2.2. 
Study Drug Administration 
Study drug will be administered as described in Section 7.2. Immunization with meningococcal 
vaccines are to be performed according to local practice (Section 7.4.1). Daily oral antibiotic 
prophylaxis is recommended (Section 7.4.2). 
Compliance with study drug administration may be monitored with a patient diary according to 
Table 1. 
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8.2.3. 
Efficacy Procedures  
8.2.3.1. 
Serum Lactate Dehydrogenase  
Samples for LDH testing will be collected at visits according to Table 1.  
Serum LDH levels will the measured in a central lab. On days when Blood Chemistry is run 
(see Section 8.2.4.4), then LDH will be included in the panel which will also be run in a central 
lab.  
For patients who self-administer, samples may be drawn at home by the visiting nurse when 
scheduled on non-clinic visits. 
8.2.3.2. 
Transfusion Record Update 
Patients will be requested to provide updated information about the history of transfusions 
received 1 year prior to the time of screening. During the study, the rate and number of units of 
transfusion with RBCs will be recorded in the case report form (CRF) according to Table 1.  
Transfusions with RBCs during the study should follow the algorithm described in Section 7.3. 
The rate and number of units of transfusion with RBCs will be recorded in the CRF. Hemoglobin 
levels pre- and post-transfusion will be obtained (including local values). 
8.2.3.3. 
Total Hemolytic Complement Activity 
Samples for CH50 testing will be collected at visits according to Table 1.  
Serum CH50 levels will the measured in a central lab.  
For patients who self-administer, samples may be drawn at home by the visiting nurse when 
scheduled on non-clinic visits. 
8.2.3.4. 
Red Blood Cell Hemoglobin  
Red blood cell hemoglobin testing will be measured in the safety hematology panel 
(see Section 8.2.4.4) collected at visits according to Table 1 and will be run in a central lab. 
8.2.3.5. 
Free Hemoglobin  
Free hemoglobin testing will be measured in the safety hematology panel (see Section 8.2.4.4) 
collected at visits according to Table 1 and will be run in a central lab. 
8.2.3.6. 
Clinical Outcome Assessments 
The COAs are patient self-reported and will be completed according to Table 1. 
Clinical outcome assessments (COAs) will include the Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT-Fatigue) and 2 health-related quality of life (HRQoL) questionnaires 
(EORTC quality of life questionnaire-core 30 [QLQ-C30] and the EQ-5D-3L) and Patient Global 
Impression of Severity (PGIS)/Patient Global Impression of Change (PGIC). 
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The FACIT-Fatigue is a 13-item, self-reported PRO measure assessing an individual’s level of 
fatigue during their usual daily activities over the past week. This questionnaire is part of the 
FACIT measurement system, a compilation of questions measuring health-related QoL in 
patients with cancer and other chronic illnesses. The FACIT-Fatigue assesses the level of fatigue 
using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 
52, with higher scores indicating greater fatigue. Although the FACIT-Fatigue was originally 
developed to assess fatigue in patients with cancer, it has been used in trials evaluating the 
efficacy of eculizumab (Brodsky, 2008) (Hillmen, 2006). The FACIT-Fatigue has demonstrated 
content validity among patients with PNH (Weitz, 2013). 
The EORTC QLQ-C30 is a 30-item, generic questionnaire commonly used to assess HRQoL in 
patients with cancer (Stead, 1999) (Cocks, 2007). The EORTC QLQ-C30 assesses HRQoL 
across multiple domains, including global health status, global quality of life, functioning 
(physical, role, emotional, cognitive, and social functioning), symptom scales (fatigue, nausea 
and vomiting, pain, appetite loss), and single items (dyspnea, insomnia, constipation, diarrhea, 
sleep, financial impact). Although the EORTC-QLQ-30 was originally developed to assess 
HRQoL in patients with cancer, it has been used in trials evaluating the efficacy of eculizumab 
(Brodsky, 2008) (Hillmen, 2006). The EORTC-QLQ also has demonstrated content validity 
among patients with PNH (Weitz, 2013). 
The EQ-5D-3L is a self-administered, generic standardized health status measure, consisting of 
6 questions. The EQ-5D-3L descriptive system assesses 5 dimensions of health: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 
3-level scale: no problems, some problems, and extreme problems. The EQ visual analog scale 
component is a vertical, visual analog scale used by patients to rate their health. 
Patient Global Impression of Severity/Patient Global Impression of Change:  
Patient Global Impression of Severity consists of 3 self-administered PRO questions assessing 
the patient’s perception of the overall severity of the symptoms of their disease and/or of a 
specific symptom of their disease. At study visits, patients will be asked to rate the severity of 
their PNH symptoms on a 6-point Likert scale ranging from "I am not experiencing PNH 
symptoms" to "very severe"; the impact their PNH symptoms have on their ability to perform 
usual daily activities on a 5-point Likert scale ranging from “not at all impacted” to “extremely 
impacted"; and their overall fatigue on a 5-point Likert scale ranging from "not fatigued" to 
"extremely fatigued".  
Patient Global Impression of Change consists of 3 self-administered PRO questions assessing the 
patient’s perception of the change in overall severity of the symptoms of their disease and/or of a 
specific symptom of their disease compared to the start of the study. At key time points during 
the study, patients will be asked to rate the change in PNH symptoms, in their ability to perform 
usual daily activities, and in overall fatigue compared to before the start of the study on a 7-point 
Likert scale ranging from "much better" to "no change" to "much worse". 
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PGIS and PGIC questions are developed for this trial and allow for the interpretation of PRO 
findings and the investigation of a responder definition. The answers on the PGIS and PGIC 
items serve as “anchors” to help interpret the mean change in disease-specific PRO measures 
over time and to estimate responder definitions. This empirical anchor-based approach is the 
primary FDA-recommended approach for defining a responder and analyzing responder-based 
PRO results.  
Additional COAs (not assessed as part of efficacy) are described in Section 8.2.7. 
8.2.4. 
Safety Procedures  
8.2.4.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, and pulse, will be collected pre-dose at 
time points according to Table 1.   
Vital signs will be obtained after subject has been sitting quietly for at least approximately 
5 minutes. At the first visit, blood pressure should be measured from both arms. The arm with 
the higher diastolic pressure will be selected for measurement throughout the study.  
8.2.4.2. 
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 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. The same 
type/model of scale should be used throughout the study.  
8.2.4.3. 
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 subject 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. 
8.2.4.4. 
Laboratory Testing 
Samples for laboratory testing will be collected at visits according to Table 1.  
Hematology, chemistry (except Total C5, CH50, and AH50), 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 (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine kinase (CK) 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
 
 
*(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 (WBCs) 
 
Basophils 
Red cell indices 
 
Eosinophils 
Platelet count 
Reticulocytes 
Urinalysis 
pH 
Glucose 
Note: If macroscopy is abnormal then reflex to microscopy. 
Specific gravity 
Bilirubin 
Ketones 
Leukocytes  
Protein 
Nitrite 
 
Other Laboratory Tests 
Other laboratory tests include:  
 Pregnancy testing: serum human chorionic gonadotrophin pregnancy testing, urine 
pregnancy testing 
 C-Reactive protein 
 Direct Antiglobulin Test (DAT or Coombs) 
 PD and Exploratory Biomarker Procedures (Section 8.2.8) 
 Unscheduled blood collection for suspected breakthrough hemolysis events or drug 
hypersensitivity events (Section 8.1.3) 
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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 9.1. 
8.2.5. 
Drug Concentration and Measurements 
Samples for drug concentration will be collected at visits listed in Table 1 for PK analysis. The 
exact sampling time must be recorded, as allowed per local regulation. 
Any unused samples may be used for exploratory research, as allowed per local regulation. 
8.2.6. 
Anti-Drug Antibody Measurements and Samples 
Blood samples for ADA assessment 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 research, as allowed per local regulation. 
8.2.7. 
Clinical Outcome Assessments 
The following additional patient-reported outcome assessments will be collected according to 
time points listed in Table 1.  
8.2.7.1. 
Patient-Reported Outcome Assessments 
A de novo PNH symptom-specific questionnaire will collect daily information on PNH 
symptoms including: fatigue, shortness of breath, muscle weakness, headache, abdominal pain, 
pain in back/legs, chest discomfort, difficulty sleeping, difficulty thinking clearly, and difficulty 
swallowing. Patient will complete daily PNH Symptom-Specific Questionnaire on a device at 
least 7 days prior to day 1 visit. The site has the option of giving the device to the patient at the 
screening visit or at an interim visit between screening visit and at least 7 days prior to day 1. 
The instrument was developed by conducting a literature review, consulting with clinical expert 
input, and through patient interviews assessing comprehensiveness of symptoms collected and 
the patient’s ability to read, understand, and respond to the questionnaire. The questionnaire was 
developed in accordance with regulatory guidelines (FDA, 2009) and scientific best practices 
(Patrick, 2011). 
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Treatment Satisfaction Questionnaire for Medication is a generic measure that assesses patients’ 
satisfaction with their medication (Atkinson, 2004) (Atkinson, 2005). The TSQM is an 
11-question, self-administered, patient-reported outcome measure which assesses 3 domains of 
satisfaction: effectiveness (2 items), side effects (4 items), convenience (3 items), and global 
satisfaction (2 items). For each question, the patient rates their satisfaction either on a 7-point 
Likert scale (ranging from extremely dissatisfied to extremely satisfied) or a 5-point Likert scale 
(ranging from extremely dissatisfied to not dissatisfied at all) with higher scores representing 
greater satisfaction. The instrument was developed using patient input and has evidence of 
psychometric validity. 
8.2.7.2. 
Wearable Activity Tracker 
A wearable device (eg, a watch-like device on wrist, etc) for daily activity tracking will be 
provided and should be worn according to Table 1.  
Parameters may include sleep, heart rate, and activity. 
8.2.8. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Samples will be collected at time points according to Table 1. 
Biomarker measurements will be performed in specified matrix to determine effects of 
REGN3918 on relevant physiological and pathogenic processes. 
The biomarker studied will be ones believed to be relevant to the understanding of efficacy, 
pathophysiology of indication target engagement, mechanism of action and possible toxicities of 
REGN3918.  
Biomarkers studied may include but need not be limited to: 
 Parameters of intravascular hemolysis: ie, haptoglobin, reticulocyte count, and bilirubin 
 Intravascular hemolysis mediated through the alternative complement pathway: 
ie, measured by AH50 (serum), and total complement level (serum) 
 Total C5 protein (plasma) 
 Complement activation markers: ie, C5a (plasma and urine) and sC5b-9 (plasma) 
 PNH clone size: ie, PNH erythrocytes and granulocytes 
 Biomarkers of pulmonary hypertension: ie, NT-proBNP 
 NT-proBNP has been shown to be associated with increased intravascular hemolysis 
(measured by LDH) in some patients with PNH. REGN3918 is expected to reduce 
NT-proBNP significantly, similar to what has been reported for Eculizumab  
 Biomarkers of thrombosis and inflammation: ie, D-dimer, N-terminal prothrombin 
fragments (F1+2), Tissue Factor Pathway Inhibitor (TFPI), and IL-6 
 Levels of these markers were significantly elevated in PNH, including those with no 
history of clinical thrombosis. REGN3918 is expected to significantly reduce the 
levels of these markers in patients with PNH, similar to what has been reported for 
eculizumab (Helley, 2010) 
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 Urinary biomarkers of renal injury: ie, clusterin (CLU), Cystatin-C (CysC), Kidney 
Injury Molecule-1 (KIM-1), Nacetyl-beta-D-glucosaminidase (NAG), Neutrophil 
Gelatinase-Associated Lipocalin (NGAL), and osteopontin (OPN) 
 Renal diseases including acute renal failure have been reported in PNH patients 
(Ballarin, 2011). Effects of R3918 on renal injury biomarkers will be assessed in this 
study. 
The list may be altered or expanded, as it is recognized that more relevant or novel biomarkers 
may be discovered during the process of this study. 
The results of analyses performed on these samples will be presented in the CSR. 
8.2.9. 
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. 
8.2.9.1. 
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. Whole blood samples for DNA extraction 
should be collected on day 1 (predose) but can be collected at a later study visit. Whole blood 
samples for RNA extraction will be collected at time points according to Table 1. 
DNA and RNA samples will be collected for pharmacogenomics analyses. These samples will be 
single-coded as defined by the International Council for 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.  
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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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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Recording and Reporting Adverse Events 
9.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data 
collection period (see Section 9.1.2).  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 9.2.  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 9.2 for definition).   
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 9.1.4. 
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9.1.2. 
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).   
9.1.3. 
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.   
9.1.4. 
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:  
 Moderate or severe infusion reactions 
 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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9.2. 
Definitions 
9.2.1. 
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). 
9.2.2. 
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.   
9.2.3. 
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 9.1.4. 
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9.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 
2 hours (up to 24 hours) after the infusion is completed. 
9.2.5. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild: Does not interfere in a significant manner with the patient’s normal functioning level.  It 
may be an annoyance.  Prescription drugs are not ordinarily needed for relief of symptoms, but 
may be given because of personality of the patient. 
Moderate: Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
Severe: Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health.  Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild:  Mild transient reaction; infusion interruption not indicated; intervention not indicated. 
Moderate:  Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated 
for ≤24 hours. 
Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; hospitalization 
indicated for clinical sequelae; life-threatening consequences; urgent intervention indicated; 
death. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale 
(semi-colon indicates “or” within description of grade): 
Mild: Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate: Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe: Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires 
ER visit or hospitalization; necrosis or exfoliative dermatitis 
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9.2.6. 
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  
 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. 
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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. 
9.3. 
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. 
9.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, Institutional Review 
Board (IRBs)/ Ethics Committees (ECs), 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 IRB/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 IRB/EC as appropriate. 
 
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10. 
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 4. 
10.1. 
Statistical Hypothesis  
The primary objective of the study is to demonstrate a reduction in intravascular hemolysis by 
REGN3918 over 26 weeks of treatment in patients with active PNH who are treatment-naive to a 
complement inhibitor or have not recently received complement inhibitor therapy. The 
co-primary endpoints for the study are the proportion of patients achieving adequate control of 
their intravascular hemolysis, defined as LDH ≤ 1.5 x ULN at every scheduled time point 
between week 4 and week 26, inclusive, and the proportion of patients achieving transfusion 
avoidance defined as no post-baseline transfusions of RBCs per protocol. The proportions of the 
co-primary endpoints will be calculated, along with their 95% confidence intervals. 
10.2. 
Justification of Sample Size 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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10.3. 
Analysis Sets  
10.3.1. 
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 10.4.3.1 and Section 10.4.3.2).  
10.3.2. 
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. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The 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. 
10.3.4. 
Immunogenicity 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.  
ADA positive samples will be further characterized for the presence of neutralizing activity. 
The neutralizing antibody (NAb) analysis set includes all patients who received any study drug 
and who are negative in the ADA assay or with at least 1 non-missing result in the NAb assay.  
Patients who are ADA negative will be set to negative in the NAb analysis set. 
10.3.5. 
Exploratory Analysis Sets 
10.3.5.1. Exploratory Biomarker Endpoint Analysis Set 
The PD analysis sets include all subjects 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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10.3.5.2. Exploratory Clinical Outcome Assessment Analysis Set 
The COA analysis sets include all subjects who received any study drug and who had a baseline 
measurement and at least 1 non-missing COA measurement following the first dose of study 
drug. 
10.4. 
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.  
If there is no change in dosing regimen for cohort B, patients of cohort A and cohort B will be 
pooled for both safety and efficacy analysis.  If the dosing regimen is changed, cohort A and 
cohort B will be analyzed separately, and cohort B will be the primary analysis cohort. 
10.4.1. 
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 10.3.1) 
 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 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively. 
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10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
For the co-primary endpoint of the proportion of patients achieving adequate control of their 
intravascular hemolysis, defined as LDH ≤1.5 x ULN at every scheduled time point between 
week 4 and week 26, inclusive, the analysis set will consist of all FAS patients. Patients who 
have one or more of the following will be considered as not achieving adequate control of their 
intravascular hemolysis:  
 Discontinue from study treatment early 
 Have 3 consecutive missing values of the scheduled LDH measurements between 
week 4 and week 26  
 Have 50% or more missing values of the scheduled LDH measurements between 
week 4 and week 26 
 Experience breakthrough hemolysis event (as defined in the secondary endpoint) 
while on treatment through week 26 
Patients who complete study treatment, have no more than 2 consecutive missing values of the 
scheduled LDH measurements between week 4 and week 26, have fewer than 50% missing 
values of the scheduled LDH measurements between week 4 and week 26, and have no 
breakthrough hemolysis while on treatment will be evaluated based on their non-missing LDH 
measurements.   
The proportion of patients achieving adequate control of their intravascular hemolysis will be 
calculated, along with a 95% confidence interval, by approximation of a one-sample z-statistic as 
primary analysis and by exact methods as sensitivity analysis. A sensitivity analysis by multiple 
imputation of missing LDH measurements will also be performed. Multiple imputation methods 
to be applied will be detailed in the SAP.  
For the co-primary endpoint of the proportion of patients achieving transfusion avoidance, the 
analysis set will consist of all FAS patients. A transfusion will be counted only if the transfusion 
follows the predefined transfusion algorithm. A time-to-first-event analysis will be used to 
estimate the proportion of patients achieving transfusion avoidance at 26 weeks and a 95% 
confidence interval. 
Sensitivity analyses of the co-primary endpoints will also be conducted for subgroups of FAS 
patients, including all complement inhibitor-naive patients (no prior complement inhibitor 
therapy) in cohort A and cohort B, all patients in cohort B, and all complement inhibitor-naive 
patients in cohort B.  
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10.4.3.2. Secondary Efficacy Analysis 
For secondary endpoints that are defined by dichotomy of multiple measurements of a variable 
through a period of time, such as the proportion of patients achieving normalization of their 
intravascular hemolysis, defined as LDH ≤ 1.0 x ULN at every scheduled time point between 
week 4 through week 26, inclusive, the analysis set consists of all FAS patients. For this category 
of secondary endpoints, analysis (including the handling of early discontinuation and missing 
data) will follow the same approach employed for the co-primary endpoint of the proportion of 
patients achieving normalization of their intravascular hemolysis, defined as LDH ≤ 1.5 x ULN 
at every schedule time point between week 4 through week 26. 
For secondary endpoints that are defined by a change and percent change from baseline 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, such as:  
 Change in LDH levels from baseline to week 26 
 Change in RBC hemoglobin levels from baseline to week 26 
 Change in free hemoglobin levels from baseline to week 26 
 Change in patient reported outcomes (FACIT-Fatigue, EORTC-QLQ-30, and 
EQ-5D-3L) from baseline to week 26  
Means and 95% confidence intervals by a one-sample t-statistic as primary analysis will be 
reported.  The method to be used for imputing missing data for this category of secondary 
endpoints variables will be described in the SAP.  Means and 95% confidence intervals derived 
from sensitivity analysis, such as mixed-effect model for repeated measures (MMRM) analysis 
without imputation for missing data, will also be reported. 
For secondary endpoints that are defined by any occurrence of a defined event during a period, 
such as the rate of breakthrough hemolysis through week 26, the FAS will be used.  Means and 
95% confidence intervals by approximation of a one-sample z-statistic as primary analysis and 
by exact methods as sensitivity analysis will be calculated for this category of secondary 
endpoints. 
For time-to-event endpoints, such as the time to first LDH ≤ 1.5 x ULN, the analysis set will 
consist of all FAS patients. Survival analysis of data with censoring through time will be applied 
to analyze time-to-event endpoints. 
For the rate and number of units of transfusion with RBCs through week 26, the analysis set 
consists of the FAS. The rate of units of transfusion for a patient will be calculated based on the 
duration of treatment exposure of the patient.  Means and 95% confidence intervals by a one-
sample t-statistic as primary analysis will be reported. 
For the percentage of days with LDH ≤ 1.5 x ULN between week 4 and week 26, the analysis set 
will consist of all FAS patients.  Means and 95% confidence intervals by a one-sample t-statistic 
as primary analysis will be reported.  The method to be used for imputing missing data will be 
described in the SAP. 
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10.4.4. 
Safety Analysis 
10.4.4.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
 The treatment period is defined as either the first dose of study drug to last dose of 
study drug + 21 weeks or from first dose of study drug until first dose in OLE study 
(Section 7.5).  
 The posttreatment period is defined as the time after the treatment period. 
Treatment-emergent adverse events are defined as those that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the on-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 
 TEAEs by severity (according to the grading scale outlined in Section 9.2.5), 
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. 
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, and blood pressure) will be summarized by baseline and change 
from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test.  
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Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-laboratory range values. 
10.4.4.3. Treatment Exposure 
The observation period (defined as the time between the date of first study drug administration 
and the date of the end of study visit for the patient), rather than the treatment exposure, will be 
presented.  
10.4.4.4. Treatment Compliance 
Analysis of treatment compliance will be described in the SAP. 
10.4.5. 
Pharmacokinetics 
10.4.5.1. Analysis of Drug Concentration Data 
The PK endpoint is concentration of total REGN3918 in serum over time.  
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 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 (in %), minimum, Q1, median, Q3, and maximum. 
No formal statistical analysis will be performed. 
10.4.6. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response observed: 
Anti-drug antibodies response categories and titer categories that will be assessed are as follows: 
 Pre-existing immunoreactivity 
 Treatment-emergent response 
 Treatment-boosted response 
  NAb response in ADA positive patients 
 Titer value category (titer range) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
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Listings of ADA positivity, treatment-emergent ADA, NAbs, and titers presented by patient, 
time point, and dose cohort/group will be provided. Incidence of treatment-emergent ADA and 
NAbs will be assessed as absolute occurrence (N) and percent of patients (%), grouped by study 
cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on 
individual PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and 
efficacy may be provided. 
10.4.7. 
Analysis of Exploratory Pharmacodynamic and Biomarker Data 
Analysis of biomarker data is defined in the SAP. 
10.4.8. 
Analysis of Exploratory Clinical Outcome Assessment Data 
Analysis of COA data is defined in the SAP. 
10.5. 
Interim Analysis  
There will not be a formal interim analysis of the efficacy data. There will be an interim analysis 
of cohort A patient data after week 8, the purpose of which is the confirmation of the adequacy 
of the selected dose regimen, as described in Section 5.2. 
10.6. 
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. For patients enrolled but not treated, the baseline will be the last 
available measurement before enrollment. 
 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. 
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 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. 
10.7. 
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 16.1. 
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11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation [quality-checking], cleaning, correcting, releasing) will be maintained 
and stored at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history) will be done using 
internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) tool. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS (interactive voice response system/interactive web response system) – 
randomization, study drug supply 
 EDC system – data capture 
 Statistical analysis system (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
 eCOA system – capture COA  
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12. 
STUDY MONITORING  
12.1. 
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 E6 R2). 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. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source 
documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (eCRFs) within the EDC system by trained site personnel. All required CRFs must be 
completed for each and every patient enrolled in the study. 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. 
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13. 
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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14. 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1. 
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. 
14.2. 
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 the study drug will be shipped to the study 
site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written, informed consent from each patient prior to his/her participation in the study and after 
the aims, methods, objectives, and potential hazards of the study have been explained to the 
patient in language that he/she can understand. The ICF should be signed and dated by the 
patient and by the investigator or authorized designee who reviewed the ICF with the patient.  
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately. All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study. The original, 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
14.3. 
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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14.4. 
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. 
14.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable 
local guidelines and regulations. 
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15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. Regulatory approval will also be sought where required, in 
accordance with local procedures. 
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16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
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. 
16.2. 
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. 
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17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF/eCRF must be 
signed electronically by the investigator. This signed declaration accompanies each set of patient 
final CRFs/eCRFs that will be provided to the sponsor. 
17.2. 
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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18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data generated, recorded, and reported in compliance with the 
protocol, GCP, and any applicable regulatory requirement(s). The planned quality assurance and 
quality control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of 
the data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13)  
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements (Section 12.1).  
All patient data collected during the study will be recorded on paper or electronic CRF unless the 
data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient final CRFs (Section 12.3 
and Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
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19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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22. 
REFERENCES  
Al-Ani F, Chin-Yee I, Lazo-Langner A. Eculizumab in the management of paroxysmal nocturnal 
hemoglobinuria: patient selection and special considerations. Ther Clin Risk Manag 2016; 
12:1161-70. 
 
Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the treatment 
satisfaction questionnaire for medication (TSQM version II) among outpatient pharmacy 
consumers. Value Health 2005; 8 Suppl 1:S9-S24. 
 
Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, et al. Validation of a general 
measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication 
(TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes 2004; 2:12. 
 
Ballarin J, Arce Y, Torra Balcells R, Diaz Encarnacion M, Manzarbeitia F, Ortiz A, et al. Acute 
renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular 
haemosiderin accumulation and CD163 expression. Nephrol Dial Transplant 2011; 26(10):3408-
11. 
 
Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009; 113(26):6522-7. 
 
Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et al. 
Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients 
with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111(4):1840-7. 
 
Cocks K, Cohen D, Wisloff F, Sezer O, Lee S, Hippe E, et al. An international field study of the 
reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing 
the quality of life of patients with multiple myeloma. Eur J Cancer 2007; 43(11):1670-8. 
 
FDA. 2009.  Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical 
Product Development to Support Labeling Claims. 
 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin 
Microbiol Rev 1991; 4(3):359-95. 
 
Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, et al. Prophylaxis with oral 
penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 1986; 
314(25):1593-9. 
 
Griffin M, Munir T. Management of thrombosis in paroxysmal nocturnal hemoglobinuria: a 
clinician's guide. Ther Adv Hematol 2017; 8(3):119-26. 
 
Helley D, de Latour RP, Porcher R, Rodrigues CA, Galy-Fauroux I, Matheron J, et al. Evaluation 
of hemostasis and endothelial function in patients with paroxysmal nocturnal hemoglobinuria 
receiving eculizumab. Haematologica 2010; 95(4):574-81. 
 
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Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 
121(25):4985-96; quiz 5105. 
 
Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, et al. Effect of eculizumab on 
hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. 
N Engl J Med 2004; 350(6):552-9. 
 
Hillmen P, Muus P, Roth A, Elebute MO, Risitano AM, Schrezenmeier H, et al. Long-term 
safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal 
haemoglobinuria. Br J Haematol 2013; 162(1):62-73. 
 
Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al. The complement 
inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 
355(12):1233-43. 
 
ICH. 1994.  E2A. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting. In: ICH Harmoised Tripartite Guideline. 
 
Lee JW, Rottinghaus ST, Lee LWL, Pessoa V, Gualandro S, Füreder W, et al. 2018.  Results 
from a phase 3, multicenter, noninveriority study of ravulizumab (ALXN1210) versus 
eculizumab in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) naieve to 
complement inhibitors In: EHA Learning Center. 218885. Abstract LB2603. 
 
Luzzatto L, Risitano AM. Advances in understanding the pathogenesis of acquired aplastic 
anaemia. Br J Haematol 2018; 182(6):758-76. 
 
Nakayama H, Usuki K, Echizen H, Ogawa R, Orii T. Eculizumab Dosing Intervals Longer than 
17 Days May Be Associated with Greater Risk of Breakthrough Hemolysis in Patients with 
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. 
 
Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, et al. Content validity--
establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) 
instruments for medical product evaluation: ISPOR PRO Good Research Practices Task Force 
report: part 2--assessing respondent understanding. Value Health 2011; 14(8):978-88. 
 
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. 
 
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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 2018; 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. 
 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol 2006; 117(2):391-7. 
 
Soliris®. 2019.  Product information for eculizumab. Alexion Pharmaceuticals, Inc. 
 
Stead ML, Brown JM, Velikova G, Kaasa S, Wisloff F, Child JA, et al. Development of an 
EORTC questionnaire module to be used in health-related quality-of-life assessment for patients 
with multiple myeloma. European Organization for Research and Treatment of Cancer Study 
Group on Quality of Life. Br J Haematol 1999; 104(3):605-11. 
 
Wedzicha JA. Antibiotics at COPD exacerbations: the debate continues. Thorax 2008; 
63(11):940-2. 
 
Weitz I, Meyers G, Lamy T, Cahn JY, Uranga MT, Garcia Vela JA, et al. Cross-sectional 
validation study of patient-reported outcomes in patients with paroxysmal nocturnal 
haemoglobinuria. Intern Med J 2013; 43(3):298-307. 
 
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: AN OPEN-LABEL, SINGLE ARM STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF REGN3918 IN PATIENTS WITH PAROXYSMAL 
NOCTURNAL 
HEMOGLOBINURIA 
(PNH) 
WHO 
ARE 
COMPLEMENT 
INHIBITOR-NAIVE OR HAVE NOT RECENTLY RECEIVED COMPLEMENT INHIBITOR 
THERAPY 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, SINGLE ARM STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF REGN3918 IN PATIENTS WITH PAROXYSMAL 
NOCTURNAL HEMOGLOBINURIA (PNH) WHO ARE COMPLEMENT 
INHIBITOR-NAIVE 
OR 
HAVE 
NOT 
RECENTLY 
RECEIVED 
COMPLEMENT INHIBITOR THERAPY 
Protocol Number: 
Protocol R3918-PNH-1852 
Protocol Version:  
Protocol R3918-PNH-1852 Amendment 2 
 
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 
                                        VV-RIM-00076004-2.0 Approved - 21 Jun 2019 GMT-5:00


Signature Page for VV-RIM-00076004 v2.0
Signature Page for VV-RIM-00076004 v2.0 Approved
ESig Approval
19 17:12:09 GMT+0000
ESig Approval
2019 17:45:41 GMT+0000
ESig Approval
2019 11:38:41 GMT+0000
ESig Approval
00
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 53 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: ORIGNIAL 
Clinical Study Protocol Title: AN OPEN-LABEL, SINGLE ARM STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF REGN3918 IN PATIENTS 
WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) WHO 
ARE COMPLEMENT INHIBITOR-NAIVE OR HAVE NOT RECENTLY 
RECEIVED COMPLEMENT INHIBITOR THERAPY 
Compound: 
REGN3918 
Protocol Number: 
R3918-PNH-1852 
Clinical Phase:  
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date: 
Original Statistical Analysis Plan / JUL 17, 2019 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 2 of 53 
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 Precision Medicine 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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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 3 of 53 
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 ......................................................9 
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 .....................................................................10 
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 .............................................................................12 
3.4. 
The Immunogenicity Analysis Sets ............................................................................12 
3.5. 
The Exploratory Biomarker Endpoint Analysis Set ...................................................12 
3.6. 
The Exploratory Clinical Outcome Assessment 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 ..........................................................14 
4.4. 
Rescue Medication/or Prohibited Medication During Study if Applicable ................14 
4.5. 
Efficacy Variables ......................................................................................................14 
4.5.1. 
Primary Efficacy Variables .........................................................................................14 
4.5.2. 
Secondary Efficacy Variables .....................................................................................15 
4.5.3. 
Exploratory Efficacy Variables ..................................................................................16 
4.6. 
Safety Variables ..........................................................................................................16 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................16 
4.6.2. 
Adverse Events of Special Interest .............................................................................17 
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Statistical Analysis Plan 
 
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4.6.3. 
Laboratory Safety Variables .......................................................................................17 
4.6.4. 
Vital Signs ..................................................................................................................17 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................17 
4.6.6. 
Physical Examination Variables .................................................................................17 
4.7. 
Pharmacokinetic Variables .........................................................................................17 
4.8. 
Immunogenicity Variables ..........................................................................................17 
4.9. 
Pharmacodynamic Variables ......................................................................................18 
4.10. 
Clinical Outcome Assessments (COAs) .....................................................................18 
5. 
STATISTICAL METHODS .......................................................................................19 
5.1. 
Demographics and Baseline Characteristics ...............................................................19 
5.2. 
Medical History ..........................................................................................................19 
5.3. 
Prior/concomitant Medications ...................................................................................19 
5.4. 
Rescue/Prohibited Medications if applicable .............................................................20 
5.5. 
Patient Disposition ......................................................................................................20 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................20 
5.6.1. 
Measurement of Compliance ......................................................................................20 
5.6.2. 
Exposure to Investigational Product ...........................................................................20 
5.7. 
Analyses of Efficacy Variables ..................................................................................21 
5.7.1. 
Analysis of Primary Efficacy Variables .....................................................................21 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................23 
5.7.3. 
Analysis of Exploratory Variables ..............................................................................24 
5.8. 
Analysis of Safety Data ..............................................................................................25 
5.8.1. 
Adverse Events ...........................................................................................................25 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................27 
5.8.3. 
Clinical Laboratory Measurements.............................................................................27 
5.8.4. 
Analysis of Vital Signs ...............................................................................................28 
5.8.5. 
Analysis of 12-Lead ECG ...........................................................................................28 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................28 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................28 
5.9.2. 
Analysis of Immunogenicity Data ..............................................................................28 
5.9.2.1. 
Analysis of ADA Data ................................................................................................28 
5.9.2.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................29 
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Statistical Analysis Plan 
 
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5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................29 
5.9.3.1. 
Immunogenicity and Exposure ...................................................................................29 
5.9.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................30 
5.10. 
Analysis of Pharmacodynamic and Biomarker Data ..................................................30 
6. 
DATA CONVENTIONS ............................................................................................31 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................31 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................31 
6.3. 
Data Handling Convention for Missing Data .............................................................31 
6.3.1. 
Adverse events ............................................................................................................31 
6.3.2. 
PCSV ..........................................................................................................................33 
6.3.3. 
Date of first / last study drug administration ..............................................................33 
6.4. 
Visit Windows ............................................................................................................33 
6.5. 
Unscheduled Assessments ..........................................................................................39 
7. 
INTERIM ANALYSIS ...............................................................................................40 
8. 
SOFTWARE ...............................................................................................................41 
9. 
REFERENCES ...........................................................................................................42 
10. 
APPENDIX.................................................................................................................43 
10.1. 
Summary of Statistical Analyses ................................................................................43 
10.2. 
Schedule of Time and Events .....................................................................................44 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................49 
10.4. 
Posterior Probability of Assurance for LDH Normalization ......................................53 
 
LIST OF TABLES 
Table 1: 
Minimal and Maximal Planned Sample Size ..............................................................11 
 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AH50 
Alternative pathway hemolytic activity assay 
ALT 
Alanine aminotransferase 
ASS 
Anti-drug antibody analysis set 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CH50 
Total Complement hemolytic activity assay 
COA 
Clinical outcome assessment 
CRF 
Case report form (electronic or paper) 
ECG 
Electrocardiogram 
EORTC 
European Organisation for Research and Treatment of Cancer 
EoS 
End of study 
eGFR 
Estimated glomerular filtration rate 
F1+2 
D-dimer and N-terminal prothrombin fragments 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full analysis set 
GPI 
Glycophosphatidylinositol 
HRQoL 
Health-related quality of life 
HSC 
Hematopoietic stem cells 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgG4p 
Human monoclonal immunoglobulin G4P 
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
MAC 
Membrane attack complex 
MAVE 
Major adverse vascular event 
MMRM 
Mixed-effect model for repeated measures 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
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NAS 
Neutralizing antibody analysis set 
NOAEL 
No observable adverse effect level 
OLE 
Open-label extension 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PIGA 
Phosphatidylinositol glycan anchor biosynthesis class A 
PGIC 
Patient global impression of change 
PGIS 
Patient global impression of severity 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PRO 
Patient reported outcome 
PT 
Preferred term 
Q2W 
Every 2 weeks 
QLQ-C30 
Quality of life questionnaire-core 30 
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 
TEAE 
Treatment-emergent adverse event 
TFPI 
Tissue Factor Pathway Inhibitor 
t-PA 
Tissue plasminogen activator 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to first patient first 
dose as the study is designed as an open-label single-arm trial. 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 study is a single-arm study and thus patients and the investigator will be aware of treatment 
allocation. This is deemed acceptable as 1 of the 2 co-primary endpoints of the study is an 
objective, laboratory-based parameter (i.e., lactate dehydrogenase [LDH]) that is less likely to be 
biased by knowledge of treatment assignment. The other co-primary endpoint is transfusion 
avoidance, and the study protocol includes a transfusion algorithm that will standardize the 
decision to transfuse and thus minimize bias from knowledge of treatment assignment.  
The study does not include a placebo control, because there is an approved treatment for PNH 
(i.e., eculizumab), and not treating patients with active PNH increases the risk of serious or 
irreversible harm from sequelae of the disease.  
In this study, there will be two cohorts, one for dose confirmation (cohort A) and one for dose 
expansion (cohort B). Cohort A will be comprised of patients whose data will contribute to an 
initial evaluation at week 8, after 8 weeks of therapy, the purpose of which is the confirmation of 
the adequacy of the selected dose regimen. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to demonstrate a reduction in intravascular hemolysis by 
REGN3918 over 26 weeks of treatment (assessed at week 26) in patients with active PNH who 
are treatment-naive to complement inhibitor therapy or have not recently received complement 
inhibitor therapy. 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
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1.2.2. 
Secondary Objectives and Exploratory Objectives 
The secondary objectives of the study are: 
 To evaluate the safety and tolerability of REGN3918 
 To evaluate the effect of REGN3918 on parameters of intravascular hemolysis  
 To assess the concentrations of total REGN3918 in serum 
 To evaluate the incidence of treatment-emergent anti-drug antibodies (ADA) to 
REGN3918 over time 
 To evaluate the effect of REGN3918 on patient-reported outcomes (PROs) measuring 
fatigue and health-related quality of life 
The exploratory objectives of the study are: 
 To explore the effect on clinical thrombosis events 
 To explore the effect on renal function and renal injury biomarkers 
 To explore the effect of REGN3918 on complement activation and intravascular 
hemolysis relevant to PNH and other related diseases 
 To explore the effect of REGN3918 on the level of total C5 protein 
 To explore the effect of REGN3918 on PNH clone size  
 To explore the effect of REGN3918 on treatment satisfaction and a novel PRO 
measuring PNH-specific symptoms  
 To explore factors contributing to changes in well-being such as fatigue or quality of 
life in a subset of patients at participating sites (i.e., sub-study) 
 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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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This is an open-label, single arm, 26-week treatment study in patients with confirmed diagnosis 
of PNH and active signs and symptoms who either are complement inhibitor naïve or have not 
received prior treatment with a complement inhibitor, but not within 6 months prior to screening 
visit, except patients refractory to eculizumab due to the C5 variant R885H/C.  
In this study, there will be two cohorts, one for dose confirmation (cohort A) and one for dose 
expansion (cohort B). Dose confirmation will be made at the interim analysis (Section 7). The 
inclusion and exclusion criteria and schedule of events are the same for cohort A and cohort B. 
During the assessment of data from cohort A, recruitment into the study will continue, with 
patients recruited being assigned subsequently as follows: if a decision is made to expand 
cohort A, they will be assigned to cohort A. If a decision is made to progress to cohort B, they 
will be assigned to cohort B. 
Patients will be given a single loading dose of REGN3918 30 mg/kg intravenous (IV) on day 1, 
then a dose not greater than 800 mg subcutaneous (SC) once weekly (QW; ± 1 day) to week 25. 
Primary analysis is performed at week 26. 
Approximately 6 to 12 patients will be enrolled in cohort A, and 24 to 30 in cohort B. 
2.2. 
Sample Size and Power Considerations 
This is a single-arm, open-label study, and a formal power calculation for comparison with a 
control is not intended.  
For cohort A, a sample size of 6 is standard in assessing safety and tolerability of a drug dose 
first tested in patients. Also, it was assessed that sufficient assurance of efficacy with the initial 
dosing regimen will be provided for a decision to progress from cohort A to cohort B if all 
6 cohort A patients achieve an LDH ≤ 1.5 x ULN at week 8 (Section 10.4). Enrollment into 
cohort A will continue until at least 6 patients have evaluable data (ie, completed week 8 
procedures) for the cohort A analysis described in Section 7.  
For the overall study (cohort A and cohort B), we used the information from a phase 3 study of 
ravulizumab compared with eculizumab in active PNH (Lee, 2019) to understand the precision 
of estimation of the proportions of the primary endpoints to be observed from the current study. 
The observed proportion of transfusion avoidance was 73.6% in the ravulizumab arm. The 
proportion of achievement of LDH ≤ 1.5 x ULN has not yet been reported from this study but 
has been derived from the available information as 95% for ravulizumab. If we assume 
REGN3918 has ravulizumab-like effects on LDH reduction and transfusion avoidance, i.e. with 
the same observed proportions from the ravulizumab arm, the following table gives the means 
and 95% confidence intervals for the proportions of the co-primary endpoints expected to be 
observed for REGN3918, for the minimal and maximal planned overall sample sizes (cohorts A 
and B), assuming no change in dosing regimen for cohort B. Patients prematurely withdrawn 
from the study/study drug in cohort B may not be replaced. 
 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
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Table 1: 
Minimal and Maximal Planned Sample Size 
Overall Sample Size  
 
(N) 
Observeed Porportion and 
95% confidence interval for the proportion 
Transfusion avoidance 
LDH ≤ 1.5 x ULN 
Minimum: 30 
73.6% 
(58%, 89%) 
95% 
(87%, 100%) 
Maximum: 42 
73.6% 
(60%, 87%) 
95% 
(88%, 100%) 
2.3. 
Study Plan 
The Study event table is presented in Section 10.2. 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
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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 
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. Patients will be analyzed according to the treatment actually received. 
3.4. 
The Immunogenicity Analysis Sets 
The ADA analysis set (AAS) includes all patients who received any study drug and who had at 
least 1 non-missing ADA result from the REGN3918 ADA assay after the first dose of study 
drug. Patients will be analyzed according to the treatment actually received. 
The neutralizing antibody (NAb) analysis set (NAS) includes all patients who received any study 
drug and who are positive in the REGN3918 ADA assay or with at least one non-missing result 
in the REGN3918 NAb assay after first dose of the study drug. Patients who are ADA negative 
are set to negative in the NAb analysis set. Patients will be analyzed according to the treatment 
actually received. 
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. 
3.6. 
The Exploratory Clinical Outcome Assessment Analysis Set 
The exploratory clinical outcome assessment (COA) analysis set includes all FAS patients who 
had a baseline and at least 1 non-missing COA measurement following the first dose of study 
drug. 
 
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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
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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 
 PNH signs and symptoms 
 Total C5 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
In addition, the following historical data will be summarized: 
 History in the past 12 months of the following: 
o Transfusions 
o Breakthrough hemolysis 
 All available laboratory parameters for measurement of hemolysis in the past 2 years: 
o LDH 
o Hemoglobin 
o Free hemoglobin 
o PNH erythrocytes 
o PNH granulocytes 
 Neisseria meningitidis vaccination history 
 Aplastic anemia history 
 Major adverse vascular event (MAVE) history 
 PNH medical history 
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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 the latest available version of 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 will be summarized. 
Prio/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. 
4.4. 
Rescue Medication/or Prohibited Medication During Study if 
Applicable 
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 starting on Day 1 
4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variables 
The co-primary efficacy variables are: 
 The proportion of patients achieving adequate control of their intravascular 
hemolysis, defined as LDH ≤ 1.5 x ULN at every scheduled time point between week 
4 and week 26, inclusive 
 The proportion of patients achieving transfusion avoidance defined as no post 
baseline transfusion of RBCs per protocol through week 26 
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4.5.2. 
Secondary Efficacy Variables 
The secondary efficacy variables are: 
 The rate of breakthrough hemolysis through week 26, where breakthrough hemolysis is 
defined as the 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 proportion of patients achieving normalization of their intravascular hemolysis, 
defined as LDH ≤ 1.0 x ULN at every scheduled time point between week 4 through 
week 26, inclusive 
 Time (days) to first LDH ≤ 1.5 x ULN 
 Percentage of days with LDH ≤ 1.5 x ULN between week 4 and week 26, inclusive 
 Change in LDH levels from baseline to week 26 
 Percent change in LDH levels from baseline to week 26 
 The rate of transfusion with RBCs through week 26 
 The number of units of transfusion with RBCs from baseline through week 26  
 Change in RBC hemoglobin levels from baseline to week 26 
 Change in free hemoglobin levels from baseline to week 26 
 Change in total complement hemolytic activity assay (CH50) from baseline to week 26 
 Percent change in total complement hemolytic activity assay (CH50) from baseline to 
week 26 
 Change in fatigue (as measured by the FACIT-Fatigue) from baseline to week 26  
 Change in health-related quality of life (as measured by the European Organisation for 
Research and Treatment of Cancer [EORTC]-QLQ-C30) from baseline to week 26 
 
Change in health-related quality of life (as measured by the EQ-5D-3L) from baseline to 
week 26 
For the second secondary variable (the proportion of patients with normalization), patients for 
whom one or more of the following apply will be considered as not achieving normalization:  
o Discontinue from study treatment early 
o Have 3 consecutive missing values of the scheduled LDH measurements between 
week 4 and week 26  
o Have 50% or more missing values of the scheduled LDH measurements between 
week 4 and week 26, inclusive 
o Experience breakthrough hemolysis event (as defined in the secondary endpoint) 
while on treatment through week 26 
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4.5.3. 
Exploratory Efficacy Variables 
The exploratory efficacy variables are: 
 Incidence of MAVE through week 26 
 Change in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline to week 26 
 Treatment satisfaction as measured by the Treatment Satisfaction Questionnaire for 
Medication (TSQM) at week 26 
 Change in PNH symptoms as measured by the de novo PNH symptom-specific 
questionnaire at week 26 
 Change in haptoglobin from baseline to week 26 
 Change in bilirubin from baseline to week 26 
 Change in reticulocyte count from baseline to week 26 
 Change in alternative pathway hemolytic activity assay (AH50) from baseline to week 26 
 Percent change in alternative pathway hemolytic activity assay (AH50) from baseline to 
week 26 
 Change in Total C5 from baseline to week 26 
 Change in PNH erythrocytes and granulocytes from baseline to week 26 
The wearable activity tracker data will not be part of this SAP, and it will not be mentioned 
further. 
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 and of infusion reaction AEs will be graded according to the criteria given 
in the protocol.  
Section 9.4.5 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): 
 Moderate or severe infusion reactions 
 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, and 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 endpoint is concentration of total REGN3918.  Target engagement will be assessed by 
the concentration of total C5. The sampling time points are specified in Section 10.2. 
4.8. 
Immunogenicity Variables  
The immunogenicity variables are ADA status, NAb status, titer, and time point/visit. Samples in 
this study will be collected at the clinic visits specified in Section 10.2.  
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4.9. 
Pharmacodynamic Variables 
The following pharmacodynamic biomarkers are included in this study: 
 Complement activity as measured by the serum CH50 and AH50 assays  
 Complement activation markers: C5a (plasma and urine) and sC5b-9 (plasma) 
 PNH clone size: PNH erythrocytes and granulocytes 
 Biomarkers of pulmonary hypertension: NT-proBNP 
 Biomarkers of thrombosis and inflammation: D-dimer, N-terminal prothrombin 
fragments (F1+2), Tissue Factor Pathway Inhibitor (TFPI), and IL-6  
 A urinary renal injury biomarker panel: clusterin (CLU), Cystatin-C (CysC), Kidney 
Injury Molecule-1 (KIM-1), Nacetyl-beta-D-glucosaminidase (NAG), Neutrophil 
Gelatinase-Associated Lipocalin (NGAL), and osteopontin (OPN) 
4.10. 
Clinical Outcome Assessments (COAs) 
Patient-reported outcomes (PROs) are a type of clinical outcome assessment (COA) and will be 
completed according to the schedule in Section 10.2. 
COAs include the the Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue), 2 health-related quality of life (HRQoL) questionnaires (the EORTC-
QLQ-C30 and the EQ-5D-3L), the Treatment Satisfaction Questionnaire for Medication 
(TSQM), and the de novo PNH symptom-specific questionnaire.  
 
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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.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
If there is no change in dosing regimen for cohort B, patients of cohort A and cohort B will be 
pooled for both safety and efficacy analysis.  If the dosing regimen is changed, efficacy analyses 
will be performed separately for cohort A and cohort B. 
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.  In addition, 
all medical history of specific interest, as described in Section 4.2, will be summarized by patient 
incidence and percentage. 
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). 
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5.4. 
Rescue/Prohibited Medications if applicable 
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. 
5.5. 
Patient Disposition 
The following displays 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 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 The total number of patients who continued to OLE, and the total number who 
completed the study but did not continue to OLE 
 A listing of patients enrolled but not treated 
 A listing of patients prematurely discontinued from treatment, along with 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.  IV and SC doses will be analyzed separately 
and combined for this compliance analysis. 
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 for 
infusions and SCs combined and also separately. SC injection location will also be summarized. 
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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: 
 ≥ Day 28 
 ≥ Day 56 
 ≥ Day 84  
 ≥ Day 112  
 ≥ Day 140 
 ≥ Day 182 
In addition, frequencies and percentages of SC injections by location will be presented. 
5.7. 
Analyses of Efficacy Variables 
The co-primary endpoints for the study are the proportion of patients achieving adequate control 
of their intravascular hemolysis, defined as LDH ≤ 1.5 x ULN at every scheduled time point 
between week 4 and week 26, inclusive, and the proportion of patients achieving transfusion 
avoidance defined as no post-baseline transfusions of RBCs per protocol. The proportions of the 
co-primary endpoints will be calculated, along with their 95% confidence intervals. 
5.7.1. 
Analysis of Primary Efficacy Variables 
For the first co-primary variable (the proportion of patients achieving adequate control of their 
intravascular hemolysis), patients who have one or more of the following will be considered as 
not achieving adequate control of their intravascular hemolysis:  
o Discontinue from study treatment early 
o Have 3 consecutive missing values of the scheduled LDH measurements between 
week 4 and week 26, inclusive  
o Have 50% or more missing values of the scheduled LDH measurements between 
week 4 and week 26, inclusive 
o Experience breakthrough hemolysis event (as defined in the secondary endpoint) 
while on treatment through week 26 
Patients who complete study treatment, have no more than 2 consecutive missing values of the 
scheduled LDH measurements between week 4 and week 26, have fewer than 50% missing 
values of the scheduled LDH measurements between week 4 and week 26, and have no 
breakthrough hemolysis while on treatment will be evaluated based on their non-missing LDH 
measurements. The proportion of patients achieving adequate control of their intravascular 
hemolysis will be calculated, along with a 2-sided 95% confidence interval, by a normal 
approximation as primary analysis and by the exact Clopper Pearson method as a sensitivity 
analysis.  
For the co-primary variable of the proportion of patients achieving transfusion avoidance, the 
analysis set will consist of all FAS patients. A transfusion will be counted only if the transfusion 
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follows the predefined transfusion algorithm. The proportion (and 95% confidence interval) of 
patients achieving transfusion avoidance through week 26 will be calculated by the Kaplan-
Meier estimate at week 26.  Patients who have no transfusions will be censored at week 26 
(completers) or at time of early discontinuation. 
Sensitivity analysis of first co-primary endpoint  
As a sensitivity analysis to assess the effect of missing LDH values on the primary analysis of 
the first co-primary endpoint, imputation of missing LDH values from 4 weeks to 26 weeks for 
all FAS patients will be performed using the multiple imputation method. Missing data will be 
imputed 100 times to generate 100 complete data sets by using the SAS procedure MI with the 
following steps: 
 Step 1: Intermittent missing data will be imputed, leaving a monotone missing 
pattern, by the Markov Chain Monte Carlo (MCMC) method in the MI procedure.   
 Step 2: The missing data at subsequent visits will be imputed using the regression 
method for the monotone pattern. 
The primary analysis of percentage of patients achieving adequate control of their intravascular 
hemolysis will then be conducted on the 100 complete data sets. The results will be descriptively 
summarized, including mean, median, standard deviation, Q1, Q3, minimum, and maximum. 
Sensitivity analysis of second co-primary endpoint  
An analysis of transfusion avoidance will be repeated considering all transfusions, whether or not 
they were per the predefined transfusion algorithm in the protocol. 
Subgroup analysis: 
Subgroup analyses will be conducted for the co-primary endpoints by the following subgroup 
factors: 
 Study cohort (A vs B) 
 Complement inhibitor experience (naïve vs prior treatment) 
 Quartiles of RBC transfusion units in the 6 months before treatment 
 Country/region (APAC, EU [South Africa is part of EU], and US) 
 Gender 
 Baseline LDH levels (≥ median vs < median) 
 C5 variants (yes/no) 
 Weight (≥ median vs < median) 
 Baseline total C5 (≥ median vs < median) 
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5.7.2. 
Analysis of Secondary Efficacy Variables 
For the secondary variable of the rate of breakthrough hemolysis through week 26, defined as the 
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 proportion 
of patients achieving normalization of their intravascular hemolysis 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.  Signs and symptoms will be tabulated, as will 
number of breakthrough hemolyses per patient. 
For the secondary variable of the proportion of patients achieving normalization of their 
intravascular hemolysis (defined as LDH ≤ 1.0 x ULN at every scheduled time point between 
week 4 through week 26, inclusive), patients who have one or more of the following will be 
considered as not achieving adequate control of their intravascular hemolysis:  
o Discontinue from study treatment early 
o Have 3 consecutive missing values of the scheduled LDH measurements between 
week 4 and week 26, inclusive  
o Have 50% or more missing values of the scheduled LDH measurements between 
week 4 and week 26, inclusive 
o Experience breakthrough hemolysis event (as defined in the secondary endpoint) 
while on treatment through week 26 
Patients who complete study treatment, have no more than 2 consecutive missing values of the 
scheduled LDH measurements between week 4 and week 26, have fewer than 50% missing 
values of the scheduled LDH measurements between week 4 and week 26 and have no 
breakthrough hemolysis will be evaluated based on their non-missing LDH measurements.  The 
proportion of patients achieving normalization of their intravascular hemolysis 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 same sensitivity analysis described for the first co-primary endpoint will be conducted.  
For the secondary variable of the time to first LDH ≤ 1.5 x ULN, a time to first event analysis 
will be used. The median time and 95% confidence interval will be obtained with a 
Kaplan-Meier analysis.  Patients who have no values of LDH ≤ 1.5 x ULN will be censored at 
week 26 (completers) or at time of early discontinuation. 
For the secondary variable of the percentage of days with LDH ≤ 1.5 x ULN between week 4 
and week 26, inclusive, each patient’s percentage will be the number of days with LDH ≤ 1.5 x 
ULN divided by the patient’s total treatment duration (total number of days on treatment).  The 
LDH value for each day of the patient’s treatment duration will be the most recent LDH 
measurement up to the day, inclusive. The mean and 95% confidence interval will be presented.   
For the secondary variable of the number of units of transfusion of RBCs through week 26, the 
26 week total for each patient will be used.  A 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. A transfusion will be counted only if the transfusion follows the 
predefined transfusion algorithm. 
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For the secondary variable of the rate of transfusion with RBCs through 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 following secondary variables, the analysis set will consist of all FAS patients who have 
a non-missing baseline measurement of the variable: 
 Change in LDH levels from baseline to week 26 
 Percent change in LDH levels from baseline to week 26  
 Change in RBC hemoglobin levels from baseline to week 26 
 Change in free hemoglobin levels from baseline to week 26 
 Change in total complement hemolytic activity assay (CH50) from baseline to 
week 26 
 Percent change in total complement hemolytic activity assay (CH50) from baseline to 
week 26 
 Change in fatigue (as measured by the FACIT-Fatigue) from baseline to week 26  
 Change inhealth related quality of life (as measured by the EORTC-QLQ-C30) from 
baseline to week 26 by individual subscales: global health status/quality of life, 
physical functioning, role functioning, emotional functioning, cognitive functioning, 
social functioning, fatigue, pain, and dyspnea 
 Change in (health related quality of life as measured by the EQ-5D-3L) from baseline 
to week 26 
For these variables, means and 95% confidence intervals based on an MMRM analysis will be 
reported for the last applicable week. The MMRM model will include visit as a fixed term and 
assume an unstructured covariance matrix. In addition, a sensitivity analysis will be conducted 
for change and percent change in LDH from baseline to 26 weeks by Last observation carried 
forward (LOCF) imputation for 26 weeks. The justification for the LOCF imputation is that it is 
very unlikely for patients to have missing LDH before 4 weeks and a patient’s LDH should have 
reached a stable level by 4 weeks based on eculizumab and ravulizumab trial data, whether it is 
above or below 1.5 XULN. 
5.7.3. 
Analysis of Exploratory Variables 
For the exploratory variable “Incidence of MAVE through week 26,” the proportion of patients 
with at least one MAVE will be presented along with two versions of a 95% confidence interval: 
normal approximation and exact Clopper-Pearson. 
For TSMQ, mean and 95% confidence interval based on an MMRM analysis will be reported for 
week 26. The MMRM model will include visit as a fixed term and assume an unstructured 
covariance matrix. 
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For the following exploratory variables, the analysis set will consist of all FAS patients who have 
a non-missing baseline measurement of the variable: 
 Change in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline to week 26 
 Change in PNH symptoms as measured by the de novo PNH symptom-specific 
questionnaire at week 26 
 Change in haptoglobin from baseline to week 26 
 Change in bilirubin from baseline to week 26 
 Change in reticulocyte count from baseline to week 26 
 Change in alternative pathway hemolytic activity assay (AH50) from baseline to 
week 26 
 Percent change in alternative pathway hemolytic activity assay (AH50) from baseline 
to week 26 
 Change in Total C5 from baseline to week 26 
 Change in PNH erythrocytes from baseline to week 26 
 Change in PNH granulocytes from baseline to week 26 
For these variables, means and 95% confidence intervals based on an MMRM analysis will be 
reported for the last applicable week. The MMRM model will include visit as a fixed term and 
assume an unstructured covariance matrix.  
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerance 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 Section 10.3. 
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. 
Day 1 is the first day of investigational product dosing, Day –1 is the day before, and there is no 
Day 0. 
Pre-treatment AEs are defined as AEs that developed or worsened during the pre-treatment 
period. The pre-treatment period is defined as the time between when the patient gives informed 
consent and just before the start of investigational product dosing. 
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Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
on-treatment period. The on-treatment period is defined as the time from first dose of 
investigational product up to 21 weeks after the last dose of investigational product for patients 
who do not participate in the OLE.  For those patients who do participate in the OLE, the end of 
the on-treatment period is from first dose of investigational product until just before the first dose 
in the OLE study. 
Post-treatment AEs are AEs that developed or worsened during the post-treatment period.  For 
patients not entering the OLE, the post-treatment period for AEs is the time after the end of 
treatment (scheduled week 26 visit) plus 21 weeks.  Patients who do participate in the OLE will 
not have AEs of this category. 
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. 
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 SOC and PT 
 Related TEAEs by severity and SOC and PT 
 Time to first occurrence of selected TEAEs 
 Serious adverse events: All TEAEs by SOC and PT 
 Serious adverse events: Related TEAEs by SOC and PT 
 Serious adverse events: All TEAEs by SOC and PT 
 Serious adverse events: Related TEAEs by SOC and PT 
 Death: All fatal TEAEs by SOC 
 Death: Related fatal TEAEs by SOC 
 Discontinuation: All TEAEs by SOC and PT 
 Discontinuation: Related TEAEs by SOC and PT 
 Non-serious related TEAEs by SOC and PT 
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Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the safety population in each treatment 
group. 
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. 
Additionally, separate summaries of TEAEs (preferred terms) with frequency ≥1% in any 
treatment group and TEAEs (preferred terms) with frequency ≥5% in any treatment group will 
be included in the report.  
The summary of TEAEs with frequency ≥5% will also be performed for demographic factors 
including: gender, age (<65 years, ≥65 years), and race. 
5.8.2. 
Analysis of Adverse Events of Special Interest 
Treatment emergent adverse events of special interest 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. 
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.  
Baseline clinical laboratory analytes and change from Baseline in clinical laboratory analytes to 
each scheduled assessment time will be summarized with descriptive statistics. Summary 
statistics will include the number of patients, mean, median, standard deviation, quartiles, 
minimum, and maximum.  The graphs of mean (or median) value of some lab parameter vs. visit 
will also be plotted. 
A listing of all laboratory parameters will include the value, normal range, abnormal flag and 
treatment-emergent PCSV flag by subject and visit will be provided. 
For categorical urinalysis variables, counts and percentages will be presented. 
All laboratory displays will be done twice, with international units and conventional units. 
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5.8.4. 
Analysis of Vital Signs 
Vital signs (pulse, sitting blood pressures, and temperature) will be summarized by visit and 
change from Baseline to each scheduled assessment time with descriptive statistics.   The graphs 
of mean (or median) value of some vital sign parameter vs. visit will also be plotted. 
Listings will be provided with flags indicating treatment-emergent PCSVs. 
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 by visit and change from Baseline to each scheduled and 
collected assessment time.      
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). 
Listings will be provided with flags indicating PCSVs. 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data 
5.9.1. 
Analysis of Pharmacokinetic Data  
Summary of concentrations of total REGN3918 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 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 (in %), minimum, Q1, median, Q3, and maximum. 
No formal statistical analysis will be performed. 
Descriptive concentration-response (AH50, CH50 and total C5) analysis will be performed as 
appropriate. 
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 responses and titers observed in patients in the 
ADA analysis set. ADA response categories and titer categories are defined as follows: 
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ADA response catagories: 
 Pre-existing immunoreactivity, defined as either an ADA positive response in the 
REGN3918 ADA assay at baseline with all post first dose ADA results negative, OR 
a positive response at baseline with all post first dose ADA responses less than 9-fold 
over baseline titer levels. 
 Treatment-emergent response, defined as a positive response in the REGN3918 ADA 
assay post first dose when baseline results are negative or missing.  
 Treatment-boosted response, defined as a positive response in the REGN3918 ADA 
assay post first dose that is greater than or equal to 9-fold over baseline titer levels, 
when baseline results are positive 
Titer categories (Maximum titer values) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
The following listings will be provided: 
 Number (n) and percent (%) of ADA-negative patients (pre-existing 
immunoreactivity or negative in the REGN3918 ADA assay at all time points) by 
treatment groups  
 Number (n) and percent (%) of treatment-emergent ADA positive patients by 
treatment groups and ADA titer categories 
 Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories  
Listing of all ADA titer levels will be provided for treatment-emergent and treatment-boosted 
ADA response patients. 
5.9.2.2. 
Analysis of Neutralizing Antibody (NAb) Data 
The absolute occurrence (n) and percent of patients (%) with NAb positive or negative status in 
the NAb analysis set will be provided by treatment groups.   
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.9.3.1. 
Immunogenicity and Exposure 
Association between immunogenicity variables and systemic exposure to REGN3918 will be 
analyzed. Plots of REGN3918 concentration may be provided for analyzing the potential impact 
of ADA response status, titer and NAb.  
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5.9.3.2. 
Immunogenicity and Safety and Efficacy 
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]) 
Association between immunogenicity variables and efficacy endpoints may be explored (e.g. 
scatter plot or spaghetti plot).  
The above mentioned safety and efficacy analyses will be conducted using the following 
categories: 
 ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response. 
 ADA negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points. 
 NAb positive patients, that is ADA positive (treatment-emergent & treatment-boost) 
patients who were positive in the NAb assay at any time point analyzed.  
 Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA 
positive patients:  
o High,  
o Moderate 
o Low 
5.10. 
Analysis of Pharmacodynamic and Biomarker Data 
Pharmacodynamic and biomarker variable listed in Section 4.8 may be analyzed and 
summarized.  For each biomarker variable, time profile and percent of change from baseline  at 
each time point will be summarized through 26 week 
 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. If the 
scheduled Baseline Day 1 measurements are not available, screening assessments may be used; 
when scores are used, this rule applies to scores, not individual variables. 
6.2. 
Data Handling Convention for Efficacy Variables  
6.3. 
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. 
6.3.1. 
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 of AESIs. 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’. 
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’. 
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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 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’ 
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. 
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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. 
6.3.2. 
PCSV 
Patients who had post-baseline PCSV, but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.3.3. 
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.  
6.4. 
Visit Windows 
Data analyzed by visit (including efficacy, laboratory data, visit sign, ECG) will be summarized 
by the study scheduled visits described Appendix 10.2 (Schedule of Time and Events). The 
analysis visit windows will be exhaustive so that all available values obtained from unscheduled 
visits, early termination visit (ETV) and end of treatment (EOT)/end of study (EOS) have the 
potential to be summarized. No analysis visit windows will be applied for the study scheduled 
visits. 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. 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
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Efficacy Analysis Windows 
Visit 
Targeted 
Study 
Days 
LDH  
Transfusion  
Complement 
Hemolytic  
FACIT-
Fatigue, 
EORTC-
QLQ-30, 
PGIS  
EQ-5D-3L  
PGIC  
Screening 
<1 
  
  
  
  
  
  
Day 1 
1 
1 
1 
1 
[1, 7] 
[1, 14] 
  
Day 3 
3 
[2, 4] 
[2, 4] 
[2, 4] 
  
  
  
Week 1 
8 
[5, 11] 
[5, 11] 
[5, 11] 
  
  
  
Week 2 
15 
[12, 18] 
[12, 18] 
[12, 18] 
[8, 21] 
  
[12, 21] 
Week 3 
22 
[19, 25] 
[19, 25] 
[19, 25] 
  
  
  
Week 4 
29 
[26, 36] 
[26, 32] 
[26, 42] 
[22, 42] 
[15, 42] 
[22, 42] 
Week 5 
36 
  
[33, 39] 
  
  
  
  
Week 6 
43 
[36, 49] 
[40, 46] 
  
  
  
  
Week 7 
50 
  
[47, 53] 
  
  
  
  
Week 8 
57 
[50, 63] 
[54, 60] 
[43, 70] 
[43, 70] 
[43, 70] 
[43, 70] 
Week 9 
64 
  
[61, 67] 
  
  
  
  
Week 10 
71 
[64, 77] 
[68, 74] 
  
  
  
  
Week 11 
78 
  
[75, 81] 
  
  
  
  
Week 12 
85 
[78, 91] 
[82, 88] 
[71, 98] 
[71, 98] 
[71, 98] 
[71, 98] 
Week 13 
92 
  
[89, 95] 
  
  
  
  
Week 14 
99 
[92, 105] 
[96, 102] 
  
  
  
  
Week 15 
106 
  
[103, 109] 
  
  
  
  
Week 16 
113 
[106, 119] 
[110, 116] 
[99, 126] 
[99, 126] 
[99, 126] 
[99, 126] 
Week 17 
120 
  
[117, 123] 
  
  
  
  
Week 18 
127 
[120, 133] 
[124, 130] 
  
  
  
  
Week 19 
134 
  
[131, 137] 
  
  
  
  
Week 20 
141 
[134, 147] 
[138, 144] 
[127, 161] 
[127, 161] 
[127, 161] 
[127, 161] 
Week 21 
148 
  
[145, 151] 
  
  
  
  
Week 22 
155 
[148, 161] 
[152, 158] 
  
  
  
  
Week 23 
162 
  
[159, 165] 
  
  
  
  
Week 24 
169 
[162, 172] 
[166, 172] 
  
  
  
  
Week 25 
176 
[173, 179] 
[173, 179] 
  
  
  
  
Week 26 
183 
[180, 186] 
[180, 186] 
[162, 186] 
[162, 186] 
[162, 186] 
[162, 186] 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 35 of 53 
Safety Analysis Windows 
Visit 
Targeted 
Study 
Days 
Vital 
Signs   
Physical 
Exam   
Body 
Weight 
ECG 
Patient 
Safety 
Card 
Hematology, 
Blood 
Chemistries, 
Pregnancy, 
Urinalysis  
CRP 
Direct 
Antiglobulin 
Screening 
<1 
<1 
<1 
<1 
<1 
  
<1 
<1 
<1 
Day 1 
1 
1 
1 
[1,14] 
  
1-92 
[1,11] 
1 
[1, 14] 
Day 3 
3 
[2, 4] 
[2, 4] 
  
  
  
  
[2, 4] 
  
Week 1 
8 
[5, 11] 
[5, 14] 
  
  
  
  
[5, 11] 
  
Week 2 
15 
[12, 18] 
  
  
  
  
[12, 21] 
[12, 18] 
  
Week 3 
22 
[19, 25] 
  
  
  
  
  
[19, 25] 
  
Week 4 
29 
[26, 35] 
[15, 42] 
[15, 42] 
  
  
[22, 42] 
[26, 42] 
[15, 42] 
Week 5 
36 
  
  
  
  
  
  
  
  
Week 6 
43 
[36, 49] 
  
  
  
  
  
  
  
Week 7 
50 
  
  
  
  
  
  
  
  
Week 8 
57 
[50, 63] 
[43, 70] 
[43, 70] 
  
  
[43, 70] 
[43, 70] 
[43, 70] 
Week 9 
64 
  
  
  
  
  
  
  
  
Week 10 
71 
[64, 77] 
  
  
  
  
  
  
  
Week 11 
78 
  
  
  
  
  
  
  
  
Week 12 
85 
[78, 91] 
[71, 98] 
[71, 98] 
  
  
[71, 98] 
[71, 98] 
[71, 98] 
Week 13 
92 
  
  
  
  
  
  
  
  
Week 14 
99 
[92, 105] 
  
  
  
  
  
  
  
Week 15 
106 
  
  
  
  
  
  
  
  
Week 16 
113 
[106, 
119] 
[99, 126] 
[99, 126] 
  
  
[99, 126] 
[99, 126] 
[99, 126] 
Week 17 
120 
  
  
  
  
  
  
  
  
Week 18 
127 
[120, 
133] 
  
  
  
  
  
  
  
Week 19 
134 
  
  
  
  
  
  
  
  
Week 20 
141 
[134, 
147] 
[127, 161] 
[127, 
161] 
  
  
[127, 161] 
[127, 
161] 
[127, 161] 
Week 21 
148 
  
  
  
  
  
  
  
  
Week 22 
155 
[148, 
168] 
  
  
  
  
  
  
  
Week 23 
162 
  
  
  
  
  
  
  
  
Week 24 
169 
  
  
  
  
  
  
  
  
Week 25 
176 
  
  
  
  
  
  
  
  
Week 26 
183 
[169, 
186] 
[162, 186] 
[162, 
186] 
[1, 186] 
[93, 186] 
[162, 186] 
[162, 
186] 
[162, 186] 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 36 of 53 
PK and ADA Analysis Windows 
Visit 
Targeted 
Study 
Days 
PK 
ADA 
Screening 
<1 
  
  
Day 1 
1 
1 
[1, 42] 
Day 3 
3 
[2, 4] 
  
Week 1 
8 
[5, 14] 
  
Week 2 
15 
  
  
Week 3 
22 
  
  
Week 4 
29 
[15, 42] 
  
Week 5 
36 
  
  
Week 6 
43 
  
  
Week 7 
50 
  
  
Week 8 
57 
[43, 70] 
  
Week 9 
64 
  
  
Week 10 
71 
  
  
Week 11 
78 
  
  
Week 12 
85 
[71, 98] 
[43, 133] 
Week 13 
92 
  
  
Week 14 
99 
  
  
Week 15 
106 
  
  
Week 16 
113 
[99, 126] 
  
Week 17 
120 
  
  
Week 18 
127 
  
  
Week 19 
134 
  
  
Week 20 
141 
[127, 161] 
  
Week 21 
148 
  
  
Week 22 
155 
  
  
Week 23 
162 
  
  
Week 24 
169 
  
  
Week 25 
176 
  
  
Week 26 
183 
[162, 186] 
[134, 186] 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 37 of 53 
Exploratory Analysis Windows 
Visit 
Targeted 
Study 
Days 
Haptoglobin, 
Reticulocytes, 
C3, C4, C5a, NT-
proBNP, 
Thromb/Inflamm, 
Renal Injury  
Complement 
Hemolytic 
Assay, 
sC5b-9  
Total C5 
PNH 
Eryth, 
PNH Gran 
Screening 
<1 
<1 
<1 
<1 
<1 
Day 1 
1 
[1, 14] 
1 
1 
[1, 28] 
Day 3 
3 
  
[2, 4] 
[2, 14] 
  
Week 1 
8 
  
[5, 11] 
  
  
Week 2 
15 
  
[12, 18] 
  
  
Week 3 
22 
  
[19, 25] 
  
  
Week 4 
29 
[15, 42] 
[26, 35] 
[15, 42] 
  
Week 5 
36 
  
  
  
  
Week 6 
43 
  
  
  
  
Week 7 
50 
  
  
  
  
Week 8 
57 
[43, 70] 
[50, 63] 
[43, 70] 
[29, 84] 
Week 9 
64 
  
  
  
  
Week 10 
71 
  
  
  
  
Week 11 
78 
  
  
  
  
Week 12 
85 
[71, 98] 
[71, 98] 
[71, 98] 
  
Week 13 
92 
  
  
  
  
Week 14 
99 
  
  
  
  
Week 15 
106 
  
  
  
  
Week 16 
113 
[99, 126] 
[99, 126] 
[99, 126] 
[85, 133] 
Week 17 
120 
  
  
  
  
Week 18 
127 
  
  
  
  
Week 19 
134 
  
  
  
  
Week 20 
141 
[127, 161] 
[127, 161] 
[127, 161] 
  
Week 21 
148 
  
  
  
  
Week 22 
155 
  
  
  
  
Week 23 
162 
  
  
  
  
Week 24 
169 
  
  
  
  
Week 25 
176 
  
  
  
  
Week 26 
183 
[162, 186] 
[162, 186] 
[162, 186] 
[134, 186] 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 38 of 53 
Optional Analysis Windows 
Visit 
Targeted 
Study 
Days 
Future 
Biomed 
DNA 
RNA 
Screening 
<1 
  
  
  
Day 1 
1 
[1, 14] 
1 
[1,4] 
Day 3 
3 
  
  
  
Week 1 
8 
  
  
[4, 93] 
Week 2 
15 
  
  
  
Week 3 
22 
  
  
  
Week 4 
29 
[15, 42] 
  
  
Week 5 
36 
  
  
  
Week 6 
43 
  
  
  
Week 7 
50 
  
  
  
Week 8 
57 
[43, 70] 
  
  
Week 9 
64 
  
  
  
Week 10 
71 
  
  
  
Week 11 
78 
  
  
  
Week 12 
85 
[71, 98] 
  
  
Week 13 
92 
  
  
  
Week 14 
99 
  
  
  
Week 15 
106 
  
  
  
Week 16 
113 
[99, 126] 
  
  
Week 17 
120 
  
  
  
Week 18 
127 
  
  
  
Week 19 
134 
  
  
  
Week 20 
141 
[127, 161] 
  
  
Week 21 
148 
  
  
  
Week 22 
155 
  
  
  
Week 23 
162 
  
  
  
Week 24 
169 
  
  
  
Week 25 
176 
  
  
  
Week 26 
183 
[162, 186] 
  
[94,186] 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 39 of 53 
COA* Analysis Windows 
Visit 
Targeted 
Study 
Days 
TSQM 
Screening 
<1 
<1 
Day 1 
1 
  
Day 3 
3 
  
Week 1 
8 
  
Week 2 
15 
  
Week 3 
22 
  
Week 4 
29 
[1, 70] 
Week 5 
36 
  
Week 6 
43 
  
Week 7 
50 
  
Week 8 
57 
  
Week 9 
64 
  
Week 10 
71 
  
Week 11 
78 
  
Week 12 
85 
  
Week 13 
92 
  
Week 14 
99 
  
Week 15 
106 
  
Week 16 
113 
[71, 147] 
Week 17 
120 
  
Week 18 
127 
  
Week 19 
134 
  
Week 20 
141 
  
Week 21 
148 
  
Week 22 
155 
  
Week 23 
162 
  
Week 24 
169 
  
Week 25 
176 
  
Week 26 
183 
[148, 186] 
* Note: PNH symptom-specific questionnaire assessed daily (not a weekly questionnaire) 
6.5. 
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. 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


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Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 40 of 53 
7. 
INTERIM ANALYSIS 
There will not be a formal interim analysis of efficacy data.  
There will be an interim analysis of the data from cohort A at week 8, the purpose of which is the 
confirmation of the adequacy of the selected dose regimen.  
The interim analysis will be performed by a team from the Sponsor consisting of those from the 
following functions: Sample Management, Bioanalytical Sciences, Clinical Pharmacology and 
Quantitative Pharmacology, Regeneron Senior Physicians, Program Director, Precision 
Medicine, and Biostatistics and Programming. The decision to progress from cohort A to 
cohort B will be made by the Sponsor in conjunction with the global principal investigator based 
on the achievement of LDH reduction to ≤ 1.5 x ULN and safety at week 8, as follows: 
 If all 6 out of 6 cohort A patients achieve an LDH ≤ 1.5 x ULN at week 8 and the 
dosing regimen is considered well tolerated, then either the dose regimen will be 
confirmed and the study will progress to cohort B, or the dosing regimen will be 
altered, with a lower dose and/or longer dosing interval being tested in an expanded 
cohort A (up to a further 6 subjects). These revisions would not be considered 
substantial and therefore would not require a formal protocol amendment. 
 If one or more patients fails to achieve LDH ≤ 1.5 x ULN at week 8, then after 
consideration of all data (including clinical and safety data, REGN3918 PK, CH50, 
total C5, baseline LDH, and the LDH level achieved), a decision will be made to 
either:  
 Confirm the dosing regimen and progress to cohort B, or  
 Continue with the selected dosing regimen and expand cohort A up to a maximum 
of 12 patients, or  
 Increase dose and/or reduce dose interval and re-assess cohort A. This option will 
require a substantial protocol amendment. 
Posterior probabilities of assurance of achieving LDH ≤ 1.5 x ULN conditioned on observed data 
are provided in tables in Section 10.4, one assuming a non-informative prior and the other 
assuming an informative prior.  
The data to be reviewed for the analysis of cohort A include:  
 Laboratory: LDH, blood chemistry, hematology, urinalysis, CH50, drug concentration 
(PK) 
 Clinical data: Transfusion, FACIT-Fatigue, weight, AEs, concomitant medications 
 Baseline characteristics: demographics  
 Drug administration and patient disposition 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 41 of 53 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 42 of 53 
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. 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 43 of 53 
10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
 
Analysis 
Statistical 
Supportive 
Subgroup 
Other 
Endpoint 
Populations 
Method 
Analysis 
Analysis 
Analyses 
 
 
 
 
 
 
Efficacy analysis 
FAS 
Confidence intervals, Kaplan-
Meier, Exact methods   
MMRM 
with MI 
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 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 44 of 53 
10.2. 
Schedule of Time and Events 
Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Visit Location: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic Visit 
X 
X X X 
X 
X 
X 
 
 
 
X 
 
X 
Mandatory clinic visit 
Clinic, Home Healthcare, or 
Phone Call Visit1 
 
 
 
 
 
 
 
X 
X2 
X 
 
X2 
 
Cohort A: Clinic visit mandatory for 
first visits up to and including week 8. 
Section 7.2. 
Screening:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Including optional sub-studies 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
May re-screen once, as described in 
Section 8.2.1  
Medical History  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
Prior Concomitant 
Medications    
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
Historical Lab Parameters 
for Hemolysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
If possible, 2 yr history. Section 8.2.1 
Neisseria Meningitidis 
Vaccination History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
TB history and assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1  
Testing history for 
hepatitis B and C 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Testing may be performed by the central 
lab as needed per local practice. 
Section 8.2.1 
Risk assessment for 
Neisseria gonorrhea 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Section 7.8 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
Enrollment  
 
X 
 
 
 
 
 
 
 
 
 
 
 
  
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 45 of 53 
Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
R3918 IV Administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Patients should be observed for at least 
30 minutes post-infusion. Section 7.2 
R3918 SC Administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cohort A: Only W9-25 may be 
self-administered. Section 7.2  
Oral Antibiotics  
 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Per local practice. Section 7.4.2  
Meningococcal Vaccine 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Per local practice. Section 7.4.1  
IVRS/IWRS Contact 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Patient Diary 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
For self-administration. Section 7.2 
Efficacy (central):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum LDH  
X 
X X X 
X 
X 
X 
 
X 
 
X 
X 
X 
Samples not required if blood chem. 
samples are taken. Section 8.2.3.1 
Transfusion Data 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.3.2  
Complement Hemolytic 
Assay (serum CH50)    
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
Day 1, pre-dose and end of the IV 
infusion. Pre-dose at all other visits. 
Section 8.2.3.3  
FACIT-Fatigue 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Section 8.2.3.6 
EORTC-QLQ-30 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Section 8.2.3.6 
EQ-5D-3L 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Section 8.2.3.6 
PGIS  
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 Section 8.2.3.6 
PGIC  
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 Section 8.2.3.6 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 46 of 53 
Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Vital Signs 
X 
X X X 
X 
X 
X 
 
X 
 
 
 
X 
 Section 8.2.4.1  
Physical Examination 
X 
X X X 
 
 
X 
 
 
 
 
 
X 
 Section 8.2.4.2  
Body Weight 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 Section 8.2.4.2  
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 Section 8.2.4.3  
Adverse Events 
< -------------------------------------------------------x ----------------------------------------------------------- > 
 Section 9   
If breakthrough hemolysis is suspected, 
blood samples will be collected for LDH 
and other assessments. Blood may also 
be collected in the event of drug 
hypersensitivity. Section 8.1.3 
Concomitant Meds & Tx 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Section 7.12  
Patient Safety Card  
 
X 
 
 
 
 
 
 
 
 
 
 
 
For Neisseria meningitidis  
Laboratory Testing: (Central): 
 
 
 
 
 
 
 
 
 
 
 
 
  
Hematology 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Includes RBC and free hemoglobin  
See Section 8.2.4.4 for analytes 
Blood Chemistry  
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Includes serum lactate dehydrogenase  
See Section 8.2.4.4 for analytes 
Pregnancy Test 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
Serum at screening 
Urine at all other visits 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 See Section 8.2.4.4 for analytes 
C-Reactive Protein  
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
 
Direct Antiglobulin Test  
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
DAT or Coombs 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 47 of 53 
Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
PK and ADA Samples: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
PK Sample  
 
X X X 
 
 
X 
 
 
 
 
 
X 
Day 1, sample pre-dose and end of the 
IV infusion. Pre-dose at all other visits. 
Section 8.2.5  
ADA Sample   
 
X 
 
 
 
 
X (W12) 
 
 
 
 
 
X 
Pre-dose. Section 8.2.6  
Exploratory PD/Biomarkers: 
 
 
 
 
 
 
 
 
Pre-dose, unless otherwise specified 
Haptoglobin 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
Section 8.2.8  
Reticulocyte Count 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Complement Hemolytic 
Assay (serum AH50)   
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
Day 1, sample pre-dose and end of the 
IV infusion. Pre-dose at all other visits. 
Total Complement Levels 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
  
Total C5 (plasma) 
X 
X X 
 
 
 
X 
 
 
 
 
 
X 
Day 1, sample pre-dose and end of the 
IV infusion. Pre-dose at all other visits. 
C5a (plasma and urine) 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
sC5b-9 (plasma) 
X 
X X X 
X 
X 
X 
 
 
 
 
 
X 
 
PNH Erythrocyte Cells 
X 
X 
 
 
 
 
X (W8, 
W16) 
 
 
 
 
 
X 
 
PNH Granulocyte Cells 
X 
X 
 
 
 
 
X (W8, 
W16) 
 
 
 
 
 
X 
 
NT-proBNP 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Biomarkers of Thrombosis 
and Inflammation 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
May include D-dimer, F1+2, TFPI, and 
IL-6 
Renal Injury Markers 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 48 of 53 
Study Period 
Screening 
Treatment 
EoS  Notes 
Study Week  
up to -4 
0 
1 
2 
3 
Week 4 to 23 
24 
25 
26 
 
(W4, 8, 12, 
16, 20) 
(W5, 9, 13, 
17, 21) 
(W6, 10, 
14, 18, 22) 
(W7, 11, 15, 
19, 23) 
Study Day  
(W0 to W26 ± 1D) 
up to -28 
1 
3 8 
15 
22 
29, 57, 85, 
113, 141 
36, 64, 92, 
120, 148 
43, 71, 99,  
127, 155 
50, 78, 106, 
134, 162 
169 
176 
183   
Optional Samples: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Future Biomedical 
Research Serum/Plasma 
(optional) 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
As permitted by local regulatory 
policies. Section 8.2.9  
Whole Blood for DNA 
Isolation (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.9.1  
Whole Blood for RNA 
Isolation (optional) 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
Section 8.2.9.1  
Clinical Outcome Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
  
PNH Symptom-Specific 
Questionnaire    
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
To be completed daily by patient. 
Patient will complete daily PNH 
Symptom-Specific Questionnaire on a 
device at least 7 days prior to day 1 visit. 
Section 8.2.7.1 
Cohort A: Optional 
Cohort B: Mandatory when available 
TSQM 
 
 
 
 
 
 
X (W4, 
W16) 
 
 
 
 
 
X 
Section 8.2.7.1 
Cohort A: Optional 
Cohort B: Mandatory when available 
Wearable Device 
 
< ------------------------------ W0 to W12 ------------------------------------- > 
 
 
 
Should be worn according to the 
schedule set out in the study manual 
Section 8.2.7.2 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 49 of 53 
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 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 50 of 53 
Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
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. 
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 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 51 of 53 
Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
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. 
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 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 52 of 53 
Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
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 
 
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. 
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918 PNH 1852 
Statistical Analysis Plan 
 
Date: July 17, 2019 
 
CONFIDENTIAL 
Page 53 of 53 
10.4. 
Posterior Probability of Assurance for LDH Normalization 
Probability of assurance based on a non-informative prior: 
Interim Posterior Probability (IPP): Pr(Pr(LDH ≤ 1.5x ULN)>0.9) 
Interim 
n 
Observed number of patients with LDH > 1.5x ULN 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1 
0.40 
0.01 
 
 
 
 
 
 
 
 
 
2 
0.51 
0.05 
<0.01 
 
 
 
 
 
 
 
 
3 
0.59 
0.10 
<0.01 <0.01 
 
 
 
 
 
 
 
4 
0.66 
0.15 
0.02 
<0.01 <0.01 
 
 
 
 
 
 
5 
0.71 
0.20 
0.03 
<0.01 <0.01 <0.01 
 
 
 
 
 
6 
0.75 
0.25 
0.05 
<0.01 <0.01 <0.01 <0.01 
 
 
 
 
7 
0.79 
0.30 
0.07 
0.01 
<0.01 <0.01 <0.01 <0.01 
 
 
 
8 
0.81 
0.35 
0.09 
0.01 
<0.01 <0.01 <0.01 <0.01 <0.01 
 
 
9 
0.84 
0.39 
0.12 
0.02 
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 
 
10 
0.86 
0.44 
0.14 
0.03 
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 
11 
0.88 
0.48 
0.17 
0.04 
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 
12 
0.89 
0.52 
0.20 
0.06 
0.01 
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 
Note: Pr(LDH ≤ 1.5x ULN)>0.9 is the intended assurance level, and IPP is the probability of obtaining that 
assurance level based on observed data. A Jeffery’s non-informative prior Beta(0.5, 0.5) is used.  
 
Probability of assurance based on an informative prior: 
Interim Posterior Probability (IPP): Pr(Pr(LDH ≤ 1.5x ULN)>0.9) 
Interim 
n 
Observed number of patients with LDH > 1.5x ULN 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
1 
0.86 
0.44 
 
 
 
 
 
 
 
 
 
2 
0.88 
0.48 
0.17 
 
 
 
 
 
 
 
 
3 
0.89 
0.52 
0.20 
0.06 
 
 
 
 
 
 
 
4 
0.91 
0.56 
0.24 
0.07 
0.01 
 
 
 
 
 
 
5 
0.92 
0.59 
0.27 
0.09 
0.02 
<0.01 
 
 
 
 
 
6 
0.93 
0.62 
0.30 
0.10 
0.03 
<0.01 <0.01 
 
 
 
 
7 
0.94 
0.65 
0.33 
0.12 
0.04 
<0.01 <0.01 <0.01 
 
 
 
8 
0.94 
0.68 
0.36 
0.15 
0.04 
0.01 
<0.01 <0.01 <0.01 
 
 
9 
0.95 
0.71 
0.40 
0.17 
0.05 
0.01 
<0.01 <0.01 <0.01 <0.01 
 
10 
0.96 
0.73 
0.43 
0.19 
0.07 
0.02 
<0.01 <0.01 <0.01 <0.01 <0.01 
11 
0.96 
0.76 
0.46 
0.21 
0.08 
0.02 
<0.01 <0.01 <0.01 <0.01 <0.01 
12 
0.97 
0.78 
0.49 
0.24 
0.09 
0.03 
<0.01 <0.01 <0.01 <0.01 <0.01 
Note: Pr(LDH ≤ 1.5x ULN)>0.9 is the intended assurance level, and IPP is the probability of obtaining that 
assurance level based on observed data. An informative prior Beta(0.5, 9.5) is used, which represents a 
prior effective sample size of 0.5+9.5=10 and reflects a probability of 0.05 of failing to show LDH ≤ 1.5x 
ULN  
 
                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00


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                                        VV-RIM-00083264-1.0 Approved - 14 Aug 2019 GMT-5:00